CN108191745A - The preparation method of 2- methylol -3,4- dimethoxy-pyridines - Google Patents

Abstract

The invention discloses a preparation method of 2-hydroxymethyl-3,4-dimethoxypyridine, adding 20-30 kg of 3,4-dimethoxy-2-picoline-N-oxide into In 10-20kg of acetic acid, heat it under mechanical stirring to dissolve completely; weigh 50-75kg of acetic anhydride, slowly add it into the above system under stirring; then keep it warm at 85-95°C for 15-16h; After ~90% acetic anhydride, lower it to 18~25°C, slowly add alkali to adjust the pH to 12~13, heat up and stir for hydrolysis; add 0.8~1.2kg of dichloromethane to the system, stir for 1h, let stand to separate the liquid, and then use Equal amounts of dichloromethane were extracted twice respectively, anhydrous sodium sulfate was added to the combined extracts, stirred and dried, rotary evaporated, and dichloromethane recovered to obtain the product. The invention has high yield, mild reaction conditions, safety and reliability, reduces the consumption of acetic anhydride and reduces the cost.

Description

The preparation method of 2-hydroxymethyl-3,4-dimethoxypyridine

technical field

The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and relates to a preparation method of 2-hydroxymethyl-3,4-dimethoxypyridine.

Background technique

Pandoprazole is a proton pump inhibitor drug, which has been widely used in gastrointestinal diseases in the world in recent years, mainly for the treatment of gastric ulcer, duodenum and reflux esophagitis. It was developed by German company Byk Gulden; 2-chloroform Base-3,4-dimethoxypyridine hydrochloride is one of the two intermediates in the synthesis of pandoprazole, 2-hydroxymethyl-3,4-dimethoxypyridine is the synthesis of 2-chloromethyl-3, An important intermediate of 4-dimethoxypyridine hydrochloride.

In the prior art, the synthetic method of Pandoprazole intermediate 2-chloromethyl-3,4-dimethoxypyridine hydrochloride is to take maltol as starting raw material, through methylation reaction, ammoniation, chlorination, Oxidation, sodium methoxide methoxide, acetic anhydride isomerization to obtain 2-hydroxymethyl-3,4-dimethoxypyridine, and then chlorination to salt to obtain the product 2-chloromethyl-3,4-dimethoxy Pyridine hydrochloride. It can be seen that 2-hydroxymethyl-3,4-dimethoxypyridine is a key intermediate for the preparation of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride, and its synthesis is of great value.

Prior art 1 (preparation of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride, Li Rongdong, Xu Yan, Chinese Journal of Pharmaceutical Industry, 2000, 31(10): 475-476) specifically discloses Heat reflux with acetic anhydride and 3,4-dimethoxy-2-methylpyridine-N-oxide for 2 hours, remove the acetic anhydride under reduced pressure, add sodium hydroxide solution to the remaining oil, and stir at 80°C for 4 hours , after cooling, extracted with dichloromethane, washed with water until neutral, dried over anhydrous sodium sulfate, and evaporated to dry dichloromethane to obtain 2-hydroxymethyl-3,4-dimethoxypyridine.

Prior art 2 (preparation of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride, Liu Delong et al., Journal of Xuzhou Normal University (Natural Science Edition), 2003, 21 (1)) specifically discloses the In the methylation reaction, heat acetic anhydride to 85°C, gradually add 3,4-dimethoxy-2-methylpyridine-N-oxide, then reflux at 135°C for 3 hours, remove acetic anhydride under reduced pressure, and Sodium hydroxide solution was added to the residual oil, and stirred at 80°C for 3.5 hours. After cooling, the reaction solution was extracted with dichloromethane, washed with water until neutral, dried with anhydrous sodium sulfate, and dichloromethane was distilled off to obtain 2- Hydroxymethyl-3,4-dimethoxypyridine.

Prior Art 3 (Application No.: 201010136871.8, Name: Industrial Preparation Method of Pantoprazole Intermediate Pyridine Hydrochloride, Publication Date: 2010.11.03) specifically discloses: (1) Preparation of 3-methoxy-2- Methyl-4H-pyran-4-one; (2) preparation of 3-methoxy-2-methyl-4(IH)-pyridinone; (3) preparation of 4-chloro-3-methoxy-2 -methylpyridine; (4) preparation of 4-chloro-3-methoxyl-2-methylpyridine-N-oxide; (5) preparation of 3,4-dimethoxyl-2-methylpyridine-N -oxide; (6) preparation of 2-hydroxymethyl-3,4-dimethoxypyridine; (7) preparation of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride. Add acetic anhydride to 3,4-dimethoxy-2-methylpyridine-N-oxide for hydroxymethylation reaction, then raise the temperature to 50-60°C for 16 hours, distill off the acetic anhydride, and add Adjust the pH to 9 with a strong base, stir at 65-70°C for 2 hours, after cooling, extract with organic solvent for 3-4 times, evaporate the organic solvent to obtain brown yellow 2-hydroxymethyl-3,4-dimethoxy Pyridine solid.

Prior art 4 (application number: 201110172014.8, name: a preparation method of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride, publication date: 2012.01.04) specifically discloses that maltol is used as Raw materials, sequentially undergo methylation, ammoniation, chlorination, oxidation, methoxy substitution, hydroxymethylation and secondary chlorination to generate 2-chloromethyl-3,4-dimethoxypyridine hydrochloride Salt. In the methylolation reaction, heat acetic anhydride to 80-90°C, gradually add 3,4-dimethoxy-2-methylpyridine-N-oxide, and then reflux at 120-140°C for 2-4h, Remove acetic anhydride under reduced pressure, add sodium hydroxide solution to the remaining oil, stir at 80-90°C for 3-4h, after cooling, extract the reaction solution three times with dichloromethane, wash with water until neutral, add anhydrous sodium sulfate Dry, evaporate dichloromethane, cool and crystallize to obtain 2-hydroxymethyl-3,4-dimethoxypyridine.

In summary, in the method for preparing 2-hydroxymethyl-3,4-dimethoxypyridine, all use 3,4-dimethoxy-2-methylpyridine-N-oxide as raw material, adopt A large excess of acetic anhydride is used as a reactant and as a reaction solvent. Due to the excessive amount of acetic anhydride in the preparation process, the cost of the enterprise is increased, the reaction temperature of the production process is high, the safety factor is reduced, and the reaction yield is low, resulting in the synthesis of Pandoprazole intermediate— The overall yield of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride decreased, thereby affecting the industrial production of pandoprazole.

Prior art 5 (application number: 201410823414.4, name: a preparation method of pantoprazole intermediate 2-chloromethyl-3,4-dimethoxypyridine hydrochloride, publication date: 2015.04.29) specific Disclosed is a preparation method of pantoprazole intermediate 2-chloromethyl-3,4-dimethoxypyridine hydrochloride: starting with 3-hydroxy-2-methyl-4-pyrone Raw materials, 2-chloromethyl-3,4-dimethoxypyridine hydrochloride prepared by five-step reaction of ammoniation, methoxylation, oxidation, hydroxymethylation and chlorination, in the hydroxymethylation reaction Use 3,4-dimethoxy-2-methylpyridine N-oxide and acetic anhydride to reflux at high temperature for 4 hours, then remove acetic anhydride under reduced pressure, add water to the oil, and adjust the pH value to 8-9 with lye, Then add solid NaOH, stir at 80°C for 4h, cool, extract with dichloromethane, wash with water until neutral, add anhydrous sodium sulfate to dry, evaporate dichloromethane to obtain white crystal 2-hydroxymethyl-3,4- Dimethoxypyridine, see Figure 1. Although the reaction yield reaches 90%, the reaction temperature is high, solid alkali is added in the reaction process, it is difficult to control, and the safety is low, and the reaction uses excessive acetic anhydride as solvent and reactant, which increases the cost of the enterprise.

Therefore, there is an urgent need for a high-yield, safe and reliable preparation method of 2-hydroxymethyl-3,4-dimethoxypyridine.

Contents of the invention

In order to solve the above problems, the present invention provides a preparation method of 2-hydroxymethyl-3,4-dimethoxypyridine, which has high yield, mild reaction conditions, safety and reliability, reduces the amount of acetic anhydride, reduces costs, and solves the problem of Problems existing in the prior art.

The technical scheme adopted in the present invention is a preparation method of 2-hydroxymethyl-3,4-dimethoxypyridine, which is specifically carried out according to the following steps:

Step 1, in proportion, add 20~30kg of 3,4-dimethoxy-2-methylpyridine-N-oxide into 10~20kg of acetic acid, heat to 75~85℃ under mechanical stirring, and dissolve completely ;

Step 2, weigh 50-75kg of acetic anhydride, and slowly add it into the system of step 1 under stirring at 80-85°C, the dripping rate of acetic anhydride is 10-15kg/h; then keep it warm at 85-95°C 15 to 16 hours to obtain the reaction solution;

Step 3: Distill the reaction solution under reduced pressure at 85-90°C and 0.092MPa to distill 80-90% acetic anhydride, then lower it to 18-25°C, slowly add alkali to adjust the pH to 12-13, heat up to 45-55°C and stir Hydrolyze for 2 hours, and drop to 18-25°C after complete hydrolysis;

Step 4: Add 0.8-1.2 kg of dichloromethane to the system, stir for 1 hour, let stand to separate the liquids, then extract twice with an equal amount of dichloromethane, and add 0.5-0.8 kg of anhydrous sodium sulfate to the combined extract , stirring and drying, rotary evaporation, recovery of dichloromethane, that is.

The present invention is also characterized in that, further, in the step 3, the alkali is NaOH solution with a mass concentration of 20%.

The beneficial effects of the present invention are that the present invention first dissolves 3,4-dimethoxy-2-picoline-N-oxide with acetic acid to make 3,4-dimethoxy-2-picoline-N -Oxide is dispersed in the reaction system in a molecular state, while increasing the reaction rate, the yield of the target product is increased by 15-20%; dissolve 3,4-dimethoxy-2-methylpyridine-N-oxide with acetic acid , so that 3,4-dimethoxy-2-picoline-N-oxide is dispersed in the reaction system in a molecular state. While improving the yield, the consumption of acetic anhydride is reduced, and the cost is saved.

The dropping rate of acetic anhydride in the present invention is 50-65kg/hour, and the acylation effect can be fully exerted in this time period, and the rearrangement of the acylated product (C) can be increased to generate 2-hydroxymethyl-3,4-dimethoxy The amount of pyridine precursor 3,4-dimethoxy-2-methylpyridine acetate (D) reduces the amount of by-product 3,4-dimethoxy-2-methyl-5-methylpyridine acetate (E) Generate, increase conversion rate.

Description of drawings

In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings that need to be used in the description of the embodiments or the prior art. Obviously, the accompanying drawings in the following description are only These are some embodiments of the present invention. Those skilled in the art can also obtain other drawings based on these drawings without creative work.

Fig. 1 is a flow chart of the existing preparation method of 2-hydroxymethyl-3,4-dimethoxypyridine.

Fig. 2 is the preparation flowchart of the embodiment of the present invention.

Fig. 3 is a high performance liquid chromatogram of 2-hydroxymethyl-3,4-dimethoxypyridine prepared in Example 2 of the present invention.

Detailed ways

The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments. It should be understood that the examples are only used to illustrate the present invention, but not to limit the protection scope of the present invention. In addition, it should be understood that after reading the content of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope of protection defined in the present application.

Example 1,

The preparation method of 2-hydroxymethyl-3,4-dimethoxypyridine is shown in Figure 2, and specifically carried out according to the following steps:

Step 1, add 20kg of 3,4-dimethoxy-2-methylpyridine-N-oxide into 20kg of acetic acid, heat to 75°C under mechanical stirring, and dissolve completely;

Step 2: Weigh 50kg of acetic anhydride, and slowly add it to the system of step 1 under stirring at 80°C, the dropping rate of acetic anhydride is 15kg/h; then keep warm at 85°C for 16h to obtain a reaction solution;

Step 3: Distill the reaction solution under reduced pressure at 85°C and 0.092MPa to remove 90% acetic anhydride, then lower it to room temperature (18-25°C), slowly add alkali to adjust the pH to 12-13, the alkali is 20% mass concentration NaOH, heat up to 55°C and stir to hydrolyze for 2 hours, then cool down to room temperature (18-25°C) after complete hydrolysis;

Step 4, add 1.2kg of dichloromethane to the system, stir for 1h, let stand to separate the liquid, then extract twice with dichloromethane, add 0.8kg of anhydrous sodium sulfate to the combined extract, stir and dry, rotary evaporate, and recover Dichloromethane; in reddish-brown crystals, namely 2-hydroxymethyl-3,4-dimethoxypyridine.

Example 2,

The preparation method of 2-hydroxymethyl-3,4-dimethoxypyridine is specifically carried out according to the following steps:

Step 1, add 25kg of 3,4-dimethoxy-2-picoline-N-oxide into 12.5kg of acetic acid, heat to 80°C under mechanical stirring, and dissolve completely;

Step 2: Weigh 70kg of acetic anhydride, and at 83°C, slowly add it into the system of step 1 under stirring. The drop rate of acetic anhydride is 14.8kg/hour, add it in 5h, keep it warm at 88°C for 14h, and obtain the reaction solution ;

Step 3: Distill the reaction solution under reduced pressure at 85°C and 0.092MPa to distill 85% acetic anhydride, then lower it to room temperature (18-25°C), slowly add alkali to adjust the pH to 12-13, the alkali is 20% mass concentration NaOH solution, heated up to 50°C, stirred and hydrolyzed for 2 hours, and cooled to room temperature (18-25°C) after complete hydrolysis;

Step 4, add 1 kg of dichloromethane to the system, stir for 1 h, let stand to separate the liquid, then extract 2 times with dichloromethane, add 0.7 kg of anhydrous sodium sulfate to the combined extract, stir and dry, rotary evaporate, and recover two Chloromethane, in reddish-brown crystals, that is, 2-hydroxymethyl-3,4-dimethoxypyridine.

Example 3,

The preparation method of 2-hydroxymethyl-3,4-dimethoxypyridine is specifically carried out according to the following steps:

Step 1, add 30kg of 3,4-dimethoxy-2-methylpyridine-N-oxide into 10kg of acetic acid, heat to 85°C under mechanical stirring, and dissolve completely;

Step 2, weighing 75kg of acetic anhydride, at 85°C, slowly adding to the system of step 1 under stirring, the dripping rate of acetic anhydride is 10kg/h;

Step 3: Distill the reaction solution under reduced pressure at 90°C and 0.092MPa to distill 80% acetic anhydride, then lower it to room temperature (18-25°C), slowly add alkali to adjust the pH to 12-13, and the alkali is 20% mass concentration NaOH, heat up to 45°C and stir for 2 hours to hydrolyze, then cool down to room temperature (18-25°C) after complete hydrolysis;

Step 4, add 0.8 kg of dichloromethane to the system, stir for 1 h, let stand to separate the liquid, then extract twice with dichloromethane, add 0.5 kg of anhydrous sodium sulfate to the combined extract, stir and dry, rotary evaporate, and recover Dichloromethane; in reddish-brown crystals, namely 2-hydroxymethyl-3,4-dimethoxypyridine.

The reaction principle of generating 2-hydroxymethyl-3,4-dimethoxypyridine precursor 3,4-dimethoxy-2-acetate methyl pyridine (D):

The present invention first dissolves 3,4-dimethoxy-2-picoline-N-oxide with acetic acid, so that 3,4-dimethoxy-2-picoline-N-oxide is dispersed in molecular state In the reaction system, while increasing the reaction rate, the yield of the target product is increased by 15-20%.

Acetic acid (HAc) reacts with the NaOH remaining in the B5 (2-methyl-3-methoxy-4-chloropyridine-N-oxide) raw material in the previous process to generate acetyl CH ₃ CO ^- (or denoted as Ac ^- ), and acetyl CH ₃ CO ^- reacts with 3,4-dimethoxy-2-methylpyridine-N-oxide (A) to generate 3,4-dimethoxy-2-methyl- Acetylpyridine-N-oxide (B), and the further reaction with (B) acylation to generate (C) has a promoting effect; acetic acid (HAc) is conducive to the rearrangement of acylated product (C) to generate 2-hydroxymethyl- 3,4-dimethoxypyridine precursor 3,4-dimethoxy-2-acetate methylpyridine (D), can also inhibit the by-product 3,4-dimethoxy-2-methyl - Formation of 5-methylpyridine acetate (E).

If acetic anhydride is added dropwise too quickly or directly into the reaction system, the acylation rate is less than the decomposition rate, which is unfavorable for the carrying out of the esterification reaction; Can give full play to the acylation effect, increase the rearrangement of the acylated product (C) to generate 2-hydroxymethyl-3,4-dimethoxypyridine precursor 3,4-dimethoxy-2-acetate methyl pyridine ( D) amount, reduce the generation of by-product 3,4-dimethoxy-2-methyl-5-methylpyridine acetate (E), and improve the conversion rate.

According to the reaction principle, the consumption ratio of acetic anhydride and 3,4-dimethoxy-2-methylpyridine-N-oxide compound should be 1:1, and acetic anhydride of the present invention and 3,4-dimethoxy-2 -The mass ratio of picoline-N-oxide is 2 to 3:1, which is significantly lower than the ratio of 5 to 8:1 in the prior art, and 3,4-dimethoxy-2-picoline is dissolved with acetic acid -N-oxide, so that 3,4-dimethoxy-2-methylpyridine-N-oxide is dispersed in the reaction system in a molecular state. Under this condition, the acylation reaction ability is enhanced, and the acetic anhydride can be fully utilized Acylation improves the yield while reducing the consumption of acetic anhydride and saving costs.

In step 3 of the present invention, after distilling the acetic anhydride out of the reaction solution under reduced pressure, lower it to room temperature (18-25° C.), slowly add alkali to adjust the pH to 12-13, heat up and stir for 2 hours to hydrolyze and then lower it to room temperature; Acetic anhydride is distilled and recycled for continued use, reducing the consumption of acetic anhydride and reducing costs. Add alkali after cooling down to room temperature because there will be residual acetic anhydride, because the water in the lye will hydrolyze with unreacted acetic anhydride to generate acetic acid, and the reaction between acetic acid and sodium hydroxide is a violent and exothermic reaction If the temperature is not lowered or the concentration of lye is too high, safety accidents will easily occur. If the concentration of lye is too low, the amount of lye cannot be increased, which will bring difficulties to subsequent processing. Therefore, the alkali adopts a NaOH solution with a mass concentration of 20%. In the reaction process of the present invention, an intermediate product C will be generated, and C will be hydrolyzed under alkaline conditions and a temperature of 50° C. to obtain the product 2-hydroxymethyl-3,4-dimethoxypyridine. If the pH is too high or too low, it cannot Very good hydrolysis into products reduces the yield of products, so adjust the pH to 12-13.

The 2-hydroxymethyl-3,4-dimethoxypyridine prepared in Example 2 has a yield of 95.6% by weight, and the purity is shown in the high-performance liquid chromatogram, and the purity is 94.95%, as shown in Figure 3. The corresponding parameters of each peak in the phase chromatogram are shown in Table 1.

Table 1 The parameters corresponding to the peaks of the high performance liquid chromatography of 2-hydroxymethyl-3,4-dimethoxypyridine prepared by the present invention

peak number Retention time/min Peak width/min Peak area/mAU×s Peak height/mAU Peak Area % 1 1.732 0.0734 33.12424 6.50594 1.9916 2 2.810 0.0912 1579.15222 251.79262 94.9464 3 5.534 0.1320 50.92773 5.94121 3.0620

According to Figure 3 and Table 1, it can be seen that the 2-hydroxymethyl-3,4-dimethoxypyridine prepared in Example 2 has a higher purity and meets the requirements for production and use; 2-chloromethyl-3,4-dimethyl Oxypyridine hydrochloride is one of the two intermediates in the synthesis of Pandoprazole, and 2-hydroxymethyl-3,4-dimethoxypyridine is the synthesis of 2-chloromethyl-3,4-dimethoxypyridine An important intermediate of hydrochloride; the purity of 2-hydroxymethyl-3,4-dimethoxypyridine is relatively high, thereby improving the synthesis of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride Purity and productive rate, further speaking, finally influence the purity and the yield of pandoprazole.

comparative example,

Add 25kg of 3,4-dimethoxy-2-methylpyridine-N-oxide into the reaction kettle, then add 70kg of acetic anhydride, and dissolve it completely under mechanical stirring; then slowly raise the temperature to 88°C for 6- After 9h, the reaction solution was obtained; after the reaction solution was distilled off 85% acetic anhydride under reduced pressure at 85°C and 0.092MPa, it was lowered to room temperature (18-25°C), stirred with 90kg of water, and slowly added NaOH with a mass concentration of 20%. pH to 12-13, then heat up to 50°C and stir for 2 hours to hydrolyze, then drop to room temperature (18-25°C) after complete hydrolysis; add 1 kg of dichloromethane to the system, stir for 1 hour, let stand to separate liquids, and then extract with dichloromethane Twice, add 0.7 kg of anhydrous sodium sulfate to the combined extracts, stir and dry, rotary evaporate, and recover dichloromethane; obtain reddish-brown crystals, namely 2-hydroxymethyl-3,4-dimethoxypyridine. The calculated yield by weighing is 75.8%, obviously less than the yield of Example 2.

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the protection scope of the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present invention are included in the protection scope of the present invention.

Claims (2)

1. a kind of preparation method of 2- methylols -3,4- dimethoxy-pyridine, which is characterized in that specifically according to following steps into Row：

Step 1, in proportion, by 20~30kg 3,4- dimethoxy -2- methylpyridine N oxides are added to 10~20kg's In acetic acid, 75~85 DEG C are heated under mechanical agitation, is completely dissolved；

Step 2, it weighs the acetic anhydride of 50~75kg, at 80~85 DEG C, is added slowly with stirring in the system of step 1, acetic acid The drop rate of acid anhydride is 10~15kg/h；Then 15~16h is kept the temperature at 85~95 DEG C, obtains reaction solution；

Step 3, after reaction solution being evaporated under reduced pressure out 80~90% acetic anhydrides under 85~90 DEG C, 0.092MPa, 18~25 are down to DEG C, slowly plus adjusting PH with base is to 12~13, and heat up 45~55 DEG C of stirring hydrolysis 2h, and 18~25 DEG C are down to after hydrolysis completely；

Step 4, add methylene chloride 0.8~1.2kg into system, stirs 1h, stands liquid separation, then extracted respectively with equivalent dichloromethane Take 2 times, into the extract liquor of merging plus 0.5~0.8kg of anhydrous sodium sulfate, stir drying, revolving, recycling dichloromethane to get.

2. a kind of preparation method of 2- methylols -3,4- dimethoxy-pyridine according to claim 1, which is characterized in that In the step 3, alkali is the NaOH solution of mass concentration 20%.