Synthesis method of compound 5-oxo-5, 6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester

Abstract

The invention discloses a synthesis method of a compound 5-oxo-5, 6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester, and belongs to the technical field of organic synthesis. The synthesis method of the compound, namely, the 5-oxo-5, 6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester, disclosed by the invention, comprises the following steps: by taking N-tert-butyloxycarbonyl-3-piperidone as a raw material, carrying out dehydrogenation reaction to obtain the 5-oxo-5, 6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester. The synthesis method provided by the invention has the advantages of short steps, simple operation, mild reaction conditions, low cost, high yield and simple post-treatment, and can realize manufacturability amplification.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to a method for synthesizing tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate. Background Art

[0002] Pyridine compounds have good chemical stability, biological activity and photophysical properties, and are widely used in the fields of medicine, pesticides, dyes, polymer materials, etc. Tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate is an important pyridine compound and also an important molecular building block. As a key precursor, it is used in the synthesis of various inhibitors. For example, in Patent US2011 / 053925, it is used in the synthesis of hydroxamate deacetylase inhibitors, which can treat, inhibit or prevent all or part of the pathological conditions or diseases mediated by deacetylase; in Patent WO2014 / 139328, it is used in the synthesis of pyrrolo[2,3-b]pyridine CDK9 kinase inhibitors, which can be used to treat diseases including cancer; in Patent WO2022 / 109161, it is used in the synthesis of selective inhibitors of plasma kallidin, which can be used to treat or prevent hereditary angioedema, uveitis, posterior uveitis, wet age-related macular edema, diabetic macular edema, diabetic retinopathy and retinal vein occlusion.

[0003] In the prior art, the conventional synthesis route of tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate uses 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile and N-allyl-N-(2-hydroxy-3-butenyl)amine as raw materials and is prepared through three-step reactions. The synthesis process requires expensive metal catalysts, and the overall synthesis route is relatively long and the yield is low. Therefore, it is of great significance to develop a new method for synthesizing tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate. Summary of the Invention

[0004] In view of the above problems existing in the prior art, the applicant of the present invention provides a method for synthesizing tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate. The present invention uses N-tert-butoxycarbonyl-3-piperidone as a raw material and generates tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate through a dehydrogenation reaction. It has low cost, short steps, easy operation, relatively mild reaction conditions, low safety hazards, and high yield.

[0005] The technical solution of the present invention is as follows:

[0006] A method for synthesizing tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate, said synthesis method comprising: using N-Boc-3-piperidone as a raw material, and obtaining tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate through a dehydrogenation reaction.

[0007] Preferably, said synthesis method specifically comprises the following steps:

[0008] S1. Dissolve said N-Boc-3-piperidone in organic solvent I, add 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide, and stir to react to obtain a reaction solution;

[0009] S2. Post-treat the reaction solution in step S1 to obtain tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate.

[0010] Preferably, in S1, said organic solvent I comprises at least one of dimethyl sulfoxide, acetonitrile, N,N-dimethylacetamide, and N,N-dimethylformamide.

[0011] Preferably, in S1, the mass-volume ratio g / mL of said N-Boc-3-piperidone to said organic solvent I is 1:(5 - 40).

[0012] Preferably, in S1, the molar ratio of said N-Boc-3-piperidone to said 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide is 1.0:(1.0 - 3.0).

[0013] Preferably, in S1, the temperature of said stirring reaction is 50 - 200 °C;

[0014] and / or, the time of said stirring reaction is 10 - 40 h.

[0015] Preferably, in S1, the temperature of said stirring reaction is 50 - 130 °C;

[0016] and / or, the time of said stirring reaction is 10 - 20 h.

[0017] Preferably, in S2, said post-treatment comprises the following steps: cooling the reaction solution and adding it to water, extracting with organic solvent II, combining the organic phases and concentrating, and purifying.

[0018] Preferably, in S2, said organic solvent II comprises at least one of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane.

[0019] Preferably, in S2, the purification method comprises at least one of trituration, column chromatography, recrystallization, and distillation.

[0020] The beneficial technical effects of the present invention are as follows:

[0021] The present invention provides a method for synthesizing the compound tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate. First, the raw materials are optimized, and the compound N-Boc-3-piperidone, which is inexpensive and easily available, is selected as the raw material, and then the target compound tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate is obtained through a one-step dehydrogenation reaction.

[0022] The synthesis method of the present invention has the advantages of easily available raw materials, short steps, simple operation, mild reaction conditions, without the use of dangerous organometallic reagents and expensive metal catalysts, low cost and ideal yield, and simple post-treatment, and can achieve process scale-up. BRIEF DESCRIPTION OF THE DRAWINGS [[ID=^11]]

[0023] Figure 1 1H NMR spectrum of the compound tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate synthesized in Example 1 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0024] The present invention will be specifically described below with reference to the drawings and examples.

[0025] A method for synthesizing the compound tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate, the synthesis method comprising: using N-Boc-3-piperidone as a raw material and obtaining tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate through a dehydrogenation reaction.

[0026] >In some embodiments, the synthesis method specifically comprises the following steps:

[0027] S1. Dissolve the N-Boc-3-piperidone in organic solvent I, add 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide, and stir the reaction to obtain a reaction solution;

[0028] S2. Post-treat the reaction solution in step S1 to obtain tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate.

[0029] The structural formula of the N-Boc-3-piperidone is as follows:

[0030]

[0031] The structural formula of the 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide is as follows:

[0032]

[0033] The structural formula of tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate is as follows:

[0034]

[0035] The synthetic route of tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate is as follows:

[0036]

[0037] The present invention provides a method for synthesizing the compound tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate. First, the raw materials are optimized, and N-tert-butoxycarbonyl-3-piperidone, which is inexpensive and easily available, is selected as the raw material. Under the action of 1-hydroxy-1,2-benziodoxol-3(1H)-one, a dehydrogenation reaction occurs, and the target compound tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate is obtained in one step by a simple method, mild and safe reaction conditions, and an ideal yield.

[0038] In some embodiments, in S1, the organic solvent I includes at least one of dimethyl sulfoxide, acetonitrile, N,N-dimethylacetamide, and N,N-dimethylformamide.

[0039] In some embodiments, in S1, the mass-volume ratio of N-tert-butoxycarbonyl-3-piperidone to the organic solvent I is 1:(5-40) g / mL, including but not limited to 1:5, 1:10, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40.

[0040] In some embodiments, in S1, the molar ratio of N-tert-butoxycarbonyl-3-piperidone to 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide is 1.0:(1.0-3.0), including but not limited to 1.0:1.0, 1.0:2.0, 1.0:3.0.

[0041] In some embodiments, in S1, the temperature of the stirring reaction is 50-200 °C, including but not limited to 50 °C, 70 °C, 90 °C, 100 °C, 120 °C, 140 °C, 160 °C, 180 °C, 200 °C; the time of the stirring reaction is 10-40 h, including but not limited to 10 h, 12 h, 15 h, 20 h, 25 h, 30 h, 35 h, 40 h.

[0042] In some embodiments, in S2, the post-treatment includes the following steps: cooling the reaction solution and adding it to water, extracting with an organic solvent II, combining the organic phases and concentrating, and purifying.

[0043] In some embodiments, in S2, the organic solvent II includes at least one of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane.

[0044] In some embodiments, in S2, the purification method includes at least one of pulping, column chromatography, recrystallization, and distillation.

[0045] The technical solution of the present invention will be further explained and illustrated below through examples.

[0046] Example 1

[0047] A method for synthesizing the compound tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate, comprising the following steps:

[0048] S1. Dissolve N-Boc-3-piperidone (500.00 g, 2.51 mol, 1.00 eq) in dimethyl sulfoxide (5.0 L), and then add 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide (1.41 kg, 5.02 mol, 2.00 eq). After addition, heat the mixture to reflux and stir at 70 °C for 12 hours.

[0049] S2. After the reaction is complete, cool the reaction solution and add it to water (3.0 L). Extract twice with ethyl acetate (1.5 L × 2), combine the organic phases, and concentrate the organic phases to obtain a crude product. Add petroleum ether (3.0 L) to the crude product, cool to -10 °C, stir to precipitate a solid, filter and collect the solid to obtain the compound tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate (weight 489.10 g, purity 98%, yield 97%).

[0050] The 1H NMR spectrum of the obtained compound 2 (tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate) is as Figure 1 shown, and the characterization data are as follows:

[0051]

[0054] ,

[0053] ,

[0052] ,

[0051] , Figure 1 , , , , 1 , ,

[0050] H NMR (400 MHz, CDCl3) δ 7.03 (s, 1H), 6.16 (dt, J = 10.3, 2.2 Hz, 1H), 4.22 (s, 2H), 4.10 (s, 2H), 1.46 (s, 9H).

[0052] Example 2

[0053] It is basically the same as Example 1, except that: replace 5.0 L of dimethyl sulfoxide in step S1 with 5.0 L of N,N-dimethylformamide (DMF). The yield of tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate is shown in Table 1.

[0054] Example 3

[0055] It is basically the same as Example 1, except that: 5.0 L of dimethyl sulfoxide in Step S1 is replaced with 5.0 L of acetonitrile (MeCN), and the yield of tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate is shown in Table 1.

[0056] Example 4

[0057] It is basically the same as Example 1, except that: the molar amount of 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide in Step S1 is 2.51 mol, and the yield of tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate is shown in Table 1.

[0058] Example 5

[0059] It is basically the same as Example 1, except that: the molar amount of 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide in Step S1 is 7.53 mol, and the yield of tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate is shown in Table 1.

[0060] Example 6

[0061] It is basically the same as Example 1, except that: the temperature of the stirring reaction in Step S1 is 50 °C, and the yield of tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate is shown in Table 1.

[0062] Example 7

[0063] It is basically the same as Example 1, except that: the temperature of the stirring reaction in Step S1 is 100 °C, and the yield of tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate is shown in Table 1.

[0064] Example 8

[0065] It is basically the same as Example 1, except that: the time of the stirring reaction in Step S1 is 10 h, and the yield of tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate is shown in Table 1.

[0066] Example 9

[0067] It is basically the same as Example 1, except that: the time of the stirring reaction in Step S1 is 15 h, and the yield of tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate is shown in Table 1.

[0068] Comparative Example 1

[0069] Basically the same as Example 1, except that: 5.0 L of dimethyl sulfoxide in step S1 was replaced with 5.0 L of toluene, and the yield of tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate is shown in Table 1.

[0070] Comparative Example 2

[0071] Basically the same as Example 1, except that: 5.0 L of dimethyl sulfoxide in step S1 was replaced with 5.0 L of 1,4-dioxane, and the yield of tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate is shown in Table 1.

[0072] Table 1: Synthesis conditions and results of each example and comparative example

[0073]

[0074]

[0075] Comparing Examples 1 to 3, when different organic solvents I (dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile) were used for the reaction respectively, it can be known from Table 1 that the reaction can proceed smoothly, and the yields of the compound tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate are all relatively high, with the yield not less than 90%; among them, when dimethyl sulfoxide was used as organic solvent I for the reaction, the effect was better, and the yield of the target product was the highest, at 97%.

[0076] Comparing Examples 1, 4 and 5, when the molar ratios of the raw materials N-tert-butoxycarbonyl-3-piperidone to 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide were 1.0∶2.0, 1.0∶1.0, and 1.0∶3.0 respectively, it can be known from Table 1 that the yields of the compound tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate are all relatively high, with the yield not less than 91%; among them, when the molar ratio of the two was 1.0∶2.0 and 1.0∶3.0, the yields of the target product were basically the same, both at 97%, indicating that when the molar ratio of the two was 1.0∶2.0, the reaction effect was already relatively good.

[0077] Comparing Examples 1, 6 and 7, it can be known from Table 1 that as the temperature increased, the yield of the target product increased. When the reaction was carried out at a temperature of 70 °C, the reaction effect was basically optimal, and the yield of the target product was 97%.

[0078] Comparing Examples 1, 8 and 9, it can also be known from Table 1 that as the reaction time increased, the yield of the target product increased. When the reaction reached 12 h, the reaction effect was basically optimal, and the yield of the target product was 97%.

[0079] Comparing Example 1 with Comparative Examples 1 and 2, combined with Table 1, it can be seen that, when the other reaction conditions are the same, when the organic solvent I is replaced with toluene and 1,4-dioxane, respectively, the reaction effect is poor, and the maximum yield of the target product is only 73%. This shows that when the organic solvent I of the present invention is used in the reaction, the yield of the target product can be significantly improved.

[0080] 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 the compound tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate, characterized in that, The synthesis method includes: using N-tert-butoxycarbonyl-3-piperidone as a raw material, and obtaining tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate through a dehydrogenation reaction.

2. The synthesis method according to claim 1, wherein The synthesis method specifically includes the following steps: S1. Dissolve the N-tert-butoxycarbonyl-3-piperidone in organic solvent I, add 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide, and stir to react to obtain a reaction solution; S2. Post-treat the reaction solution in step S1 to obtain tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate.

3. The synthesis method according to claim 2, characterized in that, In S1, the organic solvent I includes at least one of dimethyl sulfoxide, acetonitrile, N,N-dimethylacetamide, and N,N-dimethylformamide.

4. The synthesis method according to claim 2, wherein In S1, the mass-volume ratio of the N-tert-butoxycarbonyl-3-piperidone to the organic solvent I is 1:(5 - 40) g / mL.

5. The synthesis method according to claim 2, characterized in that, In S1, the molar ratio of the N-tert-butoxycarbonyl-3-piperidone to the 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide is 1.0:(1.0 - 3.0).

6. The synthesis method according to claim 2, wherein In S1, the temperature of the stirring reaction is 50 - 200 °C; and / or, the time of the stirring reaction is 10 - 40 h.

7. The synthesis method according to claim 2, characterized in that, In S1, the temperature of the stirring reaction is 50 - 130 °C; and / or, the time of the stirring reaction is 10 - 20 h.

8. The synthesis method according to claim 2, characterized in that, In S2, the post-treatment includes the following steps: cool the reaction solution and add it to water, extract with organic solvent II, combine the organic phases and concentrate, and purify.

9. The synthesis method according to claim 8, characterized in that, In S2, the organic solvent II includes at least one of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane.

10. The synthesis method according to claim 8, characterized in that, In S2, the purification method includes at least one of trituration, column chromatography, recrystallization, and distillation.

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