Synthesis method of 1-(tert-butyl)-3-ethyl-4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl)-5, 6-dihydropyridine-1, 3 (2H)-dicarboxylate

Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthesis method of 1-(tert-butyl)-3-ethyl-4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl)-5, 6-dihydropyridine-1, 3 (2H)-dicarboxylate. According to the invention, 1-(tert-butyl)-3-ethyl-4-oxopiperidine-1, 3-diformate, namely the compound A, is taken as a base material, two-step reaction is carried out, the reaction conditions are relatively mild, the product yield is high, and the operation is easy.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a method for synthesizing 1-(tert-butyl)-3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylic acid ester. Background Technology

[0002] N-acetyl-4-piperidinone is an important fine organic chemical intermediate, also known as 1-acetyl-4-piperidinone, with the molecular formula C7H. 11 NO2, with a molecular weight of 141.17 and CAS Registry Number 32161-6-1, is widely used in various fields such as pharmaceuticals, pesticides, and the chemical industry. As an important organic synthesis intermediate, it plays a crucial role in the synthesis of drugs for analgesia, anti-inflammation, antihistamines, antiarrhythmias, antipsychotics, and antitumor purposes. Derivatives of N-acetyl-4-piperidinone also have significant applications.

[0003] 1-(tert-butyl)-3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylic acid ester, as a derivative of N-acetyl-4-piperidinone, plays an important role in the pharmaceutical, pesticide, and chemical industries. However, no applicable production method has been developed, and current production processes are inefficient. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention provides a method for synthesizing 1-(tert-butyl)-3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylic acid ester that is highly efficient and easy to produce.

[0005] To solve the above-mentioned technical problems, the technical solution of the present invention is as follows: A method for synthesizing 1-(tert-butyl)-3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylic acid ester, the method comprising the following steps: (1) Dissolve compound A in toluene under nitrogen protection, add N,N-diisopropylethylamine at -60 to -50°C, mix, add trifluoromethanesulfonic anhydride, keep warm, raise the temperature to 25 to 32°C, react to obtain compound B; (2) Compound B, bis-pinacol boronic acid ester, potassium acetate and Pd(dppf)Cl2·DCM were dissolved in dioxane and mixed evenly. Under nitrogen protection, the mixture was reacted at 75-85℃ to obtain 1-(tert-butyl)-3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylic acid ester.

[0006] Preferably, in step (1), the mass ratio of compound A, N,N-diisopropylethylamine and trifluoromethanesulfonic anhydride is 75:52 to 61:84.

[0007] Preferably, the reaction formula in step (1) is as follows: .

[0008] Preferably, in step (2), the mass ratio of compound B, dipinacol boronic acid ester, potassium acetate, and Pd(dppf)Cl2·DCM is 100:70:70 to 85:10.

[0009] Preferably, the reaction formula in step (2) is: . Beneficial effects

[0010] This invention uses 1-(tert-butyl)-3-ethyl-4-oxopiperidine-1,3-dicarboxylate, i.e., compound A, as the base material. It involves a two-step reaction under relatively mild conditions, resulting in high product yield and easy operation. Detailed Implementation

[0011] Unless otherwise specified, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In case of any discrepancy, the definitions in this specification shall prevail.

[0012] Unless otherwise stated, all percentages, portions, proportions, etc. are by weight.

[0013] The terms “comprising,” “including,” “having,” “containing,” “or any other variation thereof” as used herein are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to those elements, but may also include elements not expressly listed or other elements inherent to such composition, process, method, article, or apparatus.

[0014] When quantities, parts by weight, or other numerical values ​​or parameters are given as ranges, preferred ranges, or a series of upper and lower preferred values, it should be understood that they specifically disclose all ranges formed by any pair of values ​​of any larger or preferred range limit and any smaller or preferred range limit, regardless of whether the ranges are disclosed separately. For example, when describing a range of "1 to 5", the described range should be understood to include ranges such as "1 to 4", "1 to 3", "1 to 2", "1 to 2 and 4 to 5", "1 to 3 and 5", etc. Unless otherwise stated, where numerical ranges are described herein, the range is intended to include the range endpoints as well as all integers, fractions, decimals, etc., within that range.

[0015] Furthermore, the indefinite articles “a” and “an” preceding the elements or components of this disclosure are intended to indicate that there is no limitation on the number of times the said element or component appears (i.e., occurs). Therefore, “a” or “an” should be understood to include one or at least one, and unless the quantity is explicitly stated to be singular, the singular form of the said element or component also includes the plural case.

[0016] Unless otherwise specified, the materials, methods, and examples described herein are exemplary and not limiting. While similar or equivalent methods and materials may be used in implementing or testing this disclosure, suitable methods and materials are also described herein.

[0017] This disclosure is described in detail below.

[0018] Yield calculation formula: (Product mass: Product molecular weight) / (Raw material mass: Raw material molecular weight). Example 1

[0019] Synthesis of compound B: 75 g of compound A was dissolved in 900 mL of toluene in a reactor, cooled to -60 °C, and 52 g of N,N-diisopropylethylamine was added. The mixture was stirred for 20 min, and then 84 g of trifluoromethanesulfonic anhydride was added. The mixture was kept at this temperature for 1.5 h, then heated to 25 °C and reacted for 15 h. The reaction was detected by TLC. After the reaction was complete, the reaction solution was filtered, and the filter cake was washed with toluene (120 mL * 2). The filtrate was added to saturated sodium bicarbonate solution (350 mL), stirred for 15 min, separated, and the organic phase was concentrated. The concentrate was collected to obtain 108 g of compound B, with a yield of 96.9% and a purity of 99.4%. Example 2

[0020] Synthesis of Compound B: 75 g of Compound A was dissolved in 900 mL of toluene in a reactor, cooled to -60 °C, and 55 g of N,N-diisopropylethylamine was added. The mixture was stirred for 20 min, and then 84 g of trifluoromethanesulfonic anhydride was added. The mixture was kept at this temperature for 1.5 h, then heated to 28 °C and reacted for 15 h. The reaction was detected by TLC. After the reaction was complete, the reaction solution was filtered, and the filter cake was washed with toluene (120 mL * 2). The filtrate was added to saturated sodium bicarbonate solution (350 mL), stirred for 15 min, separated, and the organic phase was concentrated. The concentrate was collected to obtain 112 g of Compound B, with a yield of 100% and a purity of 99.3%. Example 3

[0021] Synthesis of compound B: 75 g of compound A was dissolved in 900 mL of toluene in a reactor, cooled to -60 °C, and 58 g of N,N-diisopropylethylamine was added. The mixture was stirred for 20 min, and then 84 g of trifluoromethanesulfonic anhydride was added. The mixture was kept at this temperature for 1.5 h, then heated to 25–32 °C and reacted for 15 h. The reaction was detected by TLC. After the reaction was complete, the reaction solution was filtered, and the filter cake was washed with toluene (120 mL * 2). The filtrate was added to saturated sodium bicarbonate solution (350 mL), stirred for 15 min, separated, and the organic phase was concentrated. The concentrate was collected to obtain 111 g of compound B, with a yield of 99.5% and a purity of 99.4%. Example 4

[0022] Synthesis of compound B: 75 g of compound A was dissolved in 900 mL of toluene in a reactor, cooled to -60 °C, and 61 g of N,N-diisopropylethylamine was added. The mixture was stirred for 20 min, and then 84 g of trifluoromethanesulfonic anhydride was added. The mixture was kept at this temperature for 1.5 h, then heated to 32 °C and reacted for 15 h. The reaction was detected by TLC. After the reaction was complete, the reaction solution was filtered, and the filter cake was washed with toluene (120 mL * 2). The filtrate was added to saturated sodium bicarbonate solution (350 mL), stirred for 15 min, separated, and the organic phase was concentrated. The concentrate was collected to obtain 105 g of compound B, with a yield of 94.2% and a purity of 98.3%.

[0023] Examples 5-8 apply to compound B prepared in Example 2. Example 5

[0024] Synthesis of 1-(tert-butyl)-3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylic acid ester: 100g of compound B, 70g of dipinacol boronic acid ester, 70g of potassium acetate and 10g of Pd(dppf)Cl2·DCM were dissolved in 1000mL of dioxane and mixed thoroughly. Under nitrogen protection, the mixture was reacted at 80℃ for 2h. HPLC detection was performed. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filter cake (150mL*2) was washed with ethyl acetate. The mother liquor was concentrated, and the concentrated residue was filtered through a silica gel filter with a hexane / ethyl acetate ratio of 3 / 1 (1500mL). The mixture was washed with a hexane / ethyl acetate ratio of 3 / 1 (800mL), and the organic phase was concentrated. The residue was added to n-hexane (400 mL), and without stirring, it was poured directly into a silica gel column and passed through the column. The mobile phase was n-hexane / ethyl acetate = 8 / 92. The target product was collected and concentrated to give 61,21-(tert-butyl)-3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylic acid ester, with a yield of 64.7% and a purity of 99.5%. Example 6

[0025] Synthesis of 1-(tert-butyl)-3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylic acid ester: 100g of compound B, 70g of dipinacol boronic acid ester, 75g of potassium acetate and 10g of Pd(dppf)Cl2·DCM were dissolved in 1000mL of dioxane and mixed thoroughly. Under nitrogen protection, the mixture was reacted at 80℃ for 2h. HPLC detection was performed. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filter cake (150mL*2) was washed with ethyl acetate. The mother liquor was concentrated, and the concentrated residue was filtered through a silica gel filter with a hexane / ethyl acetate ratio of 3 / 1 (1500mL). The mixture was washed with a hexane / ethyl acetate ratio of 3 / 1 (800mL), and the organic phase was concentrated. The residue was added to n-hexane (400 mL), and without stirring, it was poured directly into a silica gel column and passed through the column. The mobile phase was n-hexane / ethyl acetate = 8 / 92. The target product was collected and concentrated to give 130 g of 1-(tert-butyl)-3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylic acid ester, with a yield of 67.3% and a purity of 99.8%. Example 7

[0026] Synthesis of 1-(tert-butyl)-3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylic acid ester: 100g of compound B, 70g of dipinacol boronic acid ester, 80g of potassium acetate and 10g of Pd(dppf)Cl2·DCM were dissolved in 1000mL of dioxane and mixed thoroughly. Under nitrogen protection, the mixture was reacted at 80℃ for 2h. HPLC detection was performed. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filter cake (150mL*2) was washed with ethyl acetate. The mother liquor was concentrated, and the concentrated residue was filtered through a silica gel filter with a hexane / ethyl acetate ratio of 3 / 1 (1500mL). The mixture was washed with a hexane / ethyl acetate ratio of 3 / 1 (800mL), and the organic phase was concentrated. The residue was added to n-hexane (400 mL), and without stirring, it was poured directly into a silica gel column and passed through the column. The mobile phase was n-hexane / ethyl acetate = 8 / 92. The target product was collected and concentrated to give 62.3 g of 1-(tert-butyl)-3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylic acid ester, with a yield of 65.9% and a purity of 99.7%. Example 8

[0027] Synthesis of 1-(tert-butyl)-3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylic acid ester: 100g of compound B, 70g of dipinacol boronic acid ester, 85g of potassium acetate and 10g of Pd(dppf)Cl2·DCM were dissolved in 1000mL of dioxane and mixed thoroughly. Under nitrogen protection, the mixture was reacted at 80℃ for 2h. HPLC detection was performed. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filter cake (150mL*2) was washed with ethyl acetate. The mother liquor was concentrated, and the concentrated residue was filtered through a silica gel filter with a hexane / ethyl acetate ratio of 3 / 1 (1500mL). The mixture was washed with a hexane / ethyl acetate ratio of 3 / 1 (800mL), and the organic phase was concentrated. The residue was added to n-hexane (400 mL), and without stirring, it was poured directly into a silica gel column and passed through the column. The mobile phase was n-hexane / ethyl acetate = 8 / 92. The target product was collected and concentrated to give 60.2 g of 1-(tert-butyl)-3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylic acid ester, with a yield of 63.7% and a purity of 99.5%.

[0028] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A method for synthesizing 1-(tert-butyl)-3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylic acid ester, characterized in that, The synthesis method includes the following steps: (1) Dissolve compound A in toluene under nitrogen protection, add N,N-diisopropylethylamine at -60 to -50°C, mix, add trifluoromethanesulfonic anhydride, keep warm, raise the temperature to 25 to 32°C, react to obtain compound B; (2) Compound B, bis-pinacol boronic acid ester, potassium acetate and Pd(dppf)Cl2·DCM were dissolved in dioxane and mixed evenly. Under nitrogen protection, the mixture was reacted at 75-85℃ to obtain 1-(tert-butyl)-3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylic acid ester.

2. The method for synthesizing 1-(tert-butyl)-3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylic acid ester according to claim 1, characterized in that, In step (1), the mass ratio of compound A, N,N-diisopropylethylamine and trifluoromethanesulfonic anhydride is 75:52 to 61:

84.

3. The method for synthesizing 1-(tert-butyl)-3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylic acid ester according to claim 2, characterized in that, The reaction formula for step (1) is as follows: 。 4. The method for synthesizing 1-(tert-butyl)-3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylic acid ester according to claim 1, characterized in that, In step (2), the mass ratio of compound B, dipinazoboronic acid ester, potassium acetate, and Pd(dppf)Cl2·DCM is 100:70:70 to 85:

10.

5. The method for synthesizing 1-(tert-butyl)-3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylic acid ester according to claim 4, characterized in that, The reaction formula in step (2) is: 。

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