CN116239519A - A kind of synthetic method of (2-benzyloxy-4,6-dimethylpyridin-3-yl)methanol - Google Patents

Abstract

The invention discloses a synthesis method of (2-benzyloxy-4,6-dimethylpyridin-3-yl)methanol, which relates to the technical field of organic synthesis. The invention uses 4,6-dimethyl-2- Hydroxynicotinonitrile is used as a starting material, after chlorination, reacts with benzyl alcohol to introduce benzyloxy, and then synthesizes (2-benzyloxy-4,6-lutidine-3-yl ) methanol; the synthesis method has mild reaction conditions, does not use expensive catalysts, does not use explosive reducing agents, and has simple post-treatment, high product yield and purity, and is suitable for industrial production.

Description

A method for synthesizing (2-benzyloxy-4,6-dimethylpyridin-3-yl)methanol

Technical field:

The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing (2-benzyloxy-4,6-dimethylpyridin-3-yl)methanol.

Background technology:

(2-Benzyloxy-4,6-dimethylpyridin-3-yl)methanol is an important pharmaceutical intermediate that can be used for the synthesis of ZESTE enhancer homolog 2 inhibitor. EZH2 (human EZH2 gene: Cardoso, C, et al.; European J of Human Genetics, Vol. 8, No. 3, pp. 174-180, 2000) is the catalytic subunit of Polycomb Repressor Complex 2 (PRC2), which functions to silence target genes by trimethylating lysine 27 of histone H3 (H3K27me3). Histone H3 is one of the five major histones involved in the chromatin structure of eukaryotic cells. Histones characterized by a major globular domain and a long N-terminal tail are involved in the nucleosome structure, i.e., the "beaded" structure. Although histones are highly post-translationally modified, histone H3 is the most extensively modified of the five histones. The term "histone H3" alone is intentionally vague as it does not distinguish between sequence variants or modification states. Histone H3 is an important protein in the emerging field of epigenetics, where sequence variants and variable modification states are thought to play a role in the dynamic and long-term regulation of genes.

The inhibitor shown in formula I can be used to treat cancer, including solid tumors, such as brain cancer (glioma), glioblastoma, leukemia, lymphoma, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos, breast cancer, inflammatory breast cancer, Wilms' tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, gastric cancer, bladder cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, renal cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone and thyroid cancer. (2-Benzyloxy-4,6-dimethylpyridin-3-yl)methanol is an important intermediate for the synthesis of the inhibitor. The synthesis method disclosed in patent CN 107849032A requires the use of precious metal silver carbonate as a base to introduce benzyl, and DIBAL-H (diisobutylaluminum hydride) is used as a reducing agent to convert cyano into aldehyde. However, DIBAL-H is not only prone to explosion, but also produces a large amount of floccules during post-processing, which is difficult to filter and post-process. Therefore, it is particularly important to develop a new method for synthesizing (2-benzyloxy-4,6-dimethylpyridin-3-yl)methanol.

Summary of the invention:

The technical problem to be solved by the present invention is to provide a method for synthesizing (2-benzyloxy-4,6-dimethylpyridin-3-yl)methanol. The method has mild reaction conditions, does not use expensive catalysts, does not use explosive reducing agents, is simple in post-processing, and has high product yield and purity.

The technical problem to be solved by the present invention is achieved by adopting the following technical solutions:

The first object of the present invention is to provide a method for synthesizing (2-benzyloxy-4,6-dimethylpyridin-3-yl)methanol, wherein 4,6-dimethyl-2-hydroxynicotinonitrile and a chlorination reagent are subjected to a chlorination reaction to prepare an intermediate A1, and then the intermediate A1 and benzyl alcohol are subjected to a substitution reaction to prepare an intermediate A2, and then the intermediate A2 is subjected to a hydrolysis reaction to prepare an intermediate A3, and finally the intermediate A3 is subjected to a reduction reaction to prepare (2-benzyloxy-4,6-dimethylpyridin-3-yl)methanol.

The synthetic route is as follows:

合成中的应用。其中，R₁、R₂选自H、烷基、烷氧基、杂烷基、环烷基、芳香基、杂芳香基等取代基中的一种(只要R₁、R₂取代基不参与该合成方法所涉及的反应即可，因此包括但不限于这些列举出的取代基)，R₁与R₂相同或不同。The second object of the present invention is to provide the aforementioned synthesis method in compound

Application in synthesis. Wherein, R ₁ and R ₂ are selected from one of H, alkyl, alkoxy, heteroalkyl, cycloalkyl, aromatic, heteroaromatic and other substituents (as long as R ₁ and R ₂ substituents do not participate in the reaction involved in the synthesis method, thus including but not limited to these listed substituents), and R ₁ and R ₂ are the same or different.

的合成方法，先由化合物

与氯化试剂发生氯化反应制备中间体B1，再由中间体B1与苯甲醇发生取代反应制备中间体B2，然后中间体B2经水解反应制备中间体B3，最后中间体B3经还原反应制备化合物

The third object of the present invention is to provide a compound

The synthesis method comprises firstly preparing a compound

The intermediate B1 is prepared by a chlorination reaction with a chlorination reagent, and then the intermediate B1 is substituted with benzyl alcohol to prepare the intermediate B2, and then the intermediate B2 is hydrolyzed to prepare the intermediate B3, and finally the intermediate B3 is reduced to prepare the compound

The synthetic route is as follows:

The invention has the following beneficial effects: 4,6-dimethyl-2-hydroxynicotinamide is used as a starting material, chlorinated and reacted with benzyl alcohol to introduce a benzyloxy group, and then (2-benzyloxy-4,6-dimethylpyridin-3-yl)methanol is synthesized through a hydrolysis reaction and a reduction reaction in sequence; the synthesis method has mild reaction conditions, does not use expensive catalysts, does not use explosive reducing agents, and is simple in post-processing, has high product yield and purity, and is suitable for industrial production.

Description of the drawings:

FIG1 is a hydrogen NMR spectrum of the product (2-benzyloxy-4,6-dimethylpyridin-3-yl)methanol in Example 4;

FIG2 is the LCMS spectrum of the product (2-benzyloxy-4,6-dimethylpyridin-3-yl)methanol in Example 4.

Specific implementation method:

In order to make the technical means, creative features, objectives and effects achieved by the present invention easy to understand, the present invention is further described below in conjunction with specific embodiments and diagrams.

The invention provides a method for synthesizing (2-benzyloxy-4,6-dimethylpyridin-3-yl)methanol. The method comprises the following steps: firstly, 4,6-dimethyl-2-hydroxynicotinonitrile and a chlorination reagent undergo a chlorination reaction to prepare an intermediate A1, then the intermediate A1 undergoes a substitution reaction with benzyl alcohol to prepare an intermediate A2, then the intermediate A2 undergoes a hydrolysis reaction to prepare an intermediate A3, and finally the intermediate A3 undergoes a reduction reaction to prepare the (2-benzyloxy-4,6-dimethylpyridin-3-yl)methanol.

The synthetic route is as follows:

Preferably, the chlorination agent is at least one of phosphorus oxychloride and thionyl chloride, more preferably phosphorus oxychloride.

Preferably, the molar ratio of the 4,6-dimethyl-2-hydroxynicotinamide to the chlorination reagent is 1:(2-4), more preferably 1:2.

Preferably, the molar ratio of the intermediate A1 to benzyl alcohol is 1:(1.1-1.5), more preferably 1:1.2.

Preferably, the substitution reaction is carried out under alkaline conditions, and the base is at least one of potassium tert-butoxide, sodium hydroxide, and potassium hydroxide, and more preferably potassium tert-butoxide.

Preferably, the hydrolysis reaction uses NaOH as the hydrolysis system.

Preferably, the reduction reaction uses at least one of sodium borohydride and potassium borohydride as a reducing agent, and sodium borohydride is more preferably used.

合成中的应用。其中，R₁、R₂选自H、烷基、烷氧基、杂烷基、环烷基、芳香基、杂芳香基等取代基中的一种(只要R₁、R₂取代基不参与该合成方法所涉及的反应即可，因此包括但不限于这些列举出的取代基)，R₁与R₂相同或不同。The present invention also provides the above-mentioned synthesis method in compound

Application in synthesis. Wherein, R ₁ and R ₂ are selected from one of H, alkyl, alkoxy, heteroalkyl, cycloalkyl, aromatic, heteroaromatic and other substituents (as long as R ₁ and R ₂ substituents do not participate in the reaction involved in the synthesis method, thus including but not limited to these listed substituents), and R ₁ and R ₂ are the same or different.

的合成方法，先由化合物

与氯化试剂发生氯化反应制备中间体B1，再由中间体B1与苯甲醇发生取代反应制备中间体B2，然后中间体B2经水解反应制备中间体B3，最后中间体B3经还原反应制备化合物

The present invention also provides a compound as described above

The synthesis method comprises firstly preparing a compound

The intermediate B1 is prepared by a chlorination reaction with a chlorination reagent, and then the intermediate B1 is substituted with benzyl alcohol to prepare the intermediate B2, and then the intermediate B2 is hydrolyzed to prepare the intermediate B3, and finally the intermediate B3 is reduced to prepare the compound

The synthetic route is as follows:

The reaction conditions are the same as those of the above-mentioned synthesis method of (2-benzyloxy-4,6-dimethylpyridin-3-yl)methanol.

Example 1

Preparation of intermediate A1:

4,6-dimethyl-2-hydroxynicotinonitrile (1.2 kg, 8 mol) was dissolved in POCl ₃ (2.4 L), and the temperature was raised to 120°C for reaction for 12 h; the reaction was stopped, the reaction solution was cooled to room temperature, and then the reaction solution was slowly poured into ice water for quenching, filtered, the filter cake was washed with water, and dried to obtain intermediate A1. The HPLC purity was 99.9%, and the yield was 88%.

Example 2

Preparation of intermediate A1:

4,6-dimethyl-2-hydroxynicotinonitrile (1.2 kg, 8 mol) was dissolved in POCl ₃ (2.4 L), and the temperature was raised to 120°C for reaction for 12 h; the reaction was stopped, the reaction solution was cooled to room temperature, and then the reaction solution was slowly poured into ice water for quenching, filtered, the filter cake was washed with water, and dried to obtain intermediate A1. The HPLC purity was 99.9%, and the yield was 89%.

Example 3

Preparation of intermediate A2:

The intermediate A1 (2.3 kg, 13.85 mol), benzyl alcohol (2.6 L) and acetonitrile (11.5 L) were mixed, and then potassium tert-butoxide (2.6 L) was slowly added at low temperature, and the temperature was raised to 80°C for reaction for 12 hours after the addition was completed; the reaction was stopped, the reaction solution was cooled to room temperature, filtered, the filter cake was washed with acetonitrile, the acetonitrile in the filtrate was removed by rotary evaporation, methanol was added for pulping, filtered, the filter cake was washed with methanol, and dried to obtain the intermediate A2. The HPLC purity was 98.4%, and the yield was 69%.

Example 4

Preparation of intermediate A2:

The intermediate A1 (2.3 kg, 13.85 mol), benzyl alcohol (2.6 L) and acetonitrile (11.5 L) were mixed, and then sodium hydroxide (2.6 L) was slowly added at low temperature, and the temperature was raised to 80°C for reaction for 12 hours after the addition was completed; the reaction was stopped, the reaction solution was cooled to room temperature, filtered, the filter cake was washed with acetonitrile, the acetonitrile in the filtrate was removed by rotary evaporation, methanol was added for pulping, filtered, the filter cake was washed with methanol, and dried to obtain the intermediate A2. The HPLC purity was 98.0%, and the yield was 66%.

Example 5

Preparation of intermediate A3:

Weigh the intermediate A2 (23.8 g, 0.1 mol), 20% NaOH aqueous solution (148 mL), and add a mixed solvent (400 mL) of methanol and dimethyl sulfoxide in a volume ratio of 1:1, slowly add 30% hydrogen peroxide solution (27 mL) at room temperature, and continue to react at room temperature for 2 h after the addition is complete; stop the reaction, remove part of the solvent under reduced pressure, add ice water and stir to precipitate solids, filter, and dry to obtain intermediate A3. HPLC purity is 98.5%, and the yield is 94%.

Example 6

Preparation of intermediate A3:

Weigh the intermediate A2 (23.8 g, 0.1 mol), 20% NaOH aqueous solution (148 mL), and add a mixed solvent (400 mL) of methanol and dimethyl sulfoxide in a volume ratio of 1:1, slowly add 30% hydrogen peroxide solution (27 mL) at room temperature, and continue to react at room temperature for 2 h after the addition is complete; stop the reaction, remove part of the solvent under reduced pressure, add ice water and stir to precipitate solids, filter, and dry to obtain the intermediate A3. The HPLC purity is 98.8%, and the yield is 96%.

Example 7

Preparation of (2-benzyloxy-4,6-dimethylpyridin-3-yl)methanol:

Add intermediate A3 (10 g, 0.041 mol), sodium borohydride (2.38 g, 0.06 mol) and tetrahydrofuran (50 L) into the reaction kettle, replace _{with N2} , fill with _H2 , and then heat to 110°C for 48 h; stop the reaction, add saturated ammonium chloride solution to the reaction solution to quench the reaction, remove tetrahydrofuran by rotary evaporation, add dichloromethane and water for extraction, take the organic phase, and spin dry to obtain (2-benzyloxy-4,6-dimethylpyridin-3-yl)methanol with HPLC purity of 99.5% and yield of 100%.

Example 8

Preparation of (2-benzyloxy-4,6-dimethylpyridin-3-yl)methanol:

Add intermediate A3 (10 g, 0.041 mol), sodium borohydride (2.38 g, 0.06 mol) and tetrahydrofuran (50 L) into the reaction kettle, replace _{with N2} , fill with _H2 , and then heat to 110°C for 48 h; stop the reaction, add saturated ammonium chloride solution to the reaction solution to quench the reaction, remove tetrahydrofuran by rotary evaporation, add dichloromethane and water for extraction, take the organic phase, and spin dry to obtain (2-benzyloxy-4,6-dimethylpyridin-3-yl)methanol with HPLC purity of 99.5% and yield of 99%.

According to Examples 3 and 4, the yield of synthesizing intermediate A2 from intermediate A1 is low. Although potassium tert-butoxide is used as an acid-binding agent to promote the forward progress of the reaction, other catalysts still need to be added to increase the yield of intermediate A2, otherwise the utilization rate of intermediate A1 is not high.

The present invention also provides another method for synthesizing (2-benzyloxy-4,6-dimethylpyridin-3-yl)methanol, wherein 4,6-dimethyl-2-hydroxynicotinonitrile and a chlorination reagent are subjected to a chlorination reaction to prepare an intermediate A1, and then the intermediate A1 and benzyl alcohol are subjected to a substitution reaction to prepare an intermediate A2, and then the intermediate A2 is subjected to a hydrolysis reaction to prepare an intermediate A3, and finally the intermediate A3 is subjected to a reduction reaction to prepare (2-benzyloxy-4,6-dimethylpyridin-3-yl)methanol.

Preferably, the substitution reaction is carried out under alkaline conditions in the presence of nickel cobalt oxide, and the base is at least one of potassium tert-butoxide, sodium hydroxide, and potassium hydroxide, and more preferably potassium tert-butoxide.

Preferably, the amount of the nickel-cobalt oxide is 0.05-0.1% of the mass of the intermediate A1, and more preferably 0.1%.

The remaining reaction conditions were the same as above.

Example 9

Preparation of intermediate A2:

The intermediate A1 (2.3 kg, 13.85 mol), benzyl alcohol (2.6 L) and acetonitrile 11.5 L were mixed, and then 2.6 L of potassium tert-butoxide and nickel cobalt oxide (1.15 g) were slowly added at low temperature, and the temperature was raised to 80°C for reaction for 12 hours after the addition was completed; the reaction was stopped, the reaction solution was cooled to room temperature, filtered, the filter cake was washed with water and acetonitrile in turn, the acetonitrile in the filtrate was removed by rotary evaporation, methanol was added for pulping, filtered, the filter cake was washed with methanol, and dried to obtain the intermediate A2. The HPLC purity was 99.1%, and the yield was 82%.

Example 10

Preparation of intermediate A2:

The intermediate A1 (2.3 kg, 13.85 mol), benzyl alcohol (2.6 L) and acetonitrile 11.5 L were mixed, and then 2.6 L of potassium tert-butoxide and nickel cobalt oxide (2.3 g) were slowly added at low temperature, and the temperature was raised to 80°C for reaction for 12 hours after the addition was completed; the reaction was stopped, the reaction solution was cooled to room temperature, filtered, the filter cake was washed with water and acetonitrile in turn, the acetonitrile in the filtrate was removed by rotary evaporation, methanol was added for pulping, filtered, the filter cake was washed with methanol, and dried to obtain the intermediate A2. The HPLC purity was 99.3%, and the yield was 89%.

The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited to the above embodiments. The above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims (10)

1. A method for synthesizing (2-benzyloxy-4, 6-dimethylpyridine-3-yl) methanol is characterized in that: firstly, 4, 6-dimethyl-2-hydroxy nicotinonitrile and a chlorinating agent undergo a chlorination reaction to prepare an intermediate A1, then the intermediate A1 and benzyl alcohol undergo a substitution reaction to prepare an intermediate A2, then the intermediate A2 undergoes a hydrolysis reaction to prepare an intermediate A3, and finally the intermediate A3 undergoes a reduction reaction to prepare (2-benzyloxy-4, 6-dimethylpyridine-3-yl) methanol;

the synthetic route is as follows:

2. the synthesis method according to claim 1, wherein: the chlorinating agent is at least one of phosphorus oxychloride and thionyl chloride, and more preferably phosphorus oxychloride.

3. The synthesis method according to claim 1, wherein: the molar ratio of the 4, 6-dimethyl-2-hydroxy nicotinonitrile to the chlorinating agent is 1 (2-4), more preferably 1:2.

4. The synthesis method according to claim 1, wherein: the molar ratio of the intermediate A1 to benzyl alcohol is 1 (1.1-1.5), and more preferably 1:1.2.

5. The synthesis method according to claim 1, wherein: the substitution reaction is carried out under alkaline conditions, and the alkali is at least one of potassium tert-butoxide, sodium hydroxide and potassium hydroxide, and more preferably potassium tert-butoxide.

6. The synthesis method according to claim 1, wherein: the hydrolysis reaction adopts NaOH as a hydrolysis system.

7. The synthesis method according to claim 1, wherein: the reduction reaction uses at least one of sodium borohydride and potassium borohydride as a reducing agent, and sodium borohydride is further preferable.

8. The method of any one of claims 1-7 in a compound

Application in synthesis.

9. According toThe use according to claim 8, characterized in that: r is R ₁ 、R ₂ Selected from one of H, alkyl, alkoxy, heteroalkyl, cycloalkyl, aryl, heteroaryl, R ₁ And R is R ₂ The same or different.

10. A compound as claimed in claim 8 or 9

The synthesis method of (2) is characterized in that: first from the compound->

The intermediate B1 is prepared by chlorination reaction with a chlorinating reagent, the intermediate B2 is prepared by substitution reaction of the intermediate B1 and benzyl alcohol, the intermediate B3 is prepared by hydrolysis reaction of the intermediate B2, and the compound->

The synthetic route is as follows:

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