2-(piperidin-2-yl)-2-(p-tolyl)ethyl acetate hydrochloride

Abstract

The application belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 2-(piperidin-2-yl)-2-(p-tolyl)ethyl acetate hydrochloride. The application uses p-methyl phenylacetonitrile, 2-bromopyridine and HCl as raw materials, and prepares the final product through three steps. By optimizing the base reagent of step 1 and the adding state of hydrogen chloride of step 2, the reaction yield is improved, and the yield of each step is close to 90%. The method has the advantages of low cost, easy-to-obtain raw materials, simple reaction process, no need to use special equipment such as low temperature, convenient process operation, safety and high yield, promotes the commercial production of 2-(piperidin-2-yl)-2-(p-tolyl)ethyl acetate hydrochloride, and has a wide application prospect.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride. Background Technology

[0002] Methylphenidate hydrochloride is a psychostimulant primarily used clinically to treat various types of depression, mild brain dysfunction (such as ADHD), and narcolepsy. Its structural formula is as follows:

[0003]

[0004] 2-(piperidin-2-yl)-2-(p-tolyl)methyl acetate hydrochloride is an analogue of this compound and has similar clinical efficacy. Currently, there are few reported methods for synthesizing 2-(piperidin-2-yl)-2-(p-tolyl)methyl acetate hydrochloride. For example, international patent publication number WO2022029151A1 discloses a method for synthesizing 2-(piperidin-2-yl)-2-(p-tolyl)methyl acetate hydrochloride and its analogues. However, existing techniques suffer from long synthetic steps, low yields, and the need for reaction conditions involving low temperatures of -78°C or expensive raw materials.

[0005] Therefore, existing technologies cannot achieve a safe, simple, low-cost, and high-yield synthesis of methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride, which greatly limits the large-scale production of methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride. Summary of the Invention

[0006] To address the problems of existing technologies, this invention provides a method for preparing 2-(piperidin-2-yl)-2-(p-tolyl)acetic acid methyl ester hydrochloride, with the aim of preparing 2-(piperidin-2-yl)-2-(p-tolyl)acetic acid methyl ester hydrochloride safely, simply, and efficiently.

[0007] This invention provides a method for preparing methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride intermediate, which includes the following reaction 1:

[0008]

[0009] The product is obtained by reacting p-methylphenylacetonitrile, 2-bromopyridine with NaNH2.

[0010] Preferably, the reaction temperature of reaction 1 is 20-50°C; and / or, the reaction time of reaction 1 is 2-5 hours.

[0011] This invention provides a method for preparing methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride intermediate, which includes the following reaction 2:

[0012]

[0013] Hydrogen chloride gas is passed through a methanol solution of 2-(pyridin-2-yl)-2-(p-tolyl)acetonitrile, and water is added after the reaction to obtain the product.

[0014] Preferably, the reaction temperature of reaction 2 is 20-40℃; and / or, the reaction time of reaction 2 is 5-10h; and / or, the reaction continues for 1-3h after the addition of water; and / or, the mass concentration of the methanol solution of 2-(pyridin-2-yl)-2-(p-tolyl)acetonitrile is 6.2%-16.7%; and / or, the molar ratio of 2-(pyridin-2-yl)-2-(p-tolyl)acetonitrile to hydrogen chloride is 1:5-15.

[0015] Preferably, the 2-(pyridin-2-yl)-2-(p-tolyl)acetonitrile is prepared according to reaction 1 as follows:

[0016]

[0017] The product is obtained by reacting p-methylphenylacetonitrile, 2-bromopyridine with NaNH2.

[0018] Preferably, the reaction temperature of reaction 1 is 20-50°C; and / or, the reaction time of reaction 1 is 2-5 hours.

[0019] This invention provides a method for preparing methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride, which includes the following reaction 3:

[0020]

[0021] 2-(pyridin-2-yl)-2-(p-tolyl)methyl acetate hydrochloride is obtained by reacting it with a reducing agent;

[0022] The 2-(pyridin-2-yl)-2-(p-tolyl)methyl acetate hydrochloride is prepared by any of the above methods for preparing the 2-(piperidin-2-yl)-2-(p-tolyl)methyl acetate hydrochloride intermediate.

[0023] Preferably, the reducing agent is hydrogen, and the reaction 3 is carried out under a 5-10% palladium on carbon catalyst.

[0024] Preferably, the pressure of the hydrogen gas is 1-2 MPa; and / or, the mass ratio of 2-(pyridin-2-yl)-2-(p-tolyl)acetic acid methyl ester hydrochloride to palladium on carbon is 1:0.01-0.1.

[0025] Preferably, the reaction temperature of reaction 3 is 30-60°C; and / or, the reaction time of reaction 3 is 4-10 h.

[0026] This invention provides a method for preparing methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride. The method uses p-methylphenylacetonitrile, 2-bromopyridine, and HCl as raw materials, and proceeds through a three-step reaction to obtain the final product. By preferably using sodium amide as the base reagent in step 1 and preferably adding hydrogen chloride in the gaseous state in step 2, the reaction yield is improved, with the yield of each step approaching 90%. This method has the advantages of low cost, readily available raw materials, simple reaction process, no need for special equipment such as low-temperature treatment, convenient and safe operation, and high yield. It promotes the commercial production of methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride and has broad application prospects.

[0027] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0028] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0029] Figure 1 The 1H NMR spectrum of methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride ( 1 HNMR spectrum. Detailed Implementation

[0030] In the following examples and experimental cases, reagents and raw materials not specifically described are all commercially available products.

[0031] The structure of the compound is obtained through 1 It was determined by H NMR. 1 The H NMR measurements were performed using a 400 MHz NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6) as the solvent.

[0032] Example 1: A method for preparing methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride

[0033] This embodiment provides a method for preparing methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride, which includes the following steps:

[0034]

[0035] (1) Synthesis of compound 2: 2-(pyridin-2-yl)-2-(p-tolyl)acetonitrile

[0036] 50 g of p-methylphenylacetonitrile (1.0 eq) was dissolved in 500 g of toluene, and 78.3 g of 2-bromopyridine (1.3 eq) was added to a three-necked flask. Sodium amino acid (22.3 g, 1.5 eq) was added at a controlled temperature of 40 °C. After the addition was complete, the system was reacted at 40 °C for 4 h. Once the reaction was complete, water was added to quench the reaction, and the mixture was concentrated. Then, 250 g of n-heptane was added, crystals were precipitated, and the mixture was filtered to obtain the final product.

[0037] The product yield was 88%.

[0038] product 1 The H NMR data are as follows:

[0039] δ8.45(d,1H),7.6(d,1H),7.38(d,1H),7.05-7.13(d,5H),5.06(s,1H),2.19(s,3H).

[0040] (2) Synthesis of compound 3: methyl 2-(pyridin-2-yl)-2-(p-tolyl)acetate hydrochloride

[0041] Compound 2 (50 g, 1.0 eq) was dissolved in methanol (500 g), and the temperature was controlled at 35 °C. Hydrogen chloride gas (87.6 g, 10 eq) was slowly passed through the solution, and the reaction was carried out for 9 h. Then water (0.86 g, 2 eq) was added, and the reaction was carried out for 2 h. The organic phase was concentrated until no fraction was distilled off. Methyl tert-butyl ether (250 g) was added, crystallization was carried out, and the solution was filtered to obtain the final product.

[0042] The product yield was 86%.

[0043] product 1 The H NMR data are as follows:

[0044] δ8.45(d,1H),7.6(d,1H),7.38(d,1H),7.05-7.13(d,5H),4.89(s,1H),3.66(s,3H),2.18(s,3H).

[0045] (3) Synthesis of compound 4: methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride

[0046] Compound 3 (50 g, 1.0 eq) was dissolved in anhydrous methanol (500 g), heated to 55 °C, 5% palladium on carbon (5 g) was added, hydrogen gas was introduced at 1 MPa, and the reaction was maintained for 9 h. After the reaction was completed, the organic phase was concentrated until no fraction was distilled off, methyl tert-butyl ether (250 g) was added, crystallization was performed, and the mixture was filtered to obtain the final product.

[0047] The product yield was 90%.

[0048] product 1 H NMR such as Figure 1 As shown, the specific data is as follows:

[0049] δ7.12(d,2H),6.93(d,2H),3.75(t,1H),3.62(s,3H),3.46(t,1H),2.79(t,2H),2.19(s,3H),1.45-1.56(t,6H).

[0050] Example 2: A method for preparing methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride

[0051] This embodiment provides a method for preparing methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride, which includes the following steps:

[0052] (1) Synthesis of compound 2: 2-(pyridin-2-yl)-2-(p-tolyl)acetonitrile

[0053] 50 g of p-methylphenylacetonitrile (1.0 eq) was dissolved in 500 g of toluene, and 66.3 g of 2-bromopyridine (1.1 eq) was added to a three-necked flask. Sodium amino acid (17.8 g, 1.2 eq) was added at a controlled temperature of 40 °C. After the addition was complete, the system was reacted at 40 °C for 4 h. Once the reaction was complete, the mixture was quenched, concentrated, and 250 g of n-heptane was added. Crystallization was then observed, and the mixture was filtered to obtain the final product.

[0054] The product yield was 78%.

[0055] product 1 The H NMR data are as follows:

[0056] δ8.45(d,1H),7.6(d,1H),7.38(d,1H),7.05-7.13(d,5H),5.06(s,1H),2.19(s,3H).

[0057] (2) Synthesis of compound 3: methyl 2-(pyridin-2-yl)-2-(p-tolyl)acetate hydrochloride

[0058] Compound 2 (50 g, 1.0 eq) was dissolved in methanol (500 g) at 35 °C. Hydrogen chloride gas (43.8 g, 5 eq) was slowly introduced and the reaction was carried out for 9 h. Then water (0.86 g, 2 eq) was added and the reaction was carried out for 2 h. The organic phase was concentrated until no fraction was distilled off. Methyl tert-butyl ether (250 g) was added, crystallization was carried out, and the mixture was filtered to obtain the final product.

[0059] The product yield was 78%.

[0060] product 1 The H NMR data are as follows:

[0061] δ8.45(d,1H),7.6(d,1H),7.38(d,1H),7.05-7.13(d,5H),4.89(s,1H),3.66(s,3H),2.18(s,3H).

[0062] (3) Synthesis of compound 4: methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride

[0063] Compound 3 was dissolved in anhydrous methanol (500g), heated to 55°C, 5% palladium on carbon (3g) was added, hydrogen gas was introduced at 1MPa, and the reaction was maintained for 9h. After the reaction was completed, the organic phase was concentrated until no fraction was distilled off, methyl tert-butyl ether (250g) was added, crystallization was performed, and the mixture was filtered to obtain the final product.

[0064] The product yield was 83%.

[0065] product 1 The H NMR data are as follows:

[0066] δ7.12(d,2H),6.93(d,2H),3.75(t,1H),3.62(s,3H),3.46(t,1H),2.79(t,2H),2.19(s,3H),1.45-1.56(t,6H).

[0067] Example 3: A method for preparing methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride

[0068] This embodiment provides a method for preparing methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride, which includes the following steps:

[0069] (1) Synthesis of compound 2: 2-(pyridin-2-yl)-2-(p-tolyl)acetonitrile

[0070] 50 g of p-methylphenylacetonitrile (1.0 eq) was dissolved in 500 g of toluene, and 78.3 g of 2-bromopyridine (1.3 eq) was added to a three-necked flask. Sodium amino acid (17.8 g, 1.2 eq) was added at a controlled temperature of 40 °C. After the addition was complete, the system was reacted at 25 °C for 4 h. Once the reaction was complete, the mixture was quenched, concentrated, and 250 g of n-heptane was added. Crystallization was then observed, and the mixture was filtered to obtain the final product.

[0071] The product yield was 81%.

[0072] product 1 The H NMR data are as follows:

[0073] δ8.45(d,1H),7.6(d,1H),7.38(d,1H),7.05-7.13(d,5H),5.06(s,1H),2.19(s,3H).

[0074] (2) Synthesis of compound 3: methyl 2-(pyridin-2-yl)-2-(p-tolyl)acetate hydrochloride

[0075] Compound 2 (50 g, 1.0 eq) was dissolved in methanol (500 g), and the temperature was controlled at 25 °C. Hydrogen chloride gas (87.6 g, 10 eq) was slowly passed through the solution, and the reaction was carried out for 9 h. Then water (0.86 g, 2 eq) was added, and the reaction was carried out for 2 h. The organic phase was concentrated until no fraction was distilled off. Methyl tert-butyl ether (250 g) was added, crystallization was carried out, and the mixture was filtered to obtain the final product.

[0076] The product yield was 80%.

[0077] product 1 The H NMR data are as follows:

[0078] δ8.45(d,1H),7.6(d,1H),7.38(d,1H),7.05-7.13(d,5H),4.89(s,1H),3.66(s,3H),2.18(s,3H).

[0079] (3) Synthesis of compound 4: methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride

[0080] Compound 3 was dissolved in anhydrous methanol (500g), heated to 35°C, 5% palladium on carbon (5g) was added, hydrogen gas was introduced at 1MPa, and the reaction was maintained for 9h. After the reaction was completed, the organic phase was concentrated until no fraction was distilled off, methyl tert-butyl ether (250g) was added, crystallization was performed, and the mixture was filtered to obtain the final product.

[0081] The product yield was 86%.

[0082] product 1 The H NMR data are as follows:

[0083] δ7.12(d,2H),6.93(d,2H),3.75(t,1H),3.62(s,3H),3.46(t,1H),2.79(t,2H),2.19(s,3H),1.45-1.56(t,6H).

[0084] Example 4: A method for preparing methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride

[0085] This embodiment provides a method for preparing methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride, which includes the following steps:

[0086] (1) Synthesis of compound 2: 2-(pyridin-2-yl)-2-(p-tolyl)acetonitrile

[0087] 50 g of p-methylphenylacetonitrile (1.0 eq) was dissolved in 500 g of toluene, and 78.3 g of 2-bromopyridine (1.3 eq) was added to a three-necked flask. Sodium amino acid (22.3 g, 1.5 eq) was added at a controlled temperature of 40 °C. After the addition was complete, the system was reacted at 40 °C for 2 h. Once the reaction was complete, the mixture was quenched, concentrated, and then 250 g of n-heptane was added. Crystallization was observed, and the mixture was filtered to obtain the final product.

[0088] The product yield was 83%.

[0089] product 1 The H NMR data are as follows:

[0090] δ8.45(d,1H),7.6(d,1H),7.38(d,1H),7.05-7.13(d,5H),5.06(s,1H),2.19(s,3H).

[0091] (2) Synthesis of compound 3: methyl 2-(pyridin-2-yl)-2-(p-tolyl)acetate hydrochloride

[0092] Compound 2 (50 g, 1.0 eq) was dissolved in methanol (500 g), and the temperature was controlled at 35 °C. Hydrogen chloride gas (87.6 g, 10 eq) was slowly passed through the solution, and the reaction was carried out for 5 h. Then water (0.86 g, 2 eq) was added, and the reaction was carried out for 1 h. The organic phase was concentrated until no fraction was distilled off. Methyl tert-butyl ether (250 g) was added, crystallization was carried out, and the mixture was filtered to obtain the final product.

[0093] The yield of the product was 75%.

[0094] product 1 The H NMR data are as follows:

[0095] δ8.45(d,1H),7.6(d,1H),7.38(d,1H),7.05-7.13(d,5H),4.89(s,1H),3.66(s,3H),2.18(s,3H).

[0096] (3) Synthesis of compound 4: methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride

[0097] Compound 3 (50 g, 1.0 eq) was dissolved in anhydrous methanol (500 g), heated to 55 °C, 5% palladium on carbon (5 g) was added, hydrogen gas was introduced at 1 MPa, and the reaction was maintained for 5 h. After the reaction was completed, the organic phase was concentrated until no fraction was distilled off, methyl tert-butyl ether (250 g) was added, crystallization was performed, and the mixture was filtered to obtain the final product.

[0098] The product yield was 79%.

[0099] product 1 The H NMR data are as follows:

[0100] δ7.12(d,2H),6.93(d,2H),3.75(t,1H),3.62(s,3H),3.46(t,1H),2.79(t,2H),2.19(s,3H),1.45-1.56(t,6H).

[0101] Example 5: A method for preparing methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride

[0102] This embodiment provides a method for preparing methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride, which includes the following steps:

[0103]

[0104] (1) Synthesis of compound 2: 2-(pyridin-2-yl)-2-(p-tolyl)acetonitrile

[0105] 50 g of p-methylphenylacetonitrile (1.0 eq) was dissolved in 500 g of toluene, and 78.3 g of 2-bromopyridine (1.3 eq) was added to a three-necked flask. Sodium hydride (22.5 g, 1.5 eq) was added at a controlled temperature of 40 °C. After the addition was complete, the system was reacted at 40 °C for 4 h. Once the reaction was complete, the mixture was quenched, concentrated, and then 250 g of n-heptane was added. Crystallization was observed, and the mixture was filtered to obtain the final product.

[0106] The product yield was 65%.

[0107] product 1 The H NMR data are as follows:

[0108] δ8.45(d,1H),7.6(d,1H),7.38(d,1H),7.05-7.13(d,5H),5.06(s,1H),2.19(s,3H).

[0109] (2) Synthesis of compound 3: methyl 2-(pyridin-2-yl)-2-(p-tolyl)acetate hydrochloride

[0110] Compound 2 (50 g, 1.0 eq) was dissolved in methanol (500 g) at 35 °C. Concentrated hydrochloric acid (243.3 g, 10 eq) was added and the reaction was carried out for 9 h. Then water (0.86 g, 2 eq) was added and the reaction was carried out for 2 h. The organic phase was concentrated until no fraction was distilled off. Methyl tert-butyl ether (250 g) was added, crystallization was carried out, and the mixture was filtered to obtain the final product.

[0111] The yield of the product was 66%.

[0112] product 1 The H NMR data are as follows:

[0113] δ8.45(d,1H),7.6(d,1H),7.38(d,1H),7.05-7.13(d,5H),4.89(s,1H),3.66(s,3H),2.18(s,3H).

[0114] (3) Synthesis of compound 4: methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride

[0115] Compound 3 (50 g, 1.0 eq) was dissolved in anhydrous ethanol (500 g), heated to 55 °C, 5% palladium on carbon (5 g) was added, hydrogen gas was introduced at 1 MPa, and the reaction was maintained for 9 h. After the reaction was completed, the organic phase was concentrated until no fraction was distilled off, methyl tert-butyl ether (250 g) was added, crystallization was performed, and the mixture was filtered to obtain the final product.

[0116] The product yield was 88%.

[0117] product 1 The H NMR data are as follows:

[0118] δ7.12(d,2H),6.93(d,2H),3.75(t,1H),3.62(s,3H),3.46(t,1H),2.79(t,2H),2.19(s,3H),1.45-1.56(t,6H).

[0119] The relationship between changes in experimental conditions and yield in the above embodiments is shown in Table 1-3:

[0120] Table 1 shows the relationship between experimental conditions and yield in step (1).

[0121]

[0122] Table 2 shows the relationship between experimental conditions and yield in step (2).

[0123]

[0124]

[0125] Table 3 shows the relationship between experimental conditions and yield in step (3).

[0126]

[0127] The above results show that the type of alkali in step (1) has a significant impact on the product yield, and sodium amino acid is the preferred alkali reagent in step (1) of this invention; the state of hydrogen chloride introduction in step (2) has a significant impact on the product yield, and the yield is significantly improved when hydrogen chloride gas is directly introduced into the reaction solution.

[0128] As can be seen from the above embodiments, the present invention provides a method for preparing methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride. This method uses p-methylphenylacetonitrile, 2-bromopyridine, and HCl as raw materials, and proceeds through a three-step reaction to obtain the final product. By preferably using sodium amide as the base reagent in step 1 and preferably adding hydrogen chloride in the gaseous state in step 2, the reaction yield is improved, making the yield of each step close to 90%. This method has the advantages of low cost, readily available raw materials, simple reaction process, no need for special equipment such as low-temperature treatment, convenient and safe operation, and high yield, promoting the commercial production of methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride, and has broad application prospects.

Claims

1. A process for the preparation of 2-(piperidin-2-yl)-2-(p-tolyl)ethyl acetate hydrochloride, characterized in that, The reaction comprises the following reaction 1, reaction 2 and reaction 3: Reaction 1: reaction of p-methylphenylacetonitrile and 2-bromopyridine with NaNH2; the reaction temperature of the reaction 1 is 20-50 DEG C, and the reaction time is 2-5h; Reaction 2: hydrogen chloride gas is introduced into a methanol solution of 2-(pyridin-2-yl)-2-(p-tolyl)acetonitrile, and then water is added after reaction; the reaction temperature of the reaction 2 is 20-40 DEG C, and the reaction time is 5-10h; Reaction 3: reaction of 2-(pyridin-2-yl)-2-(p-tolyl)acetonitrile with a reducing agent, and then the reaction 3 is obtained; the reaction temperature of the reaction 3 is 30-60 DEG C, and the reaction time is 4-10h.

2. The method of claim 1, wherein: In the reaction 2, the water is added and then reacted for 1-3h; and / or, the mass concentration of the methanol solution of 2-(pyridin-2-yl)-2-(p-tolyl)acetonitrile is 6.2%-16.7%; and / or, the molar ratio of the amount of 2-(pyridin-2-yl)-2-(p-tolyl)acetonitrile to hydrogen chloride is 1:5-15.

3. The method of claim 1, wherein: The reducing agent is hydrogen, and the reaction 3 is carried out under the catalysis of 5-10% palladium-carbon.

4. The method of claim 3, wherein: The pressure of the hydrogen is 1-2 MPa; and / or, the mass ratio of 2-(pyridin-2-yl)-2-(p-tolyl)acetonitrile to palladium-carbon is 1:0.01-0.1.

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