Preparation process of 2-hydroxy-5-methylpyridine

Abstract

The invention relates to the technical field of chemical synthesis, and provides a preparation process of 2-hydroxy-5-methylpyridine, which comprises the following steps: S1, adding 3-methylpyridine-N-oxide, acetic anhydride and a catalyst into a reaction kettle, heating to reflux, carrying out heat preservation reflux for 8-9 hours, and carrying out vacuum desolvation to obtain a desolvation residual liquid for later use; and S2, adding deionized water into the desolventizing residual liquid obtained in the step S1, heating to 75-85 DEG C, carrying out a heat preservation reaction for 60-70 min, carrying out vacuum desolventizing, and adding a solvent for recrystallization to obtain the 2-hydroxy-5-methylpyridine. The preparation process of the 2-hydroxy-5-methylpyridine, provided by the invention, has the characteristics of low toxicity, environment friendliness and simplicity in operation, and the obtained 2-hydroxy-5-methylpyridine is relatively high in yield.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and in particular to a preparation process of 2-hydroxy-5-methylpyridine. Background Art

[0002] 2-Hydroxy-5-methylpyridine is a pharmaceutical intermediate that can be used to prepare pirfenidone. Pirfenidone is a new pyridone compound with broad-spectrum anti-fibrotic effects. It is a white or light yellow crystalline powder that can prevent and reverse the formation of fibrosis and scars. It also has good therapeutic effects on fibrotic diseases such as renal interstitial fibrosis and liver fibrosis. It is also widely used in phase II clinical studies of kidney disease, hypertrophic cardiomyopathy, adult type I multiple neurofibromatosis, adolescent type I multiple neurofibromatosis, plexiform neurofibroma, diabetes with kidney disease and uterine leiomyoma. Therefore, 2-hydroxy-5-methylpyridine is an important intermediate for the production of pirfenidone, and the research on the preparation process of 2-hydroxy-5-methylpyridine has become increasingly important.

[0003] At present, the preparation of 2-hydroxy-5-methylpyridine is mainly prepared using 2-amino-5-methylpyridine as the starting material. This method has been developed to be mature and has an ideal yield, but 2-amino-5-methylpyridine has certain toxicity and poses certain safety hazards to operators and users. In addition, some researchers choose to use 1-nitrile-1-butene or morpholine and formaldehyde as raw materials to prepare 2-hydroxy-5-methylpyridine, but there are disadvantages such as long reaction route, complicated operation and low yield.

[0004] Patent CN 109593060A discloses a method for preparing an anti-fibrosis drug. The pirfenidone prepared in the application includes a preparation process of 2-hydroxy-5-methylpyridine, which is prepared by using 2-amino-5-methylpyridine as a starting material, adopting a reverse diazotization hydrolysis method, and then extracting and recrystallizing. It has the advantages of simple operation and high yield, but does not solve the problem of high toxicity of 2-amino-5-methylpyridine.

[0005] Therefore, there is an urgent need on the market for a preparation process for 2-hydroxy-5-methylpyridine that is low in toxicity, environmentally friendly, simple to operate and has a high yield. Summary of the invention

[0006] In view of the problems existing in the prior art, the present invention selects 3-methylpyridine-N-oxide as a raw material to synthesize 2-hydroxy-5-methylpyridine, adds a catalyst, and optimizes the synthesis steps and reaction conditions of this process, thereby solving the problems of high raw material toxicity, complex process and unsatisfactory yield in the existing preparation process of 2-hydroxy-5-methylpyridine.

[0007] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0008] In one aspect, the present invention provides a process for preparing 2-hydroxy-5-methylpyridine, comprising the following steps:

[0009] S1, add 3-methylpyridine-N-oxide, acetic anhydride and catalyst into a reaction kettle, heat to reflux, keep reflux for 8-9 hours, vacuum desolventize, and obtain desolventized residual liquid for standby use;

[0010] S2. Add deionized water to the residual solution from step S1, raise the temperature to 75-85° C., keep the temperature for 60-70 min, vacuum desolventize, add solvent for recrystallization, and obtain 2-hydroxy-5-methylpyridine.

[0011] The applicant chose 3-methylpyridine-N-oxide as the raw material, added excess acetic anhydride to carry out acylation rearrangement reaction under the action of a catalyst, and then synthesized 2-hydroxy-5-methylpyridine and by-product 2-hydroxy-3-methylpyridine through a hydrolysis reaction, and finally obtained the target product 2-hydroxy-5-methylpyridine through recrystallization from ethyl acetate. This method is safe, environmentally friendly, simple to operate and has a high yield.

[0012] In some embodiments of the present invention, the mass ratio of 3-methylpyridine-N-oxide to acetic anhydride in step S1 is 1:(9-10).

[0013] Preferably, the mass ratio of 3-methylpyridine-N-oxide to acetic anhydride in step S1 is 1:9.2.

[0014] In some embodiments of the present invention, the mass ratio of 3-methylpyridine-N-oxide to the catalyst in step S1 is 1:(0.1-0.3).

[0015] Preferably, in step S1, the mass ratio of 3-methylpyridine-N-oxide to the catalyst is 1:0.2.

[0016] In some embodiments of the present invention, the method for preparing the catalyst in step S1 comprises the following steps:

[0017] (1) Add vinyl imidazole to a reaction vessel, add acetonitrile and octadecane bromide in sequence, heat to 50-70° C. and stir for 71-73 hours, cool to 0-5° C., filter and wash the precipitate, dry, and grind to obtain a porogen for later use;

[0018] (2) adding diammonium hydrogen phosphate to deionized water, stirring, adding the porogen of step (1), stirring, adding phosphoric acid aqueous solution to adjust the pH to 5.5-6.5, adding oyster shell powder, stirring, heating to 140-150° C. and stirring for 23-25 ​​h, cooling to room temperature, washing, freeze-drying, adding anhydrous ethanol to soak, drying, and obtaining a carrier for use;

[0019] (3) The carrier of step (2) is mixed with acetone, heated to 50-60° C., and stirred to obtain solution 1; palladium acetate and acetone are mixed, stirred to obtain solution 2; solution 2 is added dropwise to solution 1, refluxed, cooled to room temperature, centrifuged, washed, and dried to obtain a catalyst.

[0020] Wherein, in the step (1), the molar ratio of vinyl imidazole to octadecane bromide is 1:(1-1.2).

[0021] Preferably, in step (1), the molar ratio of vinylimidazole to octadecane bromide is 1:1.1.

[0022] In some embodiments of the present invention, in step (2), the mass ratio of diammonium hydrogen phosphate, oyster shell powder and porogen is 1:(0.5-1):(0.2-0.3).

[0023] Preferably, in step (2), the mass ratio of diammonium hydrogen phosphate, oyster shell powder and porogen is 1:0.75:0.25.

[0024] In some embodiments of the present invention, in step (3), the mass ratio of the carrier to palladium acetate is 1:(0.02-0.06).

[0025] Preferably, in step (3), the mass ratio of the carrier to palladium acetate is 1:0.04.

[0026] The acylation rearrangement reaction of 3-methylpyridine-N-oxide under acetic anhydride conditions often requires the synergistic effect of a catalyst to ensure the acylation rearrangement reaction. Transition metal palladium can achieve the direct acylation reaction of nitrogen oxides with high selectivity under mild conditions, thereby enhancing the yield of 2-hydroxy-5-methylpyridine. However, the service life of palladium-based catalysts is relatively short due to the violent catalytic reaction, and palladium-based catalysts are easily affected by external factors such as oxidation, resulting in reduced catalytic activity and selectivity.

[0027] The applicant used oyster shell as calcium source and diammonium hydrogen phosphate as phosphorus source, and prepared a carrier by hydrothermal method under the action of porogen, and used the carrier to fix transition metal palladium to obtain a catalyst with excellent stability and catalytic activity. On the one hand, the applicant used vinyl imidazole and octadecane bromide as raw materials to prepare an imidazole ionic liquid as a porogen. The introduction of octadecane bromide makes the porogen have a long chain structure and greater steric hindrance, so that it has a larger pore size relative to traditional porogens, and can make the carrier have a larger pore size so that the transition metal palladium can be better loaded therein; on the other hand, the surface of the carrier prepared by the applicant using oyster shell as calcium source and diammonium hydrogen phosphate as phosphorus source contains abundant hydroxyl groups, so that it can form coordination with palladium ions, thereby stably loading palladium in the carrier; further, the imidazole group in the porogen and the phosphate in diammonium hydrogen phosphate form an interaction force, thereby improving the stability of the carrier, so that the catalyst has better stability.

[0028] In some embodiments of the present invention, the mass ratio of deionized water to the residual solution in step S2 is (1-1.1):1.

[0029] Preferably, in step S2, the mass ratio of deionized water to the desolventizing residual liquid is 1:1.

[0030] In some embodiments of the present invention, the temperature of the vacuum desolventizing in step S2 is 115-125° C. and the pressure is -0.02 MPa to 0 MPa.

[0031] Preferably, the temperature of the vacuum desolventizing in step S2 is 120° C. and the pressure is -0.01 MPa.

[0032] In some embodiments of the present invention, in step S2, the solvent for recrystallization is ethyl acetate.

[0033] In some embodiments of the present invention, the yield of 2-hydroxy-5-methylpyridine prepared by the preparation process described in the above technical solution is not less than 80%.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] (1) The present invention provides a preparation process of 2-hydroxy-5-methylpyridine, which uses 3-methylpyridine-N-oxide as a raw material, undergoes an acylation rearrangement reaction under the action of excess acetic anhydride and a catalyst, and optimizes the synthesis steps and reaction conditions of the process, so that the preparation process of 2-hydroxy-5-methylpyridine is low in toxicity, environmentally friendly, simple to operate and has a high yield.

[0036] (2) The present invention is based on a palladium catalyst, with oyster shell as a calcium source, diammonium hydrogen phosphate as a phosphorus source and a long-chain imidazolium ionic liquid as a porogen to synthesize a carrier, and palladium is loaded in the carrier to synthesize a catalyst, so that the catalyst has high catalytic activity, high stability and high selectivity.

[0037] (3) The yield of 2-hydroxy-5-methylpyridine obtained by the preparation process of the present invention is not less than 80%. DETAILED DESCRIPTION

[0038] The present invention will be described below in conjunction with specific embodiments. It should be noted that the following embodiments are examples of the present invention and are only used to illustrate the present invention, but not to limit the present invention. Other combinations and various modifications within the concept of the present invention may be performed without departing from the spirit or scope of the present invention.

[0039] In the following examples, except for the catalyst, the other compound monomers and related reagents used can be purchased from the market, among which oyster shell powder was purchased from Xi'an Ruierli Bioengineering Co., Ltd.

[0040] Preparation Example 1

[0041] The synthesis method of catalyst A comprises the following steps:

[0042] (1) 0.1 mol of vinyl imidazole was added to a reaction vessel, followed by 100 ml of acetonitrile and 0.11 mol of octadecane bromide, heated to 60° C. and stirred for 72 h, cooled to 5° C., the precipitate was filtered and washed with ether, dried at 60° C. for 8 h, and ground to obtain a porogen for use;

[0043] (2) 8 g of diammonium hydrogen phosphate was added to 50 ml of deionized water, stirred for 20 min, 2 g of the porogen of step (1) was added, stirred for 1 h, 30 wt % phosphoric acid aqueous solution was added to adjust the pH to 6, 6 g of oyster shell powder was added, stirred for 1 h, heated to 145 ° C and stirred for 24 h, cooled to room temperature, washed with deionized water 3 times, freeze-dried at -40 ° C for 12 h, soaked in anhydrous ethanol for 24 h, and dried at 60 ° C for 8 h to obtain a carrier for use;

[0044] (3) 5 g of the carrier of step (2) was mixed with 100 ml of acetone, heated to 55° C., and stirred for 30 min to obtain solution 1. 0.2 g of palladium acetate was mixed with 50 ml of acetone, and stirred for 20 min to obtain solution 2. Solution 2 was added dropwise to solution 1, refluxed for 24 h, cooled to room temperature, centrifuged, washed with acetone three times, and dried at 40° C. for 2 h to obtain catalyst A.

[0045] Preparation Example 2

[0046] Catalyst B, the specific implementation method is the same as that of catalyst A, except that in step (1), the molar number of octadecane bromide is replaced with 0.08 mol.

[0047] Preparation Example 3

[0048] Catalyst C, the specific implementation method is the same as that of catalyst A, except that in step (2), the mass of oyster shell powder is replaced with 3g.

[0049] Preparation Example 4

[0050] Catalyst D has the same specific implementation as Catalyst A, except that in step (2), the mass of the porogen is replaced with 1 g.

[0051] Preparation Example 5

[0052] Catalyst E, the specific implementation manner is the same as that of Catalyst A, except that in step (3), the mass of palladium acetate is replaced with 0.08 g.

[0053] Example 1

[0054] A preparation process of 2-hydroxy-5-methylpyridine comprises the following steps:

[0055] S1, 5g 3-methylpyridine-N-oxide, 46g acetic anhydride and 1g catalyst A were added to a reaction kettle, the temperature was raised to reflux, the temperature was kept at reflux for 8.5h, and vacuum desolventizing was performed until no solvent was evaporated to obtain the desolventizing residue for standby use;

[0056] S2, add deionized water to the residual solution of step S1, raise the temperature to 80°C, keep the temperature for 65 minutes, vacuum desolventize at 120°C and -0.01MPa until no solvent is evaporated, add ethyl acetate for recrystallization, and obtain 2-hydroxy-5-methylpyridine.

[0057] Wherein, the mass ratio of the deionized water added in step S2 to the desolventizing residual liquid is 1:1.

[0058] Example 2

[0059] A preparation process of 2-hydroxy-5-methylpyridine comprises the following steps:

[0060] S1, add 5g 3-methylpyridine-N-oxide, 45g acetic anhydride and 0.5g catalyst A into a reaction kettle, heat to reflux, keep reflux for 8h, vacuum desolventize until no solvent is evaporated, and obtain the desolventized residue for standby use;

[0061] S2, add deionized water to the residual solution of step S1, raise the temperature to 75°C, keep the temperature for 70 minutes, vacuum desolventize at 115°C and -0.02MPa until no solvent is evaporated, add ethyl acetate for recrystallization, and obtain 2-hydroxy-5-methylpyridine.

[0062] Wherein, the mass ratio of the deionized water added in step S2 to the desolventizing residual liquid is 1:1.

[0063] Example 3

[0064] A preparation process of 2-hydroxy-5-methylpyridine comprises the following steps:

[0065] S1, add 5g 3-methylpyridine-N-oxide, 50g acetic anhydride and 1.5g catalyst A into a reaction kettle, heat to reflux, keep reflux for 9h, vacuum desolventize until no solvent is evaporated, and obtain the desolventized residue for standby use;

[0066] S2, add deionized water to the residual solution of step S1, raise the temperature to 85°C, keep the temperature for 60 minutes, vacuum desolventize at 125°C, 0MPa until no solvent is evaporated, add ethyl acetate for recrystallization, and obtain 2-hydroxy-5-methylpyridine.

[0067] Wherein, the mass ratio of the deionized water added to the desolventizing residual liquid in step S2 is 1:1.1.

[0068] Example 4

[0069] This embodiment provides a preparation process of 2-hydroxy-5-methylpyridine, and the specific implementation method is the same as that of Example 1, except that the mass of acetic anhydride in step S1 is 40 g.

[0070] Example 5

[0071] This embodiment provides a preparation process of 2-hydroxy-5-methylpyridine. The specific implementation method is the same as that of Example 1, except that the mass of catalyst A in step S1 is 0.4 g.

[0072] Example 6

[0073] This embodiment provides a preparation process of 2-hydroxy-5-methylpyridine. The specific implementation method is the same as that of Example 1, except that the mass of catalyst A in step S1 is 1.7 g.

[0074] Example 7

[0075] This embodiment provides a preparation process of 2-hydroxy-5-methylpyridine. The specific implementation method is the same as that of Example 1, except that catalyst A is replaced by catalyst B in equal amounts.

[0076] Example 8

[0077] This embodiment provides a preparation process of 2-hydroxy-5-methylpyridine. The specific implementation method is the same as that of Example 1, except that catalyst A is replaced by catalyst C in equal amounts.

[0078] Example 9

[0079] This embodiment provides a preparation process of 2-hydroxy-5-methylpyridine. The specific implementation method is the same as that of Example 1, except that catalyst A is replaced by catalyst D in equal amounts.

[0080] Example 10

[0081] This embodiment provides a preparation process of 2-hydroxy-5-methylpyridine. The specific implementation method is the same as that of Example 1, except that catalyst E replaces catalyst A in equal amounts.

[0082] Embodiment 11

[0083] This embodiment provides a preparation process of 2-hydroxy-5-methylpyridine, and the specific implementation method is the same as that of Example 1, except that catalyst A is replaced by an equal amount of palladium acetate.

[0084] Comparative Example 1

[0085] This comparative example provides a preparation process of 2-hydroxy-5-methylpyridine, and the specific implementation method is the same as that of Example 1, except that catalyst A is not added.

[0086] Performance Testing

[0087] The yields of 2-hydroxy-5-methylpyridine described in Examples 1-11 and Comparative Example 1 were tested, and the test results are shown in Table 1.

[0088] The yield of 2-hydroxy-5-methylpyridine was measured by HPLC.

[0089] Table 1

[0090]

[0091]

[0092] As can be seen from the data in Table 1, 2-hydroxy-5-methylpyridine in Examples 1-3 of the present invention has the characteristics of high yield as a whole. Among them, Example 4 changes the ratio of acetic anhydride and 3-methylpyridine-N-oxide in step S1, so that the content of acetic anhydride is not in an excessive state, so that 3-methylpyridine-N-oxide cannot fully undergo acylation rearrangement reaction, thereby causing the yield of 2-hydroxy-5-methylpyridine to decrease significantly; Example 5-6 changes the amount of catalyst added, so that the catalyst cannot fully promote the acylation rearrangement reaction of 3-methylpyridine-N-oxide, and then shows the phenomenon of decreased yield of 2-hydroxy-5-methylpyridine; Example 7-10 changes the ratio of key components when synthesizing the catalyst, so that the catalytic activity, stability and selectivity of the catalyst decrease, and then the yield of 2-hydroxy-5-methylpyridine decreases; Example 11 and Comparative Example 1 are respectively conventional catalysts palladium acetate instead of catalyst A and the case where catalyst A is not added, and the test finds that the yield of the prepared 2-hydroxy-5-methylpyridine shows poor results.

[0093] The above implementation modes are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with this technology to understand the content of the present invention and implement it, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A process for preparing 2-hydroxy-5-methylpyridine, characterized in that: The following steps are involved: S1, add 3-methylpyridine-N-oxide, acetic anhydride and catalyst into a reaction kettle, heat to reflux, keep reflux for 8-9 hours, vacuum desolventize, and obtain desolventized residual liquid for standby use; S2. Add deionized water to the residual solution from step S1, raise the temperature to 75-85° C., keep the temperature for 60-70 min, vacuum desolventize, add solvent for recrystallization, and obtain 2-hydroxy-5-methylpyridine.

2. The process for preparing 2-hydroxy-5-methylpyridine according to claim 1, characterized in that: The mass ratio of 3-methylpyridine-N-oxide to acetic anhydride in step S1 is 1:(9-10).

3. The preparation process of 2-hydroxy-5-methylpyridine according to claim 1, characterized in that: The mass ratio of 3-methylpyridine-N-oxide to the catalyst in step S1 is 1:(0.1-0.3).

4. The process for preparing 2-hydroxy-5-methylpyridine according to claim 1, characterized in that: The method for preparing the catalyst in step S1 comprises the following steps: (1) Add vinyl imidazole to a reaction vessel, add acetonitrile and octadecane bromide in sequence, heat to 50-70° C. and stir for 71-73 hours, cool to 0-5° C., filter and wash the precipitate, dry, and grind to obtain a porogen for later use; (2) adding diammonium hydrogen phosphate to deionized water, stirring, adding the porogen of step (1), stirring, adding phosphoric acid aqueous solution to adjust the pH to 5.5-6.5, adding oyster shell powder, stirring, heating to 140-150° C. and stirring for 23-25 ​​h, cooling to room temperature, washing, freeze-drying, adding anhydrous ethanol to soak, drying, and obtaining a carrier for use; (3) The carrier of step (2) is mixed with acetone, heated to 50-60° C., and stirred to obtain solution 1; palladium acetate and acetone are mixed, stirred to obtain solution 2; solution 2 is added dropwise to solution 1, refluxed, cooled to room temperature, centrifuged, washed, and dried to obtain a catalyst.

5. The process for preparing 2-hydroxy-5-methylpyridine according to claim 4, characterized in that: In the step (2), the mass ratio of diammonium hydrogen phosphate, oyster shell powder and porogen is 1:(0.5-1):(0.2-0.3).

6. The process for preparing 2-hydroxy-5-methylpyridine according to claim 4, characterized in that: In the step (3), the mass ratio of the carrier to palladium acetate is 1:(0.02-0.06).

7. The process for preparing 2-hydroxy-5-methylpyridine according to claim 1, characterized in that: The mass ratio of deionized water to the desolventizing residual liquid in step S2 is (1-1.1):

1.

8. The process for preparing 2-hydroxy-5-methylpyridine according to claim 1, characterized in that: The vacuum desolventizing in step S2 is carried out at a temperature of 115-125° C. and a pressure of -0.02 MPa to 0 MPa.

9. The process for preparing 2-hydroxy-5-methylpyridine according to claim 1, characterized in that: In the step S2, the solvent for recrystallization is ethyl acetate.

10. The process for preparing 2-hydroxy-5-methylpyridine according to any one of claims 1 to 9, characterized in that: The yield of the prepared 2-hydroxy-5-methylpyridine is not less than 80%.

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