A kind of synthesis method of 3-(6-methoxy-2-pyridine)-propionic acid

Abstract

The present invention belongs to the field of pharmaceutical synthesis, and specifically relates to a method for synthesizing 3-(6-methoxy-2-pyridine)-propionic acid. The method comprises the following steps: 6-methoxy-2-pyridinemethanol reacts with p-toluenesulfonyl chloride to obtain a p-toluenesulfonate intermediate, and then the p-toluenesulfonate intermediate reacts with a bromide salt to obtain 2-(bromomethyl)-6-methoxypyridine; 2-(bromomethyl)-6-methoxypyridine reacts with diethyl malonate under the action of a base to generate 3-(6-methoxy-2-pyridylmethyl)-diethyl malonate, and 3-(6-methoxy-2-pyridylmethyl)-diethyl malonate is hydrolyzed and decarboxylated to obtain 3-(6-methoxy-2-pyridine)-propionic acid. The invention uses 6-methoxy-2-pyridinemethanol as a starting material, and performs hydrolysis and decarboxylation after three-step substitution reaction to obtain 3-(6-methoxy-2-pyridine)-propionic acid. The method has the advantages of fewer reaction steps, economical and cheap reagents, mild reaction conditions and high product purity, and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical synthesis, and specifically relates to a method for synthesizing 3-(6-methoxy-2-pyridine)-propionic acid. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] 3-(6-Methoxy-2-pyridine)-propionic acid can be used as a pharmaceutical intermediate for the synthesis of pyridine and To11-like receptor inhibitor drugs (CN114591339B). The current synthesis method of 3-(6-methoxy-2-pyridine)-propionic acid mainly uses 6-methoxypyridine-2-carboxaldehyde as a raw material, and undergoes a Witting reaction with phosphorus ylide to obtain substituted pyridyl ethyl acrylate, which is then subjected to Pd / C-H2 hydrogenation reduction and then hydrolysis to obtain (Angew. Chem. Int. Ed., 2019, 58, 18513-18518). The problems with this route are: 1. The Witting reagent is expensive, which increases the production cost; 2. The reaction produces a large amount of triphenylphosphine, which increases the difficulty of product purification and post-treatment. In addition, triphenylphosphine has a large molecular weight, and its removal as waste does not conform to the principle of atom economy; 3. The reduction of double bonds requires the use of expensive Pd / C as a catalyst, which is not conducive to cost control, and the flammable and explosive nature of the reducing agent hydrogen also increases the safety risks of the production process. Summary of the invention

[0004] In order to solve the deficiencies of the prior art, the purpose of the present invention is to provide a method for synthesizing 3-(6-methoxy-2-pyridine)-propionic acid. The present invention uses 6-methoxy-2-pyridinemethanol as a starting material, and hydrolyzes and decarboxylates the 3-(6-methoxy-2-pyridine)-propionic acid after three-step substitution reaction. The method has the advantages of fewer reaction steps, economical and cheap reagents, mild reaction conditions, and high product purity, and is suitable for industrial production.

[0005] In order to achieve the above object, the present invention is implemented through the following technical solutions:

[0006] In a first aspect, a method for synthesizing 3-(6-methoxy-2-pyridine)-propionic acid comprises the following steps:

[0007]

[0008] S1, 6-methoxy-2-pyridinemethanol and p-toluenesulfonyl chloride react to obtain a p-toluenesulfonate intermediate, and then the p-toluenesulfonate intermediate reacts with a bromide salt to obtain 2-(bromomethyl)-6-methoxypyridine;

[0009] S2. 2-(Bromomethyl)-6-methoxypyridine reacts with diethyl malonate in the presence of a base to generate 3-(6-methoxy-2-pyridylmethyl)-diethyl malonate. 3-(6-methoxy-2-pyridylmethyl)-diethyl malonate is hydrolyzed and decarboxylated to obtain 3-(6-methoxy-2-pyridine)-propionic acid.

[0010] Preferably, in step S1, triethylamine is used as a base in the reaction between 6-methoxy-2-pyridinemethanol and p-toluenesulfonyl chloride, and the molar ratio of 6-methoxy-2-pyridinemethanol, triethylamine and p-toluenesulfonyl chloride is 1:(0.9-1.1):(0.9-1.1).

[0011] Preferably, in step S1, the reaction temperature of 6-methoxy-2-pyridinemethanol and p-toluenesulfonyl chloride is 27-30° C. and the reaction time is 5-7 h.

[0012] Preferably, in step S1, the bromide salt includes at least one of sodium bromide, potassium bromide and lithium bromide.

[0013] Preferably, in step S1, the molar ratio of 6-methoxy-2-pyridinemethanol to bromide salt is 1:(1-2.5).

[0014] Preferably, in step S1, acetone is used as a solvent when the p-toluenesulfonate intermediate and the bromide salt are reacted, and the reaction is heated under reflux for 7 to 9 hours.

[0015] Preferably, in step S2, the base includes at least one of sodium methoxide, sodium ethoxide, sodium hydroxide, potassium tert-butoxide and sodium tert-butoxide.

[0016] Preferably, in step S2, the molar ratio of 6-methoxy-2-pyridinemethanol to the base and diethyl malonate is 1:(1.5-2.5):(0.9-1.1).

[0017] Preferably, in step S2, the temperature for reacting 2-(bromomethyl)-6-methoxypyridine with diethyl malonate in the presence of a base is 15 to 30° C. and the time is 10 to 14 h.

[0018] Preferably, in step S2, the reaction temperature of the hydrolysis is 40-80° C., and the reaction time is 3-5 h.

[0019] The beneficial effects achieved by one or more technical solutions of the present invention are as follows:

[0020] The invention uses 6-methoxy-2-pyridinemethanol as a starting material, sequentially reacts with p-toluenesulfonyl chloride, bromide salt and diethyl malonate to undergo nucleophilic substitution reaction, and the obtained intermediate undergoes hydrolysis and decarboxylation to obtain 3-(6-methoxy-2-pyridine)-propionic acid. Each step of the reaction can be carried out under normal pressure, the reaction conditions are mild, and no high-cost catalysts and reagents are required.

[0021] The total yield of 3-(6-methoxy-2-pyridine)-propionic acid obtained by the synthesis method of the invention is higher than 50%, and no by-products that are difficult to separate are generated during the reaction process, which is conducive to obtaining a high-purity product. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0023] Figure 1 The present invention provides a hydrogen nuclear magnetic spectrum of 3-(6-methoxy-2-pyridine)-propionic acid synthesized by the present invention. DETAILED DESCRIPTION

[0024] The existing synthesis route of 3-(6-methoxy-2-pyridine)-propionic acid requires the use of expensive Witting reagent and Pd / C catalyst. The by-product triphenylphosphine oxide is difficult to separate, and the flammable and explosive nature of hydrogen during the reaction increases safety risks.

[0025] To solve the above technical problems, a first typical embodiment of the present invention provides a method for synthesizing 3-(6-methoxy-2-pyridine)-propionic acid, comprising the following steps:

[0026]

[0027] S1, 6-methoxy-2-pyridinemethanol and p-toluenesulfonyl chloride react to obtain a p-toluenesulfonate intermediate, and then the p-toluenesulfonate intermediate reacts with a bromide salt to obtain 2-(bromomethyl)-6-methoxypyridine;

[0028] S2. 2-(Bromomethyl)-6-methoxypyridine reacts with diethyl malonate in the presence of a base to generate 3-(6-methoxy-2-pyridylmethyl)-diethyl malonate. 3-(6-methoxy-2-pyridylmethyl)-diethyl malonate is hydrolyzed and decarboxylated to obtain 3-(6-methoxy-2-pyridine)-propionic acid.

[0029] In one or more examples of this embodiment, in step S1, triethylamine is used as a base in the reaction of 6-methoxy-2-pyridinemethanol and p-toluenesulfonyl chloride, and the molar ratio of 6-methoxy-2-pyridinemethanol, triethylamine and p-toluenesulfonyl chloride is 1:(0.9~1.1):(0.9~1.1).

[0030] In one or more examples of this embodiment, in step S1, the temperature for the reaction of 6-methoxy-2-pyridinemethanol and p-toluenesulfonyl chloride is 27-30° C., and the reaction time is 5-7 hours.

[0031] In one or more examples of this embodiment, in step S1, the bromide salt includes at least one of sodium bromide, potassium bromide and lithium bromide.

[0032] In one or more examples of this embodiment, in step S1, the molar ratio of 6-methoxy-2-pyridinemethanol to the bromide salt is 1:(1-2.5).

[0033] In one or more examples of this embodiment, in step S1, acetone is used as a solvent during the reaction of the mesylate intermediate and the bromide salt, and the reaction is heated under reflux for 7 to 9 hours.

[0034] In one or more examples of this embodiment, in step S2, the base includes at least one of sodium methoxide, sodium ethoxide, sodium hydroxide, potassium tert-butoxide and sodium tert-butoxide.

[0035] In one or more examples of this embodiment, in step S2, the molar ratio of 6-methoxy-2-pyridinemethanol to the base is 1:(1.5-2.5).

[0036] In one or more examples of this embodiment, in step S2, the temperature of the reaction of 2-(bromomethyl)-6-methoxypyridine with diethyl malonate in the presence of a base is 15 to 30° C. and the time is 10 to 14 hours.

[0037] In one or more examples of this embodiment, in step S2, the reaction temperature of hydrolysis is 40 to 80° C., and the reaction time is 3 to 5 hours.

[0038] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in combination with specific embodiments and comparative examples.

[0039] Example 1

[0040] 700 mL of dichloromethane, 6-methoxy-2-pyridinemethanol (139 g, 1.0 mol) and triethylamine (101 g, 1.0 mol) were mixed to form a reaction system, and p-toluenesulfonyl chloride (190 g, 1.0 mol) was slowly added to the reaction system at 0°C, and the addition was completed, and the mixture was rapidly stirred at 27°C for 6 hours. After the reaction was completed, 500 mL of cold water was added to the reaction system, and after extraction and separation, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a mesylate intermediate.

[0041] The obtained mesylate intermediate was dissolved in 700 mL of acetone, solid lithium bromide (174 g, 2.0 mol) was added, and the mixture was heated under reflux for 8 h. After the reaction was completed, the acetone solvent was removed by distillation under reduced pressure, 600 mL of dichloromethane and 400 mL of water were added for extraction and separation, the organic phase was collected, and the solvent was removed by distillation under reduced pressure to obtain a crude product of 2-(bromomethyl)-6-methoxypyridine.

[0042] At 0°C, diethyl malonate (176 g, 1.1 mol) was added to 600 mL of ethanol, and then sodium hydroxide (80 g, 2.0 mol) was slowly added to the solution, stirred for 15 min, and the above-obtained 2-(bromomethyl)-6-methoxypyridine was slowly added in batches, and reacted at room temperature for 12 h. At 0°C, 200 mL of ice water was added to the reaction system, the temperature was raised to 60°C and stirred for 4 h, and the reaction was subjected to hydrolysis and decarboxylation, and the ethanol was removed by rotary evaporation. The pH was adjusted to 6-7 with a 3M AcOH aqueous solution, and 300 mL of dichloromethane was added, and the liquid was extracted. The organic phase collected, the solvent was removed by reduced pressure distillation, and the crude product was recrystallized to obtain 110 g of 3-(6-methoxy-2-pyridine)-propionic acid, with a total yield of 61% in three steps.

[0043] The H NMR spectrum of 3-(6-methoxy-2-pyridine)-propionic acid is as follows Figure 1 As shown, 1 H NMR (500MHz, DMSO) δ12.09(s,1H),7.58(dd,J=8.2,7.3Hz,1H),6.84(d,J=7.2Hz,1H ), 6.61 (d, J = 8.2Hz, 1H), 3.82 (s, 3H), 2.91 (t, J = 7.3Hz, 2H), 2.64 (t, J = 7.3Hz, 2H).

[0044] Example 2

[0045] 700 mL of dichloromethane, 6-methoxy-2-pyridinemethanol (139 g, 1.0 mol) and triethylamine (101 g, 1.0 mol) were mixed to form a reaction system, and p-toluenesulfonyl chloride (190 g, 1.0 mol) was slowly added to the reaction system at 0°C, and the addition was completed, and the mixture was rapidly stirred at 30°C for 6 hours. After the reaction was completed, 500 mL of cold water was added to the reaction system, and after extraction and separation, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a p-toluenesulfonate intermediate.

[0046] The obtained p-toluenesulfonate intermediate was dissolved in 700 mL of acetone, solid lithium bromide (174 g, 2.0 mol) was added, and the mixture was heated under reflux for 8 h. After the reaction was completed, the acetone solvent was removed by distillation under reduced pressure, 600 mL of dichloromethane and 400 mL of water were added for extraction and separation, the organic phase was collected, and the solvent was removed by distillation under reduced pressure to obtain a crude product of 2-(bromomethyl)-6-methoxypyridine.

[0047] At 5°C, diethyl malonate (176 g, 1.1 mol) was added to 600 mL of ethanol, and then sodium ethoxide (136 g, 2.0 mol) was slowly added to the solution, stirred for 15 min, and the above-obtained 2-(bromomethyl)-6-methoxypyridine was slowly added in batches, and reacted at room temperature for 12 h. At 0°C, 200 mL of ice water was slowly added to the reaction system, the temperature was raised to 60°C and stirred for 4 h, and the reaction was subjected to hydrolysis and decarboxylation, and the ethanol was removed by rotary evaporation. The pH was adjusted to 6-7 with a 3M AcOH aqueous solution, and 300 mL of dichloromethane was added, and the liquid was extracted. The organic phase collected, the solvent was removed by reduced pressure distillation, and the crude product was recrystallized to obtain 148 g of 3-(6-methoxy-2-pyridine)-propionic acid, with a total yield of 82% in three steps.

[0048] Example 3

[0049] 700 mL of dichloromethane, 6-methoxy-2-pyridinemethanol (139 g, 1.0 mol) and triethylamine (101 g, 1.0 mol) were mixed to form a reaction system, and p-toluenesulfonyl chloride (190 g, 1.0 mol) was slowly added to the reaction system at 0°C, and the addition was completed, and the mixture was rapidly stirred at 27°C for 6 hours. After the reaction was completed, 500 mL of cold water was added to the reaction system, and after extraction and separation, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a mesylate intermediate.

[0050] The obtained mesylate intermediate was dissolved in 700 mL of acetone, solid lithium bromide (174 g, 2.0 mol) was added, and the mixture was heated under reflux for 8 h. After the reaction was completed, the acetone solvent was removed by distillation under reduced pressure, 600 mL of dichloromethane and 400 mL of water were added for extraction and separation, the organic phase was collected, and the solvent was removed by distillation under reduced pressure to obtain a crude product of 2-(bromomethyl)-6-methoxypyridine.

[0051] At 5°C, diethyl malonate (176 g, 1.1 mol) was added to 600 mL of ethanol, and potassium hydroxide (124 g, 2.0 mol) was then slowly added to the solution, stirred for 15 min, and the above-obtained 2-(bromomethyl)-6-methoxypyridine was slowly added in batches, and reacted at room temperature for 12 h. At 0°C, 200 mL of ice water was added to the reaction system, the temperature was raised to 60°C and stirred for 4 h, and the reaction was subjected to hydrolysis and decarboxylation, and the ethanol was removed by rotary evaporation. The pH was adjusted to 6-7 with a 3M AcOH aqueous solution, and 300 mL of dichloromethane was added, and the liquid was extracted. The collected organic phase, the solvent was removed by reduced pressure distillation, and the crude product was recrystallized to obtain 96 g of 3-(6-methoxy-2-pyridine)-propionic acid, with a total yield of 53% in three steps.

[0052] Example 4

[0053] 700 mL of dichloromethane, 6-methoxy-2-pyridinemethanol (139 g, 1.0 mol) and triethylamine (101 g, 1.0 mol) were mixed to form a reaction system, and p-toluenesulfonyl chloride (190 g, 1.0 mol) was slowly added to the reaction system at 0°C, and the addition was completed, and the mixture was rapidly stirred at 30°C for 6 hours. After the reaction was completed, 500 mL of cold water was added to the reaction system, and after extraction and separation, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a mesylate intermediate.

[0054] The obtained mesylate intermediate was dissolved in 700 mL of acetone, solid sodium bromide (206 g, 2.0 mol) was added, and the mixture was heated under reflux for 8 h. After the reaction was completed, the acetone solvent was removed by distillation under reduced pressure, 600 mL of dichloromethane and 400 mL of water were added for extraction and separation, the organic phase was collected, and the solvent was removed by distillation under reduced pressure to obtain a crude product of 2-(bromomethyl)-6-methoxypyridine.

[0055] At 0°C, diethyl malonate (176 g, 1.1 mol) was added to 600 mL of ethanol, and then sodium ethoxide (136 g, 2.0 mol) was slowly added to the solution, stirred for 15 min, and the above-obtained 2-(bromomethyl)-6-methoxypyridine was slowly added in batches, and reacted at room temperature for 12 h. At 0°C, 200 mL of ice water was added to the reaction system, the temperature was raised to 60°C and stirred for 4 h, and the reaction was subjected to hydrolysis and decarboxylation, and the ethanol was removed by rotary evaporation. The pH was adjusted to 6-7 with a 3M AcOH aqueous solution, and 300 mL of dichloromethane was added, and the liquid was extracted. The organic phase collected, the solvent was removed by reduced pressure distillation, and the crude product was recrystallized to obtain 136 g of 3-(6-methoxy-2-pyridine)-propionic acid, with a total yield of 75% in three steps.

[0056] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing 3-(6-methoxy-2-pyridine)-propionic acid, characterized in that: The following steps are involved: S1, 6-methoxy-2-pyridinemethanol and p-toluenesulfonyl chloride react to obtain a p-toluenesulfonate intermediate, and then the p-toluenesulfonate intermediate reacts with a bromide salt to obtain 2-bromomethyl-6-methoxypyridine; triethylamine is used as a base in the reaction of 6-methoxy-2-pyridinemethanol and p-toluenesulfonyl chloride, and the molar ratio of 6-methoxy-2-pyridinemethanol, triethylamine and p-toluenesulfonyl chloride is 1:(0.9-1.1):(0.9-1.1); S2, 2-bromomethyl-6-methoxypyridine reacts with diethyl malonate under the action of a base to generate 3-(6-methoxy-2-pyridylmethyl)-diethyl malonate, and 3-(6-methoxy-2-pyridylmethyl)-diethyl malonate is hydrolyzed and decarboxylated to obtain 3-(6-methoxy-2-pyridine)-propionic acid.

2. The synthesis method according to claim 1, characterized in that In step S1, the reaction temperature of 6-methoxy-2-pyridinemethanol and p-toluenesulfonyl chloride is 27-30° C. and the reaction time is 5-7 h.

3. The synthesis method according to claim 1, characterized in that In step S1, the bromide salt includes at least one of sodium bromide, potassium bromide and lithium bromide.

4. The synthesis method according to claim 1, characterized in that In step S1, the molar ratio of 6-methoxy-2-pyridinemethanol to bromide salt is 1:(1-2.5).

5. The synthesis method according to claim 1, characterized in that In step S1, acetone is used as a solvent when the p-toluenesulfonate intermediate reacts with the bromide salt, and the reaction is heated under reflux for 7 to 9 hours.

6. The synthesis method according to claim 1, characterized in that In step S2, the base includes at least one of sodium methoxide, sodium ethoxide, sodium hydroxide, potassium tert-butoxide and sodium tert-butoxide.

7. The synthesis method according to claim 1, characterized in that In step S2, the molar ratio of 6-methoxy-2-pyridinemethanol to the base and diethyl malonate is 1:(1.5-2.5):(0.9-1.1).

8. The synthesis method according to claim 1, characterized in that In step S2, 2-bromomethyl-6-methoxypyridine reacts with diethyl malonate in the presence of a base at a temperature of 15 to 30° C. for 10 to 14 hours.

9. The synthesis method according to claim 1, characterized in that In step S2, the reaction temperature of the hydrolysis decarboxylation is 40 to 80° C., and the reaction time is 3 to 5 hours.

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