JP6382736B2 - Method for producing valsartan - Google Patents

Description

  The present invention relates to a method for producing valsartan (chemical name: N-pentanoyl-N- [2 '-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -L-valic acid).

  Following formula (1)

(Chemical name: N-pentanoyl-N- [2 ′-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -L-valic acid) is useful as an active pharmaceutical ingredient, In addition, it is used as an angiotensin II receptor antagonist in antihypertensive drugs (see Patent Document 1).

  Valsartan is known to have various crystal forms. Among them, amorphous is amorphous and has low solubility in a solvent, and can be suitably used as an active pharmaceutical ingredient. Here, the term “amorphous” means that it has no clear diffraction peak in X-ray diffraction measurement (XRD) and an endothermic peak at about 130 ° C. in differential scanning calorimetry (DSC). Defined. Patent Document 1 discloses a recrystallization method using crude valsartan and ethyl acetate, and according to this method, an amorphous can be produced. This method is a preferable method for producing an amorphous material because of its high purification efficiency, simple operation, and stable production of an amorphous material.

Japanese Patent No. 2749458

  When the present inventors performed the recrystallization method described in Patent Document 1 above using crude valsartan obtained by a general synthesis method and commercially available ethyl acetate, The amorphous recovery based on the mass of valsartan was about 78%. Valsartan, which is an active pharmaceutical ingredient, is very expensive, and a method for improving the recovery rate has been desired. Furthermore, since the above crude valsartan contains impurities and optical isomers having a structure similar to valsartan, in order to improve the quality of amorphous valsartan to be used as a drug substance, It may be required to repeat the operation, and in such a case, the improvement of the recovery rate is very beneficial.

  In order to solve the above-mentioned problems, the present inventors have conducted extensive research. As a result, it was found that the solubility of valsartan in ethyl acetate was greatly influenced by the minute amount of coexisting water. Based on this finding, the above-mentioned recrystallization conditions were examined in detail, and it was found that the recovery rate could be greatly improved by controlling the amount of water contained in the solution of valsartan and ethyl acetate before recrystallization. Specifically, when crude valsartan obtained by a general synthesis method and commercially available ethyl acetate are used, the solution before recrystallization is 0.15 mol to 0.50 mol with respect to 1 mol of valsartan. While the following water is contained, the recovery can be improved by about 10% by controlling to 0.10 mol or less.

  It is surprising that the solubility of valsartan in water is less than or equal to that of ethyl acetate, and even if the water content in ethyl acetate is very small, the recovery rate of the recrystallization operation is greatly affected. . The reason is not clear, but is estimated as follows. The molecular structure of valsartan has both a hydrophilic functional group such as a carboxyl group and a tetrazole ring, and a hydrophobic functional group such as a biphenyl skeleton and a butyl group. Therefore, the solubility of valsartan in hydrophobic ethyl acetate is greatly improved by including a small amount of hydrophilic water, which greatly affects the recovery rate of the recrystallization operation. As a result, it is speculated that the recovery rate is improved by precisely controlling the amount of water in recrystallization using ethyl acetate. In the case of esters other than ethyl acetate, there is also the influence of the water content as described above.

  That is, the present invention is a method for producing amorphous valsartan, characterized in that recrystallization is performed using a solution of valsartan and an ester whose water content is 0.10 mol or less with respect to 1 mol of valsartan. This is a method for producing amorphous valsartan.

  According to the present invention, in the method for producing amorphous valsartan by recrystallization using esters such as ethyl acetate, the recovery rate can be greatly improved.

2 is an XRD chart of the amorphous valsartan of the present invention obtained in Example 1. FIG. 2 is a DSC chart of the amorphous valsartan of the present invention obtained in Example 1. FIG.

  The present invention prepares a solution of valsartan having a water content of 0.10 mol or less per mol of valsartan from crude valsartan and esters, and then recrystallizes the amorphous valsartan. It is a manufacturing method.

(Coarse valsartan)
Since the crude valsartan in the present invention is once in a solution state, its crystal form and the like are not particularly limited. Moreover, since the production method of the present invention has a purification effect, the purity and the kind of impurities contained are not particularly limited. Therefore, the crude valsartan may be produced by a known method. For example, as described in Patent Document 1, N-[(2′-cyanobiphenyl-4-yl) methyl] -N-valeryl- Crude valsartan can be produced by subjecting (L) -valine benzyl ester to tetrazole ring formation reaction using tributyltin azide and then debenzylation reaction using palladium carbon. Alternatively, N-{[2 '-(1-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl] methyl} -N-valeryl-L- is described in Japanese Patent No. 5575783. There is a method in which a detritylation reaction is performed by heating valine benzyl ester in a solvent, and then a debenzylation reaction is performed using palladium carbon.

  Depending on the production method and its conditions, crude valsartan usually has a purity of 90 to 99%, and its crystal form is amorphous, crystalline, or a mixture thereof. Moreover, the water content is usually 0.1% by mass or more and 2.0% by mass or less, and can be preferably used in the present invention.

  It should be noted that there is no problem even if the crude valsartan is purified by a method such as recrystallization or column chromatography, which is produced by the above method or the like.

(Esters)
The esters in the present invention can be used without particular limitation as long as they can dissolve valsartan and are liquids of esters mixed with water, and the effects of the present invention can be obtained. For example, isoamyl formate, isobutyl formate, ethyl formate, butyl formate, propyl formate, hexyl formate, benzyl formate, methyl formate, amyl acetate, allyl acetate, isoamyl acetate, isobutyl acetate, isopropyl acetate, ethyl acetate, 2-ethylhexyl acetate, acetic acid Cyclohexyl, n-butyl acetate, s-butyl acetate, propyl acetate, benzyl acetate, methyl acetate, methyl cyclohexyl acetate, isoamyl propionate, ethyl propionate, butyl propionate, benzyl propionate, methyl propionate, isoamyl butyrate, isopropyl butyrate , Ethyl butyrate, butyl butyrate, methyl butyrate, allyl acetoacetate, ethyl acetoacetate, methyl acetoacetate and the like. Among these, ethyl formate, butyl formate, propyl formate, methyl formate, isobutyl acetate, isopropyl acetate, ethyl acetate, acetic acid from the point that solubility of valsartan is high, the amount used can be reduced, and the purification effect is high. n-Butyl, s-butyl acetate, propyl acetate, methyl acetate, ethyl propionate, butyl propionate, methyl propionate are preferred, isobutyl acetate, isopropyl acetate, ethyl acetate, n-butyl acetate, s-butyl acetate, propyl acetate More preferred is methyl acetate, and most preferred is ethyl acetate. In addition, the said ester may be used independently and may mix and use 2 or more.

  Esters can be used without any limitation as reagents or those available for industrial use, but from the viewpoint of water content, reagents are preferable, and reagents with low water content such as ultra-dehydrated grade are particularly preferable. For example, in the case of ethyl acetate, each water content is usually about 0.05% by mass for industrial use, about 0.03% by mass for reagent (normal grade), and about 0.001% by mass for reagent (super dehydration grade). It is.

  The amount of use is 350 parts by mass or more and 2500 parts by mass with respect to 100 parts by mass of crude valsartan. If esters in these ranges are used, the crude valsartan can be easily dissolved by heating regardless of the crystal form or purity of the crude valsartan. However, since valsartan tends to increase (isomerization) optical isomers when heated in a solution state, it is preferable that the heating temperature is lower, and therefore, the heating temperature can be further lowered. From the point which can improve a recovery rate more, 375 mass parts or more and 1500 mass parts or less are preferable with respect to 100 mass parts of crude valsartan among the said range, and 400 mass parts or more and 1000 mass parts or less are more preferable. As a matter of course, the recovery rate of valsartan varies depending on the amount of ester used. However, when the same amount of ester is used, the water content of the valsartan solution before recrystallization is 0.10 per mol of valsartan. By making it below mol, the recovery rate of valsartan is improved as compared with the case outside this range.

(Method for preparing Valsartan solution)
In the present invention, the preparation of the valsartan solution is preferably performed by mixing the crude valsartan and the esters and then heating and stirring until a solution state is obtained. The operation is preferably performed in a container, and examples of the container include a glass container, a stainless steel container, a Teflon (registered trademark) container, and a glass lining container. The container is preferably equipped with a thermometer or a temperature sensor, and more preferably with a reflux tube. Moreover, it is preferable to perform the said stirring operation using a mechanical stirrer, a magnetic stirrer, etc. from the point of stirring efficiency.

  The temperature for preparing the valsartan solution may be appropriately determined depending on the amount of the ester, etc., but is usually 30 ° C. or higher and the reflux temperature (about 77 ° C.) or lower. Among these, from the point which can suppress the isomerization in a solution state, 35 to 65 degreeC is preferable and 40 to 55 degreeC is more preferable. In addition, the preparation time is usually sufficient for 10 minutes or more, but it may be appropriately determined by visually confirming that all of the crude valsartan has been dissolved. In addition, although the said preparation operation may be under air | atmosphere, from the point which can suppress mixing of water, it is more preferable that it is under atmosphere, such as nitrogen and argon.

  The valsartan solution is preferably composed only of crude valsartan, esters and water, but is 5 parts by mass or less, preferably 1 part by mass or less with respect to 100 parts by mass of the esters and water. Organic solvents other than esters can be included. Organic solvents that can be included at this time include alcohols such as methanol and ethanol, nitriles such as acetonitrile, ketones such as acetone and methyl ethyl ketone, aromatic hydrocarbons such as toluene and xylene, dichlorometa and chloroform, etc. Examples thereof include halogenated aliphatic hydrocarbons, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone and the like.

(Method for adjusting water content of valsartan solution)
In the present invention, it is most important that the solution of valsartan and esters has a water content of 0.10 mol or less with respect to 1 mol of valsartan. If it is this range, the recovery rate of a valsartan can be improved compared with the case where the water content exceeds 0.10 mol. Among these, 0.07 mol or less is preferable, 0.04 mol or less is more preferable, and 0.02 mol or less is most preferable because the recovery rate can be further improved and the purification effect of valsartan is equal or higher. preferable.

  As a method for adjusting the amount of water, first, the amount of water contained in the solution is measured using an automatic moisture measuring device (Karl Fischer) or the like. If the amount of water is within the range of the present invention, that is, 0.10 mol or less with respect to 1 mol of valsartan, the adjustment operation is not particularly necessary, and the recrystallization operation may be continued. However, since the water content of the solution is usually 0.20 mol or more and 0.50 mol or less with respect to 1 mol of valsartan, it is necessary to remove water from the solution. Although the operation is not particularly limited, a method of mixing the valsartan solution and the adsorbent and a method of concentrating the valsartan solution are preferable operations because the adjustment efficiency is good and the operation is simple. Hereinafter, each operation will be described in detail.

(Method of mixing valsartan solution and adsorbent)
Specifically, the method of mixing the valsartan solution and the adsorbent is performed by adding the adsorbent to the valsartan solution prepared in the container, mixing and stirring, and then solid-liquid separating the valsartan solution and the adsorbent. Done. The adsorbent to be used is not particularly limited as long as it adsorbs water. However, an adsorbent that does not produce impurities by reaction with valsartan or the like is preferable. Specific examples include organic compounds such as activated carbon, organic carriers such as organic polymer compounds such as polystyrene and polyacrylamide, metal oxides such as silica, alumina, magnesia, zirconia, boria and calcia, calcium sulfate, sodium sulfate, Potassium sulfate, cesium sulfate, calcium hydrogen sulfate, sodium hydrogen sulfate, magnesium sulfate, sodium sulfite, sodium hydrogen sulfite, calcium hydrogen sulfite, calcium sulfite, potassium nitrate, sodium nitrate, ammonium nitrate, uranyl nitrate, calcium nitrate, barium nitrate, sodium nitrite Inorganic carriers such as inorganic salts, etc., and diatomaceous earth, talc, calcite, dolomite, nitrate, chili nitrate, zeolite, pyrite, chalcopyrite, hematite, chalcopyrite, galena, galena, quartz, magnetite, corundum, rock salt , Fluorite, diaspore Goethite, minerals such as gibbsite, and the like. Among these, activated carbon, sodium sulfate, magnesium sulfate, silica gel, alumina, diatomaceous earth, and zeolite are preferable because of high water removal efficiency.

  The amount of adsorbent used depends on the amount of water contained in the valsartan solution, but if 5 parts by mass or more and 50 parts by mass or less are used with respect to 100 parts by mass of valsartan, a sufficient water removal effect can be obtained. Especially, 5 to 40 mass parts is preferable and 5 to 25 mass parts is more preferable from the point that the loss of valsartan by adsorption is small. The temperature for mixing with the adsorbent is 30 ° C. or higher and the reflux temperature (about 77 ° C.) or lower, but is preferably 35 ° C. or higher and 65 ° C. or lower, more preferably 40 ° C. or higher and 55 ° C. or lower from the viewpoint that isomerization can be suppressed. preferable. In addition, the said temperature may be the same as the preparation temperature of a valsartan solution, and may differ. The mixing time may be appropriately determined by measuring the water content of the solution or the like, but usually a sufficient water removal effect can be obtained in 0.01 minutes to 2 hours.

  After mixing with the adsorbent as described above, a valsartan solution with reduced water content can be obtained by solid-liquid separation by vacuum filtration, pressure filtration, centrifugation, or the like. In the solid-liquid separation, it is preferable to wash the adsorbent or the like with an ester as long as the amount of the ester used is satisfied. In this method, the operation may be repeated as necessary.

(Method of concentrating valsartan solution)
Specifically, the method of concentrating the valsartan solution is performed by distilling off the esters from the valsartan solution prepared in a container and concentrating the solution. Since the esters and water azeotrope, the water in the valsartan solution can be removed by this method. The amount of the esters to be concentrated may be determined so that the water content falls within the scope of the present invention. The concentration operation can be carried out in an atmosphere of air, nitrogen, argon or the like, aeration thereof, or under reduced pressure. However, since the heating temperature is low, isomerization can be suppressed, and the concentration efficiency is high, the concentration is reduced under reduced pressure. It is preferable to carry out. Moreover, although the temperature to concentrate is 0 degreeC or more and reflux temperature (about 77 degreeC), from the point which can suppress isomerization, 35 to 65 degreeC is preferable and 40 to 55 degreeC is more preferable. In addition, the said temperature may be the same as the preparation temperature of a valsartan solution, and may differ.

  The amount of esters to be concentrated depends on the amount of water contained in the valsartan solution and cannot be defined unconditionally, but may be determined as appropriate by measuring the amount of water in the solution. In addition, when valsartan is precipitated after the concentration is completed, the valsartan is less pure than valsartan to be crystallized from a solution and may contain a crystal form other than the intended one. It is necessary to add a kind and make it into a solution state again. The method is the same as the method for preparing the valsartan solution described above. However, when adding esters, it is preferable to use a reagent having a low water content, such as a super-dehydrated grade, as the esters to be used. Further, the amount used may be the same as the amount of concentrated esters, or may be different as long as it is in solution. Also in this operation, the method may be repeated as necessary as in the case of mixing with the adsorbent.

(Recrystallization method from valsartan solution)
As a method for recrystallizing valsartan from the solution of valsartan obtained as described above, a method of cooling the solution is preferable because a sufficient purification effect can be obtained and the crystal form can be stably controlled. At this time, if the cooling rate of the solution is too fast, the purity of the obtained valsartan tends to decrease, and if it is too slow, it is not efficient. / Hour or more and 50 ° C./hour or less, more preferably 5 ° C./hour or more and 30 ° C./hour or less.

  The ultimate temperature at the time of cooling is usually −5 ° C. or higher and 30 ° C. or lower. However, if the temperature is high, the recovery rate tends to decrease, and if it is too low, the purity tends to decrease. It is preferable to set it to 0 ° C. or less, in particular from 0 ° C. to 15 ° C. Although it varies somewhat depending on the conditions, usually, if the target temperature is 0.01 minutes to 50 hours, valsartan is sufficiently precipitated and the maximum recovery rate can be obtained.

  The valsartan precipitated as described above is separated into solid and liquid by vacuum filtration, pressure filtration, centrifugation, etc., and washed with an organic solvent such as water or esters to sufficiently remove the mother liquor. To be released. By drying the obtained wet body of valsartan, pure amorphous valsartan from which water and esters have been removed can be obtained.

  The drying can be performed under normal pressure, reduced pressure, or aeration of an inert gas such as nitrogen or argon. The temperature at which drying is performed is 10 ° C. or more and 80 ° C. or less, but is preferably 25 ° C. or more and 75 ° C. or less, more preferably 35 ° C. or more and 65 ° C. or less from the viewpoint that sufficient drying efficiency can be obtained and isomerization can be suppressed. preferable. Further, this temperature may be changed within the range during drying. The time for carrying out the drying may be determined by confirming the residual amount of an organic solvent such as water or esters. Usually, pure amorphous valsartan can be obtained in 1 hour to 250 hours.

  In the amorphous valsartan thus obtained, the recovery rate based on the mass of the crude valsartan as a raw material is improved by about 10% compared with the case where the same amount of esters is used. The obtained amorphous valsartan is highly purified valsartan with reduced impurities and can be suitably used as a pharmaceutical product.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not restrict | limited at all by these Examples.

(Measurement of water content of solutions of valsartan, esters and valsartan)
The water content of solutions of valsartan, esters and valsartan in Examples and Comparative Examples was measured by the Karl Fischer method. The apparatus used for the measurement and the measurement conditions are as follows. In addition, the water content of valsartan and esters was expressed in mass% based on the total mass of the detected water. On the other hand, the water content of the valsartan solution was expressed as the number of moles relative to 1 mole of dissolved valsartan by converting the detected water mass into a mole.
Apparatus: Automatic moisture measuring device CA-100 manufactured by Mitsubishi Chemical Corporation
Method: Karl Fischer volumetric titration system Titration reagent: Aquamicron titrant SS-Z 3 mg manufactured by Mitsubishi Chemical
Solvent: anhydrous methanol.

(Evaluation of crystal form of valsartan)
The crystal forms of valsartan in Examples and Comparative Examples were evaluated by XRD and DSC. The equipment used for each measurement and the measurement conditions are as follows.
(XRD)
Apparatus: RINT1200 X-ray powder diffractometer manufactured by Rigaku (using CuKα radiation having a wavelength of 1.541858 angstroms)
Voltage: 40 kV
Current: 30mA
Sampling width: 0.05 °
Scan speed: 1.0 ° / min
Scan range: 5 ° to 35 °
(DSC)
Apparatus: DSC8230 differential scanning calorimeter manufactured by Rigaku Corporation Atmosphere: nitrogen (50 mL / min.)
Temperature rising speed: 10 ° C / min
Temperature increase range: 20 ° C to 150 ° C

(Evaluation of the purity of valsartan)
Valsartan purity was measured by high performance liquid chromatography (HPLC). The apparatus used for the HPLC measurement and the measurement conditions are as follows. In addition, the purity of valsartan is a value expressed as a percentage of the peak area value of valsartan in the obtained chromatogram with respect to the sum of the area values of all peaks. In the HPLC analysis under the above conditions, the detection limit is 0.003%, and the retention time of valsartan is around 13.5 minutes.
Apparatus: 2695 manufactured by Waters
Detector: Ultraviolet absorptiometer (Waters 2489)
Detection wavelength: 225 nm
Column: A stainless tube having an inner diameter of 4.6 mm and a length of 15 cm filled with 5 μm of octadecylsilylated silica gel for liquid chromatography Mobile phase: a mixed solution of 500 mL of acetonitrile, 500 mL of water and 1 mL of acetic acid Flow rate: 1 mL / min.
Column temperature: constant temperature around 35 ° C

Production Example 1 (Production of crude valsartan)
In a 500 mL three-necked flask equipped with a stirring blade and a thermometer, N-{[2 ′-(1-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl] methyl} -N-valeryl-L was added. -65 g of valine benzyl ester and 110 g of methanol were added and stirred. Next, the mixture was heated and reacted at reflux temperature for 7 hours. After cooling the obtained reaction liquid, 7.5 g (3 mass%, 50% water content) of palladium carbon was added, and the reaction was further performed at 40 ° C. for 15 hours in a hydrogen atmosphere (0.1 MPa). After removing palladium carbon from the reaction solution by pressure filtration, 18 g of isopropyl alcohol and 80 g of ion-exchanged water were added to the residue obtained by concentration, and the pH was adjusted to 8 with a 10% by mass potassium hydroxide aqueous solution. After washing twice with 70 g of toluene, 110 g of ethyl acetate was added, and the pH was adjusted to 1 with 20 g of concentrated hydrochloric acid. After separating the organic layer, the aqueous layer was extracted with 55 g of ethyl acetate. The organic layers were mixed and washed twice with 25 g of water, and then the organic layer was concentrated under reduced pressure at 50 ° C. to remove the solvent. Furthermore, the obtained residue was dried under reduced pressure at 50 ° C. to obtain 355 g of crude valsartan. Its purity was 95.43% and the water content was 1.0%.

Example 1
In a 200 mL three-necked flask equipped with a stirring blade and a thermometer, 20.0 g (45.9 mmol) of the crude valsartan obtained in Production Example 1 and ethyl acetate (special grade reagent, 0.03% moisture content) After adding 90.0 g and heating to 45 ° C., the mixture was stirred at the same temperature for 10 minutes to obtain a solution of valsartan (water content: 0.27 mol). Next, 2.5 g of zeolite was added to the solution of valsartan and stirred at 45 ° C. for 1 hour. Zeolites were removed by pressure filtration to obtain a solution of valsartan (water content 0.09 mol). The solution of valsartan was cooled to about 5 ° C. at 15 ° C./hour, stirred for 20 hours at the same temperature, and then the crystals precipitated by pressure filtration were separated by filtration. The crystals separated by filtration were washed with 4.5 g of ethyl acetate to obtain a wet body of valsartan.

  The obtained wet body of valsartan was dried under reduced pressure at 60 ° C. for 20 hours to obtain 16.8 g of valsartan (recovery rate 84.1%) as white crystals. Its purity was 99.54% and the crystal form was amorphous. Production conditions and production results are shown in Table 1. The XRD and DSC charts of the valsartan are shown in FIGS.

Example 2
The same operation as in Example 1 was performed except that the mixing operation with zeolite was performed twice. That is, a valsartan solution having a water content of 0.04 mol was cooled with respect to 1 mol of valsartan, which was obtained by performing the mixing operation with zeolite twice, and recrystallized to obtain valsartan 17 as white crystals. 0.8 g (recovery 89.2%) was obtained. Its purity was 99.53% and the crystalline form was amorphous. Production conditions and production results are shown in Table 1.

Example 3
In the same manner as in Example 1, a valsartan solution (water content 0.27 mol) was obtained. Subsequently, it concentrated under pressure reduction at 45 degreeC, and 75.0 g of ethyl acetate was distilled off. 75.0 g of ethyl acetate (reagent ultra-dehydration grade, water content 0.001%) was added and stirred at 45 ° C. to obtain a solution of valsartan. The water content was 0.07 mol with respect to 1 mol of valsartan. Subsequently, when the solution of valsartan was cooled at 15 ° C./hour, crystals were precipitated at around 32 ° C. Furthermore, after cooling to around 5 ° C. and stirring at around the same temperature for 20 hours, the crystals were separated by pressure filtration. The crystals separated by filtration were washed with 4.5 g of ethyl acetate to obtain a wet body of valsartan. The obtained wet body of valsartan was dried under reduced pressure at 60 ° C. for 20 hours to obtain 17.1 g (recovery rate: 85.7%) of valsartan as white crystals. Its purity was 99.53% and the crystalline form was amorphous. Production conditions and production results are shown in Table 1.

Example 4
The same operation as in Example 3 was performed except that the concentration operation was performed twice. That is, the valsartan solution having a water content of 0.02 mol was cooled and recrystallized with respect to 1 mol of valsartan obtained by performing the concentration operation twice, and 18.2 g of valsartan as white crystals ( Recovery rate 90.9%) was obtained. Its purity was 99.50% and the crystal form was amorphous. Production conditions and production results are shown in Table 1.

Examples 5-9
The production was carried out in the same manner as in Example 1 except that the type of ester, the amount of water and the amount used, the number of adjustments of the amount of water in the valsartan solution, the type of adsorbent and the amount used were changed. Production conditions and production results are shown in Table 1.

Example 10
The same operation as in Example 3 was performed except that the concentration operation was performed three times. That is, the solution of valsartan having a water content of 0.02 mol was cooled with respect to 1 mol of valsartan, which was obtained by performing the concentration operation three times, and recrystallized to obtain 18.2 g of valsartan as white crystals ( Recovery rate 91.0%) was obtained. Its purity was 99.50% and the crystal form was amorphous. Production conditions and production results are shown in Table 1.

Comparative Example 1
It carried out like Example 1 except not having processed with zeolite. That is, the solution of valsartan (0.27 mol with respect to 1 mol of water valsartan) was cooled and recrystallized to obtain 15.5 g of valsartan (recovery rate 77.6%) as white crystals. Its purity was 99.53% and the crystalline form was amorphous. Production conditions and production results are shown in Table 2.

Comparative Example 2
This was carried out in the same manner as in Example 5 except that the treatment with sodium sulfate was not performed. That is, a solution of valsartan having a water content of 1 mol per mol of valsartan was cooled and recrystallized to obtain 15.7 g of valsartan as a white crystal (recovery rate of 78.7%). Its purity was 99.54% and the crystal form was amorphous. Production conditions and production results are shown in Table 2.

Comparative Example 3
It implemented like Example 2 except having used 0.9 g of zeolite. That is, a solution of valsartan having a water content of 0.13 mol with respect to 1 mol of valsartan was cooled and recrystallized to obtain 16.0 g of valsartan as a white crystal (recovery rate of 79.9%). Its purity was 99.53% and the crystalline form was amorphous. Production conditions and production results are shown in Table 2.

Comparative Example 4
It carried out like Example 7 except not having processed with zeolite. That is, a valsartan solution having a water content of 1 mol per mol of valsartan was cooled and recrystallized to obtain 11.8 g of valsartan as a white crystal (recovery rate 59.2%). Its purity was 99.56% and the crystal form was amorphous. Production conditions and production results are shown in Table 2.

Comparative Example 5
It carried out like Example 8 except not having processed with zeolite. That is, the solution of valsartan having a water content of 1 mol per mol of valsartan was cooled and recrystallized to obtain 7.4 g of valsartan as a white crystal (recovery rate 37.0%). Its purity was 99.56% and the crystal form was amorphous. Production conditions and production results are shown in Table 2.

Comparative Example 6
It carried out like Example 9 except not having processed with zeolite. That is, with respect to 1 mol of valsartan, the solution of valsartan having 0.31 mol was cooled and recrystallized to obtain 10.7 g of valsartan as a white crystal (recovery rate: 53.7%). Its purity was 99.44% and the crystal form was amorphous. Production conditions and production results are shown in Table 2.

Claims (2)

  A method for producing amorphous valsartan, characterized in that recrystallization is performed using a solution of valsartan and an ester having a water content of 0.10 mol or less with respect to 1 mol of valsartan. A method for producing valsartan.   The method for producing amorphous valsartan according to claim 1, wherein the esters are ethyl acetate.

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