Method for high-valued conversion of levulinic acid derivative

Abstract

The invention belongs to the field of biomass molecule high-valued conversion, and discloses a method for high-valued conversion of a levulinic acid derivative, in particular to a method for converting the levulinic acid derivative into an organic synthesis building block, which aims at the levulinic acid derivative 4, 5-dihydro-6-methylpyridazine-3 (2H)-ketone, and converting glyoxal dimethyl acetal and 4, 5-dihydro-6-methylpyridazine-3 (2H)-ketone into an organic synthesis building block. The preparation method comprises the following steps: carrying out condensation reaction on 2, 5-dihydro-6-methylpyridazine-3 (2H)-ketone in a solvent under an alkaline condition to obtain a target acetal synthesis building block; the structural formula of the building block is shown as a formula B-1. According to the synthetic method disclosed by the invention, a synthetic route is designed, a levulinic acid derivative, namely 4, 5-dihydro-6-methylpyridazine-3 (2H)-ketone, is converted into a universal organic synthetic building block (as shown in a formula B-1), and high-value chemicals including quinoline compounds and sitroxazine can be synthesized by utilizing the synthetic building block.

Description

Technical Field

[0001] This invention belongs to the field of high-value conversion of biomass molecules, and more specifically, relates to a method for high-value conversion of levulinic acid derivatives, wherein 4,5-dihydro-6-methylpyridazine-3(2 H The )-ketone, an acetylpropionic acid derivative, is converted into an organic synthetic building block; this building block can be used in particular to synthesize a series of quinoline compounds and simultaneously produce the antihypertensive drug citrazine as a byproduct. Background Technology

[0002] Levulopyric acid is a green platform compound derived from biomass such as cellulose and agricultural waste. Its most notable characteristic is that it can be prepared from biomass (such as cellulose, starch, and agricultural waste) via acid hydrolysis, making it a renewable "green" platform compound hailed as a bridge connecting renewable resources with the future bio-based economy. Its molecule simultaneously possesses ketone carbonyl and carboxyl groups, exhibiting chemical reactivity and allowing it to be converted into high-value-added products through various reactions. As an excellent alternative to petroleum-based products, levulopyric acid and its derivatives are widely used in environmentally friendly solvents, biofuels, green plasticizers, polymer materials, and agrochemicals. For example, levulopyric acid esters are excellent green solvents, exhibiting low toxicity and easy degradation; γ-valerol (GVL), the main compound obtained after hydrogenation of levulopyric acid, can itself be used as a biofuel or converted into a component of "green gasoline" or aviation fuel. It demonstrates enormous strategic potential and application prospects in promoting sustainable development and reducing dependence on fossil resources.

[0003] 4,5-Dihydro-6-methylpyridazine-3(2) H )-Ketocones are derivatives derived from levulinic acid, typically obtained by the condensation of ethyl levulinate and hydrazine hydrate, and are an important pharmaceutical intermediate. For example, they can undergo reactions under alkaline conditions. N Alkylation is a crucial first step in constructing the molecular skeletons of cardiac drugs such as milrinone and enoximone. Currently, for 4,5-dihydro-6-methylpyridazine-3(2... H Research on the high-value transformation of )-ketones is far from sufficient and cannot meet the demand for high-value-added fine chemicals from levulinic acid. Summary of the Invention

[0004] To address the aforementioned deficiencies or improvement needs of existing technologies, the present invention aims to provide a method for the high-value conversion of levulinic acid derivatives, wherein 4,5-dihydro-6-methylpyridazine-3(2) is converted into a high-value derivative through the design of a synthetic route. HThe levulinic acid derivative )-ketone is transformed into a general organic synthesis building block (as shown in Formula B-1), which can be used to synthesize high-value chemicals including quinoline compounds and cetoxazine.

[0005] To achieve the above objectives, according to one aspect of the present invention, a method for converting levulinic acid derivatives into organic synthetic building blocks is provided, characterized in that the method is specifically designed for the levulinic acid derivative 4,5-dihydro-6-methylpyridazine-3(2) H )-ketone, with glyoxal dimethyl acetal and 4,5-dihydro-6-methylpyridazine-3(2 H The )-ketone undergoes a condensation reaction in a solvent under alkaline conditions to obtain the target acetal building block; the structural formula of the building block is shown in Formula B-1: .

[0006] As a further preferred embodiment of the present invention, the alkaline conditions are obtained by adding NaOH and / or KOH to the reaction system.

[0007] As a further preferred embodiment of the present invention, the total concentration of NaOH and KOH in the reaction system is 0.09~0.18 mol / L.

[0008] As a further preferred embodiment of the present invention, the glyoxal dimethyl acetal and the 4,5-dihydro-6-methylpyridazine-3(2) H The molar ratio of )-ketone is (1.5~2.0):1.

[0009] As a further preferred embodiment of the present invention, the condensation reaction is carried out by stirring and reflux at 90 °C to 110 °C for 5 to 7 hours.

[0010] As a further preferred embodiment of the present invention, the solvent is one of ethanol, n-propanol, and n-butanol.

[0011] According to another aspect of the present invention, the present invention provides a method for synthesizing quinoline compounds and / or citoxazine using organic synthetic building blocks, characterized in that an organic synthetic building block with a structural formula as shown in Formula B-1 is reacted with aniline or aniline derivatives in a solvent in the presence of an acid catalyst to obtain products including quinoline compounds and / or citoxazine. ; The acid catalyst is either Bi(OTf)3 or TfOH. The solvent is any one of acetonitrile, nitromethane, ethyl acetate, and 1,4-dioxane.

[0012] As a further preferred embodiment of the present invention, the reaction is carried out at 60~80 °C for 2~3 h.

[0013] As a further preferred embodiment of the present invention, the aniline derivative is 2-chloroaniline, 3,4-difluoroaniline, or 2,3-dimethylaniline.

[0014] Compared with the prior art, the above-described technical solutions conceived in this invention can achieve the following beneficial effects: (1) The method of the present invention uses 4,5-dihydro-6-methylpyridazine-3(2 H The levulinic acid derivative, α-ketone, was transformed into organic synthetic building block B-1, effectively broadening the downstream application prospects of biomass-based products levulinic acid derivatives. A useful building block molecule was synthesized using inexpensive alkaline catalysts and relatively simple reaction conditions.

[0015] (2) Compared with existing methods for the high-value conversion of levulinic acid and its derivatives, this invention retains the high-value attributes of the products while having fewer synthetic steps and a simpler synthetic method. For example, compared with the downstream conversion of levulinic acid by hydrogenation cyclization to synthesize γ-valerolactone, this invention does not require the use of hazardous hydrogen gas and complex hydrogenation catalysts.

[0016] (3) The organic synthetic building block B-1 obtained by this invention can synthesize a variety of high-value-added products, providing a practical downstream conversion route for this biomass high-value conversion method and greatly broadening the application prospects of levulinic acid. The organic synthetic building block B-1 obtained by this invention can react with aniline (or aniline derivatives) to obtain quinoline compounds, while simultaneously producing the antihypertensive drug cetuximab as a byproduct. These are all high-value-added chemicals, expanding the downstream high-value conversion route of levulinic acid. The building block B-1 synthesized by this invention still retains a relatively broad downstream conversion potential, making this high-value conversion method have richer practical application potential. Detailed Implementation

[0017] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention. Furthermore, the technical features involved in the various embodiments of this invention described below can be combined with each other as long as they do not conflict with each other.

[0018] In general, the method for converting levulinic acid derivatives into organic synthetic building blocks in this invention involves reacting glyoxal dimethyl acetal (ADA) and 4,5-dihydro-6-methylpyridazine-3(2... H The condensation of ketones under basic conditions yields the target acetal building block (as shown in Formula B-1); the condensation reaction can be carried out under reflux conditions.

[0019] Furthermore, the obtained target acetal building block (B-1) can be used as a raw material to react with aniline under acid-catalyzed conditions. This reaction yields quinoline compounds (the target product) and, as a byproduct, cetoxazine, a class of antihypertensive drugs.

[0020] The 4,5-dihydro-6-methylpyridazine-3(2) used in the following examples H )-ketone is commercially available (manufacturer: Shanghai Bide).

[0021] Example 1 Preparation of synthetic building block B-1: The preparation process of the synthetic building block is as follows: 1.12 g of 4,5-dihydro-6-methylpyridazine-3 (2 H 10 mmol of β-ketone and 2.08 g of glyoxal dimethyl acetal (ADA, 20 mmol) were added to 20 mL of a prepared 0.18 mol / L potassium hydroxide ethanol solution. The reaction mixture was stirred and refluxed at 100 °C for 7 hours. After the reaction was completed, the mixture was cooled to room temperature and separated by column chromatography using ethyl acetate / petroleum ether (2 / 1 v / v). The final yield of B-1 was 1.62 g (81% yield).

[0022] Examples 2-4 The steps in Examples 2-4 are largely the same as those in Example 1, except that the type and concentration of the added alkali and the amount of reactant ADA may differ.

[0023] The specific settings of each embodiment and the yield of B-1 obtained are shown in the table below:

[0024] Examples 5-9 The steps in Examples 5-9 are largely the same as those in Example 1, with the only difference being that the reaction temperature and reaction time may differ.

[0025] The specific settings of each embodiment and the yield of B-1 obtained are shown in the table below:

[0026] Examples 10-11 The steps in Examples 10-11 are largely the same as those in Example 1, except that the solvents used in the reaction are different.

[0027] The specific settings of each embodiment and the yield of B-1 obtained are shown in the table below:

[0028] Examples 12-15 Synthesis of high-value quinoline chemicals and byproduct citoxazine from synthetic building block B-1: Taking B-1 prepared by the method in Example 1 as an example, under atmospheric conditions, 0.2 mmol of synthetic building block B-1 and 0.1 mmol of aniline were added to a reaction tube, along with a certain amount of acid catalyst (denoted as x mol%; that is, the amount of acid catalyst used was 0.2 × x% mmol), and finally 1 mL of acetonitrile was added. The reaction solution was reacted at 80 °C for 3 h, and after the reaction was completed, it was cooled to room temperature. Separation was performed using preparative thin-layer chromatography, with ethyl acetate / petroleum ether (volume ratio 4 / 1) as the developing solvent. NMR data of the target product: ¹H NMR (400 MHz, DMSO-d6, TMS, 25 ℃) δ 13.09 (s, 1H), 9.32 (d, J = 2.2 Hz, 1H), 8.96 (d, J = 2.3 Hz, 1H), 8.07 (d, J = 8.5 Hz, 2H), 7.88 – 7.79 (m, 3H), 7.67 (t, J = 7.6 Hz, 1H), 2.35 ppm (s, 4H). ¹³C NMR (100 MHz, DMSO-d6, TMS, 25 ℃) δ 160.11, 150.25, 147.73, 145.37, 139.54, 136.29, 135.43, 131.95, 130.91,129.21, 129.12, 127.59, 127.36, 40.60, 40.45, 40.39, 40.24, 40.19, 39.98,39.77, 39.56, 39.35, 20.73 ppm.

[0029] The types and amounts of acid catalysts used in each embodiment, the corresponding yields of the target product (i.e., quinoline compounds) and the byproduct cetoxazine are shown in the table below:

[0030] Examples 16-19 The steps in Examples 16-19 are largely the same as those in Example 12, the only difference being the type of solvent added.

[0031] The types of solvents used in each example, the corresponding yields of the target product (i.e., quinoline compounds) and the byproduct cetoxazine are shown in the table below:

[0032] Examples 20-22 The steps in Examples 20-22 are largely the same as those in Example 12, with the only difference being that the reaction temperature and reaction time may differ.

[0033] The specific settings of each embodiment and the corresponding yields of the target product (i.e., quinoline compounds) and the byproduct cetoxazine are shown in the table below:

[0034] Examples 23-25 The steps in Examples 23-25 ​​are largely the same as those in Example 12, the only difference being the aniline substrates used in the reaction.

[0035] The specific settings of each embodiment and the corresponding yields of the target product (i.e., quinoline compounds) and the byproduct cetoxazine are shown in the table below:

[0036] in:

[0037] The NMR data of the target product are as follows: Example 23: 1 H NMR (400 MHz, DMSO-d6, TMS, 25 ℃) δ 13.14 (s, 1H), 9.42 (d, J = 2.2 Hz, 1H), 9.04 (d, J = 2.2 Hz, 1H), 8.04 (ddd, J = 21.5, 7.9, 1.3Hz, 2H), 7.89 (s, 1H), 7.65 (t, J = 7.8 Hz, 1H), 2.36 ppm (s, 3H). 13 C NMR (100MHz, DMSO-d6, TMS, 25 ℃) δ 160.01, 150.98, 145.40, 143.49, 136.86, 134.93,132.69, 132.32, 130.87, 128.69, 128.32, 127.88, 21.21 ppm.

[0038] Example 24: 1H NMR (400 MHz, DMSO-d6, TMS, 25 ℃) δ 13.14 (s, 1H), 9.45 –9.27 (m, 1H), 9.16 – 8.90 (m, 1H), 8.17 (dd, J = 11.1, 8.8 Hz, 1H), 8.08 (dd,J = 11.7, 7.8 Hz, 1H), 7.86 (s, 1H), 2.35 ppm (s, 3H). 13 C NMR (100 MHz, DMSO-d6, TMS, 25 ℃) δ 159.97, 150.78, 150.75, 145.37, 144.99, 144.88, 135.91,134.86, 132.12, 127.63, 124.75, 115.68, 115.52, 114.98, 114.80, 20.71 ppm.

[0039] Example 25: 1 H NMR (400 MHz, DMSO-d6, TMS, 25 ℃) δ 13.21 (s, 1H), 9.46 (d, J = 2.3 Hz, 1H), 9.03 (d, J = 2.3 Hz, 1H), 7.99 (s, 1H), 7.94 (d, J = 8.3Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 2.86 (s, 3H), 2.66 ppm (d, J = 1.9 Hz, 6H). 13 C NMR (100 MHz, DMSO-d6, TMS, 25 ℃) δ 160.16, 149.07, 146.59, 145.33,138.57, 136.46, 135.60, 134.06, 131.54, 130.29, 129.73, 126.12, 125.63,20.82, 20.75, 13.42 ppm.

[0040] Comparative Example 1 The steps of Comparative Example 1 were largely the same as those of Example 12, except that the reaction was carried out under catalyst-free conditions. The final yield of the target quinoline product was 0%, and the yield of cetoxazine was 0%.

[0041] The above embodiments are merely examples. For instance, in addition to aniline, 2-chloroaniline, 3,4-difluoroaniline, and 2,3-dimethylaniline, other aniline derivatives can also be used as aniline substrates.

[0042] Those skilled in the art will readily understand that the above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for converting levulinic acid derivatives into organic synthetic building blocks, characterized in that, For levulinic acid derivative 4,5-dihydro-6-methylpyridazine-3(2) H )-ketone, with glyoxal dimethyl acetal and 4,5-dihydro-6-methylpyridazine-3(2 H The )-ketone undergoes a condensation reaction in a solvent under alkaline conditions to obtain the target acetal building block; the structural formula of the building block is shown in Formula B-1: 。 2. The method as described in claim 1, characterized in that, The alkaline conditions are obtained by adding NaOH and / or KOH to the reaction system.

3. The method as described in claim 2, characterized in that, In the reaction system, the total concentration of NaOH and KOH is 0.09~0.18 mol / L.

4. The method as described in claim 1, characterized in that, The glyoxal dimethyl acetal and the 4,5-dihydro-6-methylpyridazine-3(2) H The molar ratio of )-ketone is (1.5~2.0):

1.

5. The method as described in claim 1, characterized in that, The condensation reaction was carried out under stirring and reflux at 90 ℃~110 ℃ for 5 to 7 hours.

6. The method as described in claim 1, characterized in that, The solvent is one of ethanol, n-propanol, and n-butanol.

7. A method for synthesizing quinoline compounds and / or citoxazine using organic synthesis building blocks, characterized in that, Organic synthetic building blocks with structural formula B-1 are reacted with aniline or aniline derivatives in a solvent in the presence of an acid catalyst to obtain products including quinoline compounds and / or citoxazine. ； The acid catalyst is either Bi(OTf)3 or TfOH. The solvent is any one of acetonitrile, nitromethane, ethyl acetate, and 1,4-dioxane.

8. The method as described in claim 7, characterized in that, The reaction was carried out at 60-80 °C for 2-3 h.

9. The method as described in claim 7, characterized in that, The aniline derivatives are 2-chloroaniline, 3,4-difluoroaniline, and 2,3-dimethylaniline.

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