JP5836851B2 - Method for producing brinzolamide - Google Patents

Description

  The present invention relates to a novel method for producing brinzolamide useful as a therapeutic agent for glaucoma.

  Brinzolamide is a compound represented by the following formula (2), and the formal name of the compound is (R) -3,4-dihydro-4-ethylamino-2- (3-methoxypropyl) -2H-thieno. [3,2-e] -1,2-thiazine-6-sulfonamido-1,1-dioxide) (hereinafter, this compound is also referred to as “target compound”). Brinzolamide is used as a therapeutic agent for glaucoma because it has a carbonic anhydrase inhibitory action.

  As a method for producing brinzolamide, (S) -3,4-dihydro-4-hydroxy-2- (3-methoxypropyl) -2H-thieno [3,2-e] -1 represented by the following formula (1): , 2-thiazine-6-sulfonamide-1,1-dioxide (hereinafter also referred to as “raw compound”) protects the sulfonamide functional group at the C (6) site and activates the hydroxyl group at the C (4) site. After the conversion, the method is generally known in which a protective group is removed from the protected sulfonamide functional group at the C (6) site after substitution with an amine (see Patent Document 1 and Non-Patent Document 1). .

  In the above series of reactions (protection, amination and deprotection), a large amount of by-products as impurities are generated. For example, the reaction mixture is neutralized and then the organic components are extracted to remove amines and inorganic salts. Then, it is necessary to purify the crude product of the target compound obtained by concentrating the extract. In the said patent document, the organic impurity was removed by recrystallizing the rough body obtained in this way with 2-propanol.

Japanese Patent No. 2854798

Organic Process Research & Development (1999), 3 (2), 114-120.

  When the crude product is purified by recrystallization using 2-propanol described in the above-mentioned patent document, the target compound with high purity can be obtained in a relatively high yield. According to the study by the present inventors, such an effect is also seen when recrystallization is performed with an alcohol other than 2-propanol, and recrystallization using another single solvent such as ethyl acetate. It was confirmed that the brinzolamide of the same purity can be obtained in a higher yield as compared with the above.

  However, purification by recrystallization using alcohols is satisfactory in terms of purity but not in terms of yield. It has also been newly found that there is a problem that it is very difficult to remove certain impurities by recrystallization using alcohol.

  Drug substances such as brinzolamide are generally very expensive. In addition, the demand for the purity of the drug substance is severe, and in order to satisfy such a requirement, it is necessary to repeat a purification process such as recrystallization. The presence of impurities that are difficult to remove increases the number of repetitive purifications. Connected. For these reasons, improving the purity and yield as much as possible and increasing the removal efficiency of impurities that are difficult to remove have great industrial significance. Accordingly, an object of the present invention is to provide a method capable of obtaining a high-purity target product (brinzolamide) in a high yield when the target compound is produced from a raw material compound.

  The inventors of the present invention have made extensive studies on the above problems. Specifically, a method for improving the yield in the recrystallization operation of the crude product after the extraction operation was examined. As a result, it has been found that the above problem can be solved by using a mixed solvent of an alcohol and a nonpolar solvent as a recrystallization solvent, and the present invention has been completed.

That is, the present invention relates to (S) -3,4-dihydro-4-hydroxy-2- (3-methoxypropyl) -2H-thieno [3,2-e] -1, represented by the following formula (1). (R) -4- (ethylamino) -3,4-dihydro-2- (3-methoxy) represented by the following formula (2) from a raw material compound consisting of 2-thiazine-6-sulfonamide-1,1-dioxide Propyl) -2H-thieno [3,2, e] -1,2-thiazine-6-sulfonamide 1,1-dioxide A method for producing a target compound comprising:
A reaction step of obtaining a reaction mixture containing the target compound by ethylamination of a hydroxyl group bonded to the 4-position carbon atom of the starting compound, a separation step of separating a crude product of the target compound from the reaction mixture, and methanol and ethanol; The crude product separated in the separation step into a mixed solvent of a low carbon chain alcohol selected from 1-propanol, 2-propanol and 1-butyl alcohol and a nonpolar solvent selected from aliphatic hydrocarbons or aromatic hydrocarbons The method is characterized in that it comprises a purification step of preparing a solution in which is dissolved and crystallizing the target compound purified from the mixed solution.

  According to the present invention, as compared with the case where recrystallization is performed using alcohol, not only a purification effect equal to or higher than that can be obtained, but also the isolation yield of the target product can be improved. Furthermore, according to the method of the present invention, a compound represented by the following formula (3) (hereinafter also referred to as “amidotosylated product”), which was difficult to remove when alcohol was used alone, is removed. It is also possible.

  The reason why such an excellent effect is obtained is not clear, but in the case of purifying the target product by crystallization from a solution, if a mixed solvent of alcohol and nonpolar solvent is used as the solvent, the crystal It is considered that the yield was improved without impairing the purity because the solubility of the target compound was lowered without giving adverse effects to the precipitation (for example, incorporating impurities during crystallization). In addition, it is considered that the nonpolar solvent is included in the solvent, so that the solubility in low-polar impurities is improved and the removal efficiency of the amidosylated compound is improved.

  The method of the present invention is a method for producing a target compound from a raw material compound, and comprises the reaction step, the separation step, and the purification step. Each step will be described in detail below.

(Reaction process)
In the reaction step, the hydroxyl group bonded to the 4-position carbon atom {C (4) site} of the raw material compound is ethylaminated to obtain a reaction mixture containing the target product. The ethylamination method is not particularly different from the conventional methods described in Patent Document 1 and Non-Patent Document 1, and can be suitably performed by, for example, the following method. That is, a protection step of protecting the sulfonamide group bonded to the carbon atom at the 6-position of the raw material compound to produce a protected raw material compound, the carbon atom at the 4-position of the protected raw material compound {C (4) An amination step for producing a protected target compound (a target compound in which a sulfonamide group bonded to the 6-position carbon atom is protected) by substituting the hydroxyl group bonded to the site} with ethylamine, the protected target compound It can be suitably carried out by a method comprising a deprotection step of deprotecting the protected sulfonamide group in to produce the target compound.

  In the protection step, the sulfonamide group bonded to the 6-position carbon atom {C (6) site} of the raw material compound is protected by heating and mixing the raw material compound and a lower alkyl orthoacetate as a protective agent in a reaction solvent. This can be suitably performed. As the lower alkyl orthoacetate, trimethyl orthoacetate is particularly preferably used because the alcohol produced as a by-product in the reaction can be easily removed. The reaction solvent is not particularly limited as long as it is an inert solvent that does not participate in the reaction. However, it is particularly preferable to use ethyl acetate or acetonitrile because the reaction temperature can be easily controlled. The reaction conditions may be appropriately determined. Usually, the raw material compound, 1.0 to 1.5 moles of lower alkyl orthoacetate with respect to 1 mole of the raw material compound, and 1.5 to 1.5 parts with respect to 1 part by weight of the raw material compound. What is necessary is just to mix 10 mass parts reaction solvent and to make it react for 1 to 24 hours under recirculation | reflux. By performing such a reaction, a raw material compound in which the sulfonamide group bonded to the 6-position carbon atom is protected (hereinafter also referred to as “imidate”) can be obtained.

  In the amination step, it is preferable that the hydroxyl group bonded to the 4-position carbon atom of the imidate is activated and then reacted with ethylamine. The activation of the hydroxyl group is obtained by, for example, obtaining an imidate concentrate by distilling off the solvent after completion of the protection step, cooling the solution obtained by dissolving the concentrate in an organic solvent such as tetrahydrofuran, and the like. It can carry out by adding 1.0-1.5 mol sulfonyl chloride compound with respect to 1 mol of imidate bodies to a solution, and stirring for 1-4 hours at the temperature of -10-15 degreeC. By such an operation, an imidate body (sulfonyl body) in which the carbon at the 4-position is sulfonylated can be obtained. Since the compound is dissolved in the reaction solution, a 70% aqueous solution of ethylamine may be added to the reaction solution to react with ethylamine. As the sulfonyl chloride compound, it is preferable to use p-toluenesulfonyl chloride because the reaction time in the subsequent desorption step can be shortened and the yield is improved.

  In the reaction (substitution reaction) between the sulfonyl compound and 70% ethylamine aqueous solution, the 70% ethylamine aqueous solution is added to the reaction solution cooled to -10 to 15 ° C. so that the amount of ethylamine is 10 to 40 mol per mol of the sulfonyl compound. And it can carry out suitably by making it react for a predetermined time. The reaction conditions may be determined as appropriate, but in general, the reaction may be performed at room temperature for about 8 to 48 hours. In this reaction, deprotection of the sulfonamide group protected by hydrolysis with water in the reaction solution can also be performed in parallel.

(Separation process)
In the separation step, the crude product of the target compound is separated from the reaction mixture obtained in the step. Separation here means separating the reaction solvent and water-soluble impurities in the reaction mixture from the crude product comprising the target compound containing organic impurities. The crude product of the target compound means a target compound containing organic impurities (such as organic by-products and residual organic solvent) as main impurities, and is usually a solid having a purity of about 65 to 80%. Or it means a viscous liquid. Separation of the crude product from the reaction mixture is accomplished by adding a base such as sodium hydrogen carbonate to the reaction solution, which is the reaction mixture, and then separating the organic components using an organic solvent (extraction solvent) such as ethyl acetate. If necessary, washing with water and drying (moisture removal) are performed, and the extraction solvent is distilled off and concentrated.

(Purification step)
In the purification step, a solution in which the crude product separated in the separation step is dissolved is prepared for a mixed solvent of alcohol and a nonpolar solvent, and the purified target compound is crystallized from the mixed solution. As the alcohol, it is preferable to use a low carbon chain alcohol such as methanol, ethanol, 1-propanol, 2-propanol, 1-butyl alcohol and the like. It is particularly preferable to use ethanol or 2-propanol because of the solubility of brinzolamide and the purity of the obtained brinzolamide, and 2-propanol is preferred because the yield (recovery) of the target product can be further increased. Most preferably it is used.

  As the nonpolar solvent, aliphatic hydrocarbons such as pentane, hexane and heptane, or aromatic hydrocarbons such as toluene can be preferably used. Among these, it is particularly preferable to use heptane because the yield (recovery rate) of the target product is high and the safety and toxicity in industrial production are low.

  The blending ratio of the alcohol and the nonpolar solvent in the mixed solvent is expressed as a volume ratio, preferably in the range of alcohol / nonpolar solvent = 1 to 10, particularly preferably in the range of 3 to 10.

  The method for preparing the solution is not particularly limited, and the crude product may be added to a mixed solvent of alcohol and a nonpolar solvent and heated to be dissolved, or the crude product may be dissolved in the alcohol and then the nonpolar solvent may be added. Good. The amount of the mixed solvent used at this time is usually 1 to 50 parts by mass with respect to 1 part by mass of the coarse body. Considering the batch yield and the operability improvement of the filtration step, 2 to 10 parts by mass is preferable.

  In order to crystallize the target compound from the solution thus prepared, the solution may be cooled. Depending on the temperature at which the solution is prepared, when the nonpolar solvent is added after the crude product is dissolved in alcohol, the target product may crystallize with the addition of the nonpolar solvent. is there. Usually, it is preferable to perform crystallization by heating the solution containing the crude product to 50 ° C. to 100 ° C. to completely dissolve the crude product and then cooling the solution to −10 ° C. to 20 ° C. The target compound precipitated by crystallization is highly purified compared to the crude product.

  As shown in Examples described later, the purity of the highly purified compound (primary purified product) obtained by performing such a purification step once is 98.0 to 99.0%. The yield is 67 to 71% based on the amount of the raw material compound used in the reaction step. In order to obtain a higher-purity target product, the purification process may be repeated.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples.

  In addition, the purity measurement of the raw material compound obtained by the Example and the comparative example, the imidate body, the sulfonyl body, and the brinzolamide (target compound) was performed as follows.

<Method for measuring purity of brinzolamide, etc.>
Apparatus: Alliance model e2695-2489 manufactured by WATERS
Detector: UV absorptiometer (measurement wavelength: 254 nm)
Column: GL Science Co., Ltd. product name Inertsil CN-3, particle diameter 5 μm, inner diameter 4.6 mm, length 25 cm,
Column temperature: 40 ° C. Constant temperature mobile phase: n-hexane / ethanol = 80/20
Flow rate: 1.0 ml / min Measurement time: 45 minutes When measured under the above conditions, the starting compound is about 29 minutes, the imidate is about 9.4 minutes, and the sulfonyl is about 8.2 minutes for brinzolamide (target compound) ) Is observed at around 19 minutes, and an amidotosylated product is observed at around 10 minutes. The purity was determined based on the peak area ratio of HPLC.

Example 1
(Reaction process)
The starting compound (50 g, 140 mmol) was dissolved in 200 mL of acetonitrile, trimethyl orthoacetate (18.54 g, 154.3 mmol) was added, and the mixture was heated to reflux at 84 ° C. for 3 hours while removing the effluent out of the system. The solution was concentrated to obtain 70.43 g of an imidate. This was dissolved in tetrahydrofuran (150 mL) and cooled to 0 ° C. When triethylamine (21.29 g, 212.5 mmol) and paratoluenesulfonyl chloride (32.09 g, 168.3 mmol) were added thereto, precipitation of the sulfonyl body occurred. The mixture was stirred for 3 hours under ice cooling to obtain a sulfonyl compound. A 70% aqueous monoethylamine solution (250 mL, 3.13 mol) was added dropwise to the resulting reaction solution under ice cooling. After the mixture was stirred overnight, 12M hydrochloric acid (240 mL) was added at 40 ° C. or lower to deprotect the sulfonyl compound.
(Separation process)
About 10 g of sodium bicarbonate was added to the reaction solution obtained by the above deprotection to adjust the pH of the mixture solution to 8, and the organic substance was extracted with ethyl acetate, and then concentrated to dryness to obtain a reaction concentrate (crude material). 65 g was obtained.
(Purification process)
A solution was prepared by dissolving 1.25 g of the crude product obtained in the above separation step in 6 ml of a mixed solvent obtained by mixing 5.4 ml of 2-propanol and 0.6 ml of heptane. In preparation of the solution, the crude product was completely dissolved by heating to 80 ° C. After preparing the solution, it was cooled to crystallize the desired product. The crystallized target product (primary purified product) was recovered by filtration, dried in vacuo, and measured for mass. The result was 0.737 g, and the yield based on the raw material compound was 68.5%. Further, when the purity of the primary purified product was measured, the purity of the target product was 98.76%, and the content of the amide tosyl compound contained as an impurity was 0.14%.

Examples 2-6
A primary purified product was obtained in the same manner as in Example 1 except that the mixed solution used in the purification step was changed to that shown in Table 1. Table 1 shows the purity of the obtained primary purified product, the content of the amidotosyl product, and the yield of the primary purified product.

Example 7
A solution was prepared by dissolving 8 parts by mass of 2-propanol with respect to 0.6 g of the brinzolamide primary purified product obtained in Example 1. In preparing the solution, the crude product was completely dissolved by heating to 80 ° C. After preparing the solution, it was cooled to crystallize the desired product. The crystallized target product was collected by filtration, vacuum-dried, purity was measured by HPLC, and purification was repeated in the same manner until the purity reached 99.8% or higher. As a result of repeating 5 times, 0.383 g of a final purified product of brinzolamide was obtained. The yield based on the primary purified product was 63.8%. The purity of the target product was 99.83%, and the content of the amide tosyl compound contained as an impurity was 0.05%.

Comparative Examples 1-7
A primary purified product was obtained in the same manner as in Example 1 except that the mixed solution used in the purification step was changed to that shown in Table 1. Table 1 shows the purity of the obtained primary purified product, the content of the amidotosyl product, and the yield of the primary purified product.

Comparative Example 8
A solution was prepared by dissolving 8 parts by mass of 2-propanol with respect to 0.6 g of the brinzolamide primary purified product obtained in Comparative Example 1. In preparing the solution, the crude product was completely dissolved by heating to 80 ° C. After preparing the solution, it was cooled to crystallize the desired product. The crystallized target product was collected by filtration, vacuum-dried, purity was measured by HPLC, and purification was repeated in the same manner until the purity reached 99.8% or higher. As a result of repeating 7 times, 0.313 g of a final purified product of brinzolamide was obtained. The yield based on the primary purified product was 52.2%. The purity of the target product was 99.83%, and the content of the amide tosyl compound contained as an impurity was 0.09%.

Claims (3)

(S) -3,4-dihydro-4-hydroxy-2- (3-methoxypropyl) -2H-thieno [3,2-e] -1,2-thiazine-6 represented by the following formula (1) (R) -4- (ethylamino) -3,4-dihydro-2- (3-methoxypropyl) -2H-thieno represented by the following formula (2) from a raw material compound consisting of sulfonamide-1,1-dioxide A method for producing a target compound comprising [3,2, e] -1,2-thiazine-6-sulfonamide 1,1-dioxide,
A reaction step of obtaining a reaction mixture containing the target compound by ethylamination of a hydroxyl group bonded to a carbon atom at the 4-position of the raw material compound;
A separation step of separating a crude product of the target compound from the reaction mixture; and
Separated in the separation step into a mixed solvent of a low carbon chain alcohol selected from methanol, ethanol, 1-propanol, 2-propanol and 1-butyl alcohol and a nonpolar solvent selected from aliphatic hydrocarbons or aromatic hydrocarbons The said method characterized by including the refinement | purification process which prepares the solution in which the said rough body melt | dissolved, and crystallizes the target compound highly purified from the said mixed solution.

The reaction step protects the sulfonamide group bonded to the 6-position carbon atom of the raw material compound to produce a protected raw material compound, and binds to the 4-position carbon atom of the protected raw material compound An amination step in which the hydroxyl group is substituted with ethylamine to produce a protected target compound, and a deprotection step in which the protected sulfonamide group in the protected target compound is deprotected to produce the target compound. The method of claim 1. The method according to claim 1 or 2 , wherein 2-propanol is used as an alcohol in the purification step.