A process for the preparation of 2,2-disubstituted-4-pyridyl butyronitrile derivatives

Abstract

The application belongs to the technical field of fine chemical intermediates synthesis, and particularly relates to a preparation method of 2,2-disubstituted-4-pyridyl butyronitrile derivative. A mixture of hydroxyethyl pyridine, nitrile and alkali agent in a molar ratio of 1:3.5-4.5:4-5 is mixed in an aprotic solvent with a dielectric constant (epsilon) less than 20 at 60-100 DEG C for 12-30 hours. After the reaction is completed, the cooled reaction system is adjusted to neutral, and the product is collected and purified. The elimination reaction of hydroxyethyl pyridine under alkaline conditions generates a carbon-carbon double bond, and the addition reaction of the carbon-carbon double bond with nitrile generates 2,2-disubstituted-4-pyridyl butyronitrile derivative. Meanwhile, the raw materials used are low in price and easy to synthesize, the cost is greatly reduced, the industrialization prospect is wider, and the operation is simple, so that the process technology has more competitive value.

Description

Technical Field

[0001] This invention belongs to the field of fine chemical intermediate synthesis technology, and specifically relates to a method for preparing a 2,2-disubstituted-4-pyridylbutyronitrile derivative. Background Technology

[0002] Fragrances can provide desired aromas or mask undesirable odors, and are widely used in soaps, detergents, various cosmetics, environmental hygiene products, as well as in the fragrance of pharmaceuticals, paper, plastics, leather, and textiles. Unfortunately, the availability of fragrance raw materials remains very limited and cannot fully meet the needs of the fragrance industry.

[0003] Pyridylbutyronitrile compounds possess long-lasting aromas such as vetiver, pepper, grapefruit, and bergamot, and can be used in fragrances and perfumes. The addition of these substances can reduce the use of natural materials, result in a more uniform presence in the finished product, provide desired odor characteristics, and expand options in the fragrance industry. A typical example is 2,2-disubstituted-4-pyridylbutyronitrile.

[0004]

[0005] However, current processes for preparing 2,2-disubstituted-4-pyridylbutyronitrile generally suffer from drawbacks such as high raw material costs, poor stability, and low yields. Therefore, developing a low-cost, simple-to-operate, low-waste, and high-purity synthesis process for 2,2-disubstituted-4-pyridylbutyronitrile is of significant value. Summary of the Invention

[0006] To solve the above-mentioned technical problems, the present invention provides a method for preparing a 2,2-disubstituted-4-pyridylbutyronitrile derivative:

[0007]

[0008] In the molecular structure of hydroxyethylpyridine, the hydroxyethyl group and the nitrogen atom are either adjacent or para to each other, and the R group... 1 H or alkyl, R 2 It is H or alkyl, and R 1 and R 2 Not both H

[0009] The aforementioned alkyl groups include chain alkyl groups and cycloalkyl groups having 1 to 6 carbon atoms, with cycloalkyl groups including cyclopropyl or cyclohexyl groups.

[0010] The preparation reaction was carried out under strongly alkaline conditions at a temperature of 60℃ to 100℃.

[0011] As a preferred method, under a protective atmosphere, hydroxyethylpyridine, nitrile, and alkali are mixed and reacted in a solvent at 60°C to 100°C. After the reaction is completed, the cooled reaction system is adjusted to neutral, and the product is collected and purified.

[0012] Furthermore, the protective atmosphere is argon, nitrogen, or helium.

[0013] Furthermore: the pK of the alkali agent a The pK values ​​are 17–30 for alkali and nitriles. a The difference between the values ​​should not exceed 6, preferably not exceed 4.

[0014] Furthermore, the alkali is a potassium, sodium, or lithium salt of bis(trimethylsilyl)amine (HMDS), with the sodium salt of HMDS (NaHMDS, structural formula below) preferred over the potassium or lithium salt of HMDS, and the potassium salt of HMDS (KHMDS) preferred over the lithium salt of HMDS (LiHMDS).

[0015]

[0016] Furthermore, the solvent is an aprotic solvent with a dielectric constant (ε) less than 20, such as toluene, tetrahydrofuran, etc.

[0017] Furthermore, the molar ratio of hydroxyethylpyridine, nitrile, and alkali is 1:3.5-4.5:4-5.

[0018] Preferably, the reaction temperature is 70℃~80℃.

[0019] Preferably, the reaction time should be between 12h and 30h, and more preferably between 16h and 25h.

[0020] The beneficial effects of this invention are as follows: In this scheme, hydroxyethylpyridine is mixed with a nitrile and then reacted in a one-step process. Under alkaline conditions, hydroxyethylpyridine undergoes an elimination reaction to generate a carbon-carbon double bond, and then undergoes an addition reaction with the nitrile to obtain a 2,2-disubstituted-4-pyridylbutadiene-nitrile derivative. No transition metal catalyst is required. The nitrile is inexpensive, and an excess ratio is chosen during the reaction to ensure that the generated carbon-carbon double bond intermediate is reacted off by the nitrile as quickly as possible, avoiding the prolonged presence of unstable olefin bonds in the reaction system. Furthermore, the raw materials used are inexpensive and easy to synthesize, significantly reducing costs and broadening the prospects for industrialization. The simple operation makes this process technology more competitive. Detailed Implementation

[0021] The present invention will be further described below with reference to embodiments (the raw materials used in the following embodiments are all industrial-grade products):

[0022] A method for preparing a 2,2-disubstituted-4-pyridylbutadiene-nitrile derivative: Under a protective atmosphere, hydroxyethylpyridine, nitrile, and an alkaline agent in a molar ratio of 1:3.5–4.5:4–5 are mixed and reacted in an aprotic solvent with a dielectric constant (ε) less than 20 at 60–100 °C for 12–30 h. After the reaction is completed, the cooled reaction system is adjusted to neutral, and the product is collected and purified.

[0023] The protective atmosphere is argon, nitrogen, or helium.

[0024] pK of alkaline agents a The pK values ​​are 17–30 for alkali and nitriles. a The difference between the values ​​is no greater than 6, preferably no greater than 4, and the alkali is specifically a potassium salt, sodium salt, or lithium salt of bis(trimethylsilyl)amine (HMDS).

[0025] The solvent is toluene or tetrahydrofuran.

[0026] The preferred reaction temperature is 70℃~80℃, and the preferred reaction time is 16h~25h.

[0027] The reaction formula for the above preparation method is:

[0028]

[0029] In the molecular structure of hydroxyethylpyridine, the hydroxyethyl group and the nitrogen atom are either adjacent or para to each other, and the R group... 1 H or alkyl, R 2 It is H or alkyl, and R 1 and R 2 Not both H

[0030] The aforementioned alkyl groups include chain alkyl groups and cycloalkyl groups having 1 to 6 carbon atoms, and cycloalkyl groups include cyclopropyl or cyclohexyl.

[0031] Example 1

[0032] Synthesis of 2,2-dimethyl-4-(2-pyridyl)butyronitrile:

[0033] Under nitrogen protection, hydroxyethylpyridine (1.0 g, 8.12 mmol) was added to tetrahydrofuran (8 mL), followed by a tetrahydrofuran solution of sodium bis(trimethylsilyl)amino(NaHMDS) (16 mL, NaHMDS concentration 2 mol / L). After thorough mixing, a tetrahydrofuran solution of isobutyronitrile (2.24 g, 32.48 mmol) (2 mL) was added dropwise. After the addition was complete, the temperature was raised to 80 °C for reflux reaction. The reaction equation is as follows:

[0034]

[0035] The reaction endpoint was monitored by TLC. After the reaction was completed, the reaction system was cooled to room temperature (25°C, the same below), and 3 mol / L hydrochloric acid was added to adjust the pH to neutral. The reaction system was extracted with ethyl acetate and water, and the organic phase was collected. The obtained organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain a yellow oily crude product. The target product was then obtained by vacuum distillation, with a yield of 75% (moles of target product ÷ moles of hydroxyethylpyridine in the feed).

[0036] (×100%, the same below), the product structure characterization is shown in Table 6.

[0037] Examples 2 to 10

[0038] Based on Example 1, with other experimental conditions remaining unchanged, the effect of changing only the type and amount of alkali on the reaction results was investigated and compared with Example 1. The results are shown in Table 1:

[0039]

[0040]

[0041] It is evident that the choice of alkali has a significant impact on the progress of the target reaction.

[0042] Examples 11 to 14

[0043] Based on Example 1, with other experimental conditions remaining unchanged, the effect on the reaction results was investigated by only changing the molar ratio of hydroxyethylpyridine to nitrile, and the results were compared with those of Example 1. The results are shown in Table 2:

[0044] Table 2

[0045]

[0046] Examples 15 to 18

[0047] Based on Example 1, with other experimental conditions remaining unchanged, the effect of changing the reaction temperature on the reaction results was investigated and compared with that of Example 1. The results are shown in Table 3:

[0048] Table 3

[0049]

[0050]

[0051] Examples 19 to 21

[0052] Based on Example 1, with other experimental conditions remaining unchanged, the effect of changing only the solvent type on the reaction results was investigated and compared with Example 1. The results are shown in Table 4:

[0053] Table 4

[0054] solvent Yield (%) Example 1 THF 75 Example 19 NMP 64 Example 20 Toluene 72 Example 21 DMSO 58

[0055] Examples 22 to 29

[0056] Based on Example 1, with all other experimental conditions remaining unchanged, only the experimental conditions were changed.

[0057]

[0058] The influence of the types of substituents on the reactants on the reaction results was investigated and compared with those in Example 1. The results are shown in Tables 5 and 6.

[0059] Table 5

[0060]

[0061] Table 6

[0062]

[0063]

[0064]

[0065] Example 29

[0066] Based on Example 1, with other experimental conditions remaining unchanged, only the starting material "hydroxyethylpyridine" was replaced with an equimolar amount of "phenylethanol" to investigate the effect on the reaction results, and the results were compared with those of Example 1. The results are shown in Table 7:

[0067] Table 7

[0068]

[0069] It is evident that the molecular structural environment in which the hydroxyethyl group is located has a decisive influence on the occurrence of the target reaction. In Example 29, the second carbon affixed to the hydroxyl group on phenylethanol is not acidic and cannot be eliminated under alkaline conditions, thus preventing the reaction from proceeding.

Claims

1. A process for the preparation of 2,2-disubstituted-4-pyridyl butyronitrile derivatives, characterized by: The preparation method is wherein R 1 is H or an alkyl group having 1 to 6 carbon atoms, a cyclopropyl group or a cyclohexyl group, R 2 is H or an alkyl group having 1 to 6 carbon atoms, a cyclopropyl group or a cyclohexyl group, and R 1 and R 2 are not simultaneously H, the substitution position of the hydroxyethyl group is the 2- or 4-position of the pyridine, the substance amount ratio of the hydroxyethylpyridine, the nitrile, and the base agent is 1:3.5-4.5:4-5, the preparation reaction is carried out under strong base conditions, the reaction temperature is 60-100°C, the pK a value of the base agent is 17-30, the difference between the pK a values of the base agent and the nitrile is not more than 6, and the solvent is an aprotic solvent having a dielectric constant of less than 20.

2. The process for preparing a 2,2-disubstituted-4-pyridyl butyric nitrile derivative according to claim 1, wherein: The preparation method is mixing hydroxyethyl pyridine, nitrile, alkali agent in a solvent under a protective atmosphere at 60-100 DEG C, adjusting the cooled reaction system to neutral after the reaction is completed, and collecting and purifying the product.

3. The method for preparing the 2,2-disubstituted-4-pyridylbutyronitrile derivative as described in claim 2, characterized in that: The protective atmosphere is argon, nitrogen or helium.

4. The process for preparing a 2,2-disubstituted-4-pyridyl butyric nitrile derivative according to claim 3, wherein: The alkali agent is potassium salt, sodium salt or lithium salt of bis(trimethylsilyl)amine.

5. The method for preparing the 2,2-disubstituted-4-pyridylbutyronitrile derivative as described in claim 2, characterized in that: The reaction temperature is 70-80 DEG C.

6. The method for preparing the 2,2-disubstituted-4-pyridylbutyronitrile derivative as described in claim 2, characterized in that: The reaction time is 12-30 hours.

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