JP5258370B2 - Industrial production method of risedronic acid - Google Patents

Description

  The present invention relates to an industrial process for producing risedronic acid.

  Formula (I):

Risedronic acid, which is 1-hydroxy-2-pyridin-3-ylethylidene diphosphonic acid represented by the following formula, is a bisphosphonate as risedronate sodium hydrate which is a 2.5 hydrate of its mono sodium salt It is a free form of a drug that is clinically used as a therapeutic agent for osteoporosis.

  Several methods for synthesizing risedronic acid have been reported so far. The basis of the synthetic method is that phosphorous acid and 3-pyridylacetic acid are used as a first step by phosphorous halogen compounds (for example, phosphorus trichloride, phosphorus oxychloride). , Phosphorus pentachloride, phosphorus tribromide, phosphorus oxybromide, etc.), and the second step is quenching with water to obtain risedronic acid.

  However, the process of the first stage has a problem that is difficult to implement as a manufacturing method on an industrial scale. For example, Patent Document 1 (Patent No. 2702419) uses a harmful solvent such as chlorobenzene, and the reaction liquid becomes a strongly sticky mass as the reaction proceeds, making it unacceptable as an industrial production method.

Therefore, studies have been made to improve the solubility of the reactants by variously changing the type of solvent used in the reaction system and to improve the stirring and fluidity of the reaction solution, and several proposals have been made so far. Both have disadvantages as industrial production methods.
For example, Patent Document 2 (Japanese Patent Publication No. 2007-502810) proposes the use of sulfolane as a reaction solvent, but sulfolane itself is expensive and unsuitable industrially.
Patent Document 3 (International Publication WO2006 / 134603) proposes to use octane or dioxane as a reaction solvent, but there are problems with the safety of octane itself and the toxicity of dioxane.

Further, Patent Document 4 (Patent No. 3857706) proposes using silicon oil as a specific solvent, but has a problem that it is not easy to clean the equipment when silicon oil is used.
Further, Patent Document 5 (US Patent Publication 2006-0258625) uses diphenyl ether as a reaction solvent, and Patent Document 6 (European Patent No. 1243592) proposes a production method using fluorobenzene as a reaction solvent. In either case, safety and cost are not sufficient.
In Patent Document 4, a method using toluene as a reaction solvent is also reported, but it has not yet been improved in terms of adhesion and solidification of the reaction solution.

On the other hand, proposals have also been made to improve the point of adhesion and solidification of the reaction solution by improving the reaction reagent. For example, Patent Document 7 (International Publication WO2007 / 023342) discloses a production method using propylphosphonic acid anhydride. Although proposed, propylphosphonic anhydride is an expensive reagent and cannot be said to be an inexpensive industrial production method.
Most of these reports use a large amount of phosphorus halogen compounds such as phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus tribromide, phosphorus oxybromide as reaction reagents, There is a problem that a large-scale exhaust gas treatment device is required for industrial production because hydrogen gas is generated.

Japanese Patent No. 2702419 Special table 2007-502810 gazette International Publication WO2006 / 134603 Japanese Patent No. 3857706 US Patent Publication 2006-0258625 European Patent No. 1243592 International Publication WO2007 / 023342

  In view of the above-mentioned present situation, the present invention, as an industrial production method of risedronic acid, has good operability, without using harmful solvents and reagents, and without generating a large amount of harmful gases, It is an object to provide a low-cost industrially applicable manufacturing method.

  As a result of intensive studies by the present inventors to solve such problems, polyphosphoric acid and phosphorus pentoxide are used as reagents for the reaction of 3-pyridylacetic acid and phosphorous acid, and in industrially used organic solvents. As a result of the reaction, it is found that there is no problem in the stirring property and fluidity of the reaction solution, and generation of harmful hydrochloric acid gas and the like can be suppressed, and the desired risedronic acid can be efficiently produced, and the present invention is completed. It came to.

  Thus, the basic aspect of the present invention is to react 3-pyridylacetic acid and phosphorous acid in an organic solvent characterized by using polyphosphoric acid and / or phosphorus pentoxide as a reaction accelerator. 1-hydroxy-2-pyridin-3-ylethylidene diphosphonic acid.

  More specifically, the present invention relates to a method for producing risedronic acid characterized by mixing 3-pyridylacetic acid, phosphorous acid and polyphosphoric acid in an organic solvent, and further adding phosphorus pentoxide to react. is there.

  The present invention is preferably a method for producing risedronic acid, wherein the organic solvent is toluene or ethyl acetate, and the reaction temperature is in the range from room temperature to the boiling temperature of the organic solvent.

As described above, the present invention is widely used industrially by using polyphosphoric acid and / or phosphorus pentoxide, preferably both polyphosphoric acid and phosphorus pentoxide as a reaction reagent for 3-pyridylacetic acid and phosphorous acid. This is a method for producing risedronic acid by reacting in an organic solvent.
According to the method of the present invention, the reaction contents are not adhered and solidified until the reaction is completed, and can be sufficiently stirred, and there is no problem in operability.
In addition, generation of harmful hydrogen halide occurs when equimolar amounts of hydrogen chloride are generated when 3-pyridylacetic acid hydrochloride is used as a raw material, but no phosphorus halide is used as a reaction reagent. No excessive hydrogen halide is produced as a by-product.
In the previous reports, the reaction is carried out using 3 times moles of phosphorus oxychloride or phosphorus trichloride, and in that case, 10 times moles of hydrogen chloride (hydrochloric acid gas) are generated with respect to the substrate. .
From that point of view, the production method of the present invention can reduce the generation of hydrochloric acid gas to 1/10, and does not require any large-scale exhaust gas treatment device, which is an industrially superior production method. The advantages are enormous.

As described above, a basic aspect of the present invention is a method for producing risedronic acid characterized by reacting 3-pyridylacetic acid, phosphorous acid, polyphosphoric acid and / or phosphorus pentoxide in an organic solvent. .
The 3-pyridyl acetic acid used in the reaction is preferably in the form of its salt, especially the hydrochloride, that is, 3-pyridyl acetic acid hydrochloride.

As the solvent to be used, an organic solvent widely used industrially is preferable, and specifically, toluene or ethyl acetate is preferably used.
In previous reports, specific solvents such as sulfolane, octane, dioxane, silicone oil, diphenyl ether or fluorobenzene were used, but these solvents have problems in terms of safety or price. In the method of the present invention, toluene or ethyl acetate is widely used industrially, and there is no problem in terms of safety or price.
In addition, although the usage-amount of the organic solvent to be used cannot be generally limited, it should just be a quantity sufficient to advance reaction, and about 0.5-1L is used with respect to 1 molar equivalent of 3-pyridyl acetate hydrochloride. It is sufficient, and can be increased or decreased as appropriate according to the situation.

  As the usage-amount of 3-pyridyl acetate hydrochloride and phosphorous acid in the manufacturing method of this invention, it is good to use 3 times mole amount of phosphorous acid with respect to 1 mole amount of 3-pyridyl acetate hydrochloride.

The production method of the present invention is characterized in that polyphosphoric acid and / or phosphorus pentoxide is used as a reaction reagent for 3-pyridylacetic acid hydrochloride and phosphorous acid.
In the present invention, the desired risedronic acid can be obtained even if only polyphosphoric acid or only phosphorus pentoxide is used as a reaction reagent. However, only polyphosphoric acid has good fluidity of the reaction solution, but is not preferable in terms of yield, and phosphorous pentoxide alone has poor fluidity of the reaction solution, and the yield is not good. According to the study by the present inventors, it has been found that addition of phosphorus pentoxide to polyphosphoric acid improves the fluidity of the reaction solution and promotes the reaction.

  The amount of polyphosphoric acid and phosphorus pentoxide used as the reaction reagent is such that polyphosphoric acid is used 2 to 5 times by weight, preferably 3 times the weight of 3-pyridyl acetate hydrochloride, and phosphorus pentoxide is phosphorus phosphite. It should be used in an equimolar amount with respect to the acid.

  Although the reaction temperature and reaction time cannot be generally limited, the reaction temperature is from room temperature to around the boiling point of the organic solvent used, preferably slightly lower than the boiling point of the solvent, and the reaction time is preferably 5 to 24 hours. Is about 15 to 20 hours.

  As the reaction proceeds, the reaction solution separates into an organic solvent phase (upper layer) and a raw material mixture phase (lower layer), but both phases are very fluid and there is no problem in stirring the reaction solution itself. . Further, after completion of the reaction, water was added to the reaction solution, and the lower layer components were dispersed in water by heating and stirring, so that there was no problem in the subsequent operations.

More specific operations will be described below.
3-pyridyl acetate hydrochloride is suspended in a commonly used organic solvent (for example, toluene, ethyl acetate, more preferably toluene), and polyphosphoric acid (2 to 5 times the weight of 3-pyridyl acetate hydrochloride, preferably Is 3 times the weight) and phosphorous acid is added at room temperature to dissolve.
At this stage, the reaction solution was separated into an organic solvent phase (upper layer) and a raw material mixture phase (lower layer), but both phases were very fluid and had no problem with stirring.
The target reaction proceeds even in this state, but phosphorus pentoxide is added to promote the reaction, followed by further heating (reaction temperature is room temperature to the boiling point of the solvent, preferably slightly lower than the boiling point of the solvent). Make it progress.
In this state, after reacting for 5 to 24 hours, preferably 15 to 20 hours, when water is dropped after the reaction and heating and stirring is continued, the lower layer components (reactants) are dispersed in water and uniformly suspended. The resulting reaction solution is obtained.
When the reaction solution is cooled and ethanol is added to the reaction solution, crystals are precipitated. The crystals are collected by filtration, washed with ethanol and water, and dried to obtain the desired risedronate (usually monohydrate). ).

  As described above, operability is good by a very simple method, and by using a general-purpose solvent / reagent, risedronic acid can be produced in high yield without generating a large amount of harmful gas. .

  The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1: Production of risedronic acid (Part 1)
In a 4-diameter flask, toluene 350 mL, 3-pyridyl acetate hydrochloride 100 g (0.58 mol), 116% polyphosphoric acid 300 g, phosphorous acid 141.7 g (1.73 mol) and phosphorus pentoxide 245 g (1.73 mol) And reacted at 95 ° C. for 16 hours. 400 mL of water was dripped after completion | finish of reaction, and it heated at 90 degreeC for 5 hours. After cooling the reaction solution to room temperature, 1200 mL of ethanol was added, and the precipitated crystals were collected by filtration, washed thoroughly with ethanol and water, and dried to obtain 105.8 g (61 in the form of monohydrate) of risedronate. %).

Example 1: Production of risedronic acid (part 2)
In Example 1, the same reaction was carried out using ethyl acetate as a solvent, and the desired risedronic acid was obtained in a yield of 58%.

  As described above, according to the present invention, risedronic acid has good operability, does not use harmful solvents and reagents, does not generate a large amount of harmful gas, and can be applied industrially at low cost. An industrial manufacturing method can be provided, and its convenience is enormous.

Claims (4)

  1-hydroxy-2-pyridin-3-yl comprising reacting 3-pyridylacetic acid and phosphorous acid in an organic solvent, characterized by using polyphosphoric acid and / or phosphorus pentoxide as a reaction accelerator A method for producing ethylidene diphosphonic acid.   The 1-hydroxy-2-pyridine-3- according to claim 1, wherein 3-pyridylacetic acid, phosphorous acid and polyphosphoric acid are mixed in an organic solvent, and phosphorus pentoxide is further added to react. A process for producing irethylidene diphosphonic acid.   The method for producing 1-hydroxy-2-pyridin-3-ylethylidene diphosphonic acid according to claim 1 or 2, wherein the organic solvent is toluene or ethyl acetate.   The process for producing 1-hydroxy-2-pyridin-3-ylethylidene diphosphonic acid according to claim 1, 2 or 3, wherein the reaction temperature is in the range from room temperature to the boiling point of the organic solvent.