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WO2012002189A1 - Procédé de fabrication de valsartan - Google Patents

Procédé de fabrication de valsartan Download PDF

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Publication number
WO2012002189A1
WO2012002189A1 PCT/JP2011/064032 JP2011064032W WO2012002189A1 WO 2012002189 A1 WO2012002189 A1 WO 2012002189A1 JP 2011064032 W JP2011064032 W JP 2011064032W WO 2012002189 A1 WO2012002189 A1 WO 2012002189A1
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Prior art keywords
valsartan
organic solvent
content
crude
ppm
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English (en)
Japanese (ja)
Inventor
隆行 宮奥
健次 田中
山本　博將
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Tokuyama Corp
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Tokuyama Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings

Definitions

  • the present invention relates to a novel method for producing valsartan, which is useful as an angiotensin II receptor antagonist for the treatment of hypertension and the like.
  • Valsartan is the official name, N-pentanoyl-N- [2 '-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -L-valine, represented by the following formula (1)
  • This valsartan is used as an angiotensin II receptor antagonist in antihypertensive drugs and the like.
  • Valsartan is used as a drug substance for the manufacture of antihypertensive drugs, so the purity must be very high.
  • various production methods have been studied for the purpose of producing high-purity valsartan (see, for example, Patent Documents 1 to 7).
  • Valsartan is considered to be influenced by its chemical structure and crystallinity, but it is a compound that is very easy to occlude a solvent therein.
  • a method for removing an organic solvent contained in valsartan hereinafter also referred to as a drying method
  • drying method a method for removing an organic solvent contained in valsartan.
  • drying methods for reducing the organic solvent contained in valsartan to 5000 ppm or less.
  • the first method is a method in which a solid crude valsartan produced by synthesis in an organic solvent is dried at room temperature, pulverized, and further dried (see Patent Document 1). More specifically, in this method, first, the crude valsartan is dried at room temperature until the content of the organic solvent is 5 to 20%, and then the dried crude valsartan is further pulverized to obtain 40 to 60 This is a method of drying at 0 ° C.
  • crude valsartan containing 10% or less of an organic solvent obtained through the synthesis step is (1) a method of pulverizing in water and then drying at 4 to 50 ° C., (2) 25 There are known a method of drying in an atmosphere of -50 ° C. and a humidity of 30% or more, or (3) a method of drying at 5-60 ° C. for a long time (see Patent Document 2). More specifically, the second method is a method of drying valsartan containing a minimum amount of 2% organic solvent by any one of the methods (1) to (3). These methods are excellent drying methods, and can reduce the content of an optical isomer of valsartan, which is an impurity (hereinafter referred to as an enantiomer of valsartan), to 0.10% or less.
  • an optical isomer of valsartan which is an impurity (hereinafter referred to as an enantiomer of valsartan), to 0.10% or less.
  • the above method is an excellent production method because the amount of the organic solvent can be reduced as compared with other known drying methods for drying valsartan at a temperature range of 20 to 60 ° C.
  • it has been found that it is difficult to reduce the organic solvent in valsartan to a high degree, specifically to less than 3000 ppm, even in the above method.
  • Patent Document 2 there is a case where water treatment is required or humidity management is required, and there is room for improvement in that the operation becomes complicated.
  • an object of the present invention is to provide a method for producing valsartan having a low content of an organic solvent and a low content of an enantiomer as an impurity.
  • the present inventors have conducted intensive research in order to solve the above problems.
  • the inventors of the present invention conducted various studies by paying attention to the relationship between the increased amount of enantiomer and the content of the organic solvent when valsartan was dried.
  • the enantiomer content greatly increased when valsartan was dried at a relatively high temperature.
  • valsartan was dried at a relatively low temperature, it was found that there is a limit in reducing the content of the organic solvent.
  • the drying method was further examined based on the above examination results. As a result, it was found that when a crude valsartan containing a predetermined amount or less of an organic solvent and a crude valsartan containing a predetermined amount or less of an enantiomer is dried at 50 to 65 ° C., the organic solvent can be efficiently reduced. . Furthermore, in this case, it has been found that an increase in enantiomers can be effectively suppressed, and as a result, highly pure valsartan can be obtained. The present invention has been completed on the basis of these results.
  • the present invention provides a valsartan enantiomer content characterized by drying crude valsartan having a valsartan enantiomer content of 0.20% or less and an organic solvent content of 3000 ppm to 25000 ppm at a temperature of 50 to 65 ° C. Is 0.25% or less, and the organic solvent content is 1000 ppm or less.
  • the crude valsartan is obtained by precipitating valsartan obtained by synthesis in an organic solvent, and then separating the precipitated valsartan crystals, so that the enantiomer content of valsartan is 0. It is preferably obtained by drying a wet body of valsartan having a content of 20% or less and an organic solvent content of 150,000 to 600,000 ppm at a temperature of less than 50 ° C.
  • valsartan having an enantiomer content of valsartan of 0.25% or less and an organic solvent content of 1000 ppm or less can be produced.
  • the organic solvent content of valsartan can be reduced to an extremely small amount as compared with the conventional production method.
  • dried and highly purified valsartan can be obtained with high yield and high efficiency.
  • Valsartan is used as an angiotensin II receptor antagonist in antihypertensive drugs and the like.
  • Valsartan obtained by the above production method can be used as the active ingredient in a highly reliable preparation without any change in crystal form or dissolution behavior.
  • valsartan can be produced without increasing the enantiomer of valsartan, which is an impurity. Therefore, its industrial utility value is extremely high.
  • FIG. 1 is a graph showing the amount of increase in enantiomers when crude valsartan having different organic solvent contents is dried at 60 ° C.
  • the present invention relates to a method for producing valsartan and high-purity valsartan.
  • the present invention provides a high-purity valsartan by preparing a crude valsartan having a predetermined range of enantiomer content and a predetermined range of organic solvent content, and drying the crude valsartan in a temperature range of a predetermined range.
  • drying means an operation for reducing the amount of organic solvent contained in the crude valsartan to be dried.
  • the organic solvent content refers to the mass ratio of the organic solvent contained in valsartan to be measured.
  • the organic solvent content is a value measured by a method by gas chromatography (GC) described in Examples described later.
  • the enantiomer content was measured by high performance liquid chromatography (HPLC) described in Examples. In the obtained chromatogram, the ratio (area%) of the peak area of the enantiomer to the total peak area of valsartan and the enantiomer was defined as the enantiomer content.
  • the purity of valsartan was measured by HPLC described in Examples. In the obtained chromatogram, the ratio (area%) of the total peak area of valsartan and the enantiomer of valsartan to the total peak area of the measurement sample was defined as the purity of valsartan.
  • the starting material is crude valsartan.
  • the crude valsartan has an organic solvent content of 3000 ppm to 25000 ppm and an enantiomer content of 0.20% or less.
  • the above crude valsartan is dried at a temperature of 50 to 65 ° C. to obtain valsartan having an enantiomer content of valsartan of 0.25% or less and an organic solvent content of 1000 ppm or less.
  • the crude valsartan used in the production method of the present invention is not particularly limited as long as it satisfies the above organic solvent content and enantiomer content, and any crude valsartan can be used.
  • this crude valsartan is close to the final product, it is preferable to have a high purity.
  • the purity of the crude valsartan cannot be limited unconditionally due to a slight difference depending on production conditions and the like, but is preferably 99.50% or more. Considering industrial production and use of valsartan after drying as the drug substance, it is preferably 99.90% or more.
  • Organic solvent contained in crude valsartan is derived from an organic solvent used for synthesis of valsartan, an organic solvent used during purification, and the like.
  • a solvent used for synthesis and purification there are usually the following organic solvents.
  • Alcohols such as methanol, ethanol, propanol, isopropyl alcohol, 1-butanol, 2-butanol, pentanol, hexanol, octanol, dimethyl ether, diethyl ether, ethyl methyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran, tetrahydropyran, dioxane, etc.
  • Ethers acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valeronitrile, isovaleronitrile, acrylonitrile and other nitriles, hexane, heptane, pentane, octane, cyclohexane, cycloheptane, methylcyclohexane, methylcycloheptane, Aliphatic hydrocarbons such as cyclooctane and decalin, acetone, methyl ethyl ketone, 3-methyl-2- Ketones such as Tanone, Pentanone, Cyclopentanone and Cyclohexanone, Aromatic hydrocarbons such as Toluene, Xylene and Ethylzenzen, Halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene, Halogenation such as dichloromethane and dichloroethane chloroform Aliphatic hydrocarbons,
  • alcohols such as methanol, ethanol, propanol, isopropyl alcohol, and 1-butanol
  • ethers such as dimethyl ether, diethyl ether, ethyl methyl ether, diisopropyl ether, and tetrahydrofuran
  • nitriles such as acetonitrile
  • hexane Aliphatic hydrocarbons such as heptane, pentane, octane, cyclohexane and methylcyclohexane, ketones such as acetone, methyl ethyl ketone and 3-methyl-2-butanone
  • aromatic hydrocarbons such as toluene and xylene
  • Halogenated aromatic hydrocarbons such as, halogenated aliphatic hydrocarbons such as dichloromethane and chloroform, ethyl acetate, propyl acetate, isopropyl
  • the organic solvent is preferably an acetate ester, an aliphatic hydrocarbon, or a mixed solvent thereof from the viewpoint of easy preparation of crude valsartan.
  • These organic solvents are organic solvents that can be suitably used when purifying valsartan synthesized by a known method. When these organic solvents are used as a solvent for recrystallization of valsartan, the enantiomer content of crude valsartan can be effectively reduced.
  • Acetic esters are used as good solvents for valsartan.
  • Aliphatic hydrocarbons are used as poor solvents for valsartan.
  • acetates are preferable, and ethyl acetate is most preferable.
  • crude valsartan having an organic solvent content of 3000 ppm to 25000 ppm is dried at 50 to 65 ° C.
  • crude valsartan having an organic solvent content exceeding 25000 ppm is dried at a temperature within the above temperature range, the content of the enantiomer increases, which is not preferable.
  • Valsartan contains an organic solvent exceeding 25000 ppm
  • Valsartan is easily dissolved in the organic solvent during drying at a temperature within the above temperature range.
  • valsartan becomes amorphous and is converted to an enantiomer. According to the above concept, it can be seen that the drying within the above temperature range and the limitation of the organic solvent content of the crude valsartan before drying have very important meanings.
  • the amount of the organic solvent contained in the crude valsartan is preferably 20000 ppm or less, and particularly preferably 15000 ppm or less.
  • the lower limit of the amount of organic solvent contained in the crude valsartan is preferably as small as possible. However, in consideration of restrictions on production facilities, economy, etc., the lower limit of the amount of organic solvent contained in the crude valsartan is practically 3000 ppm or more, preferably 4000 ppm or more, and more preferably 5000 ppm or more.
  • the organic solvent content contained in the crude valsartan is the content of a single organic solvent when the solvent is a single organic solvent. When a plurality of solvents are included, it is the total content of the plurality of organic solvents.
  • Enantiomers contained in crude valsartan are impurities. It is desirable that the enantiomer content of the final product valsartan, such as the drug substance, be as low as possible. In order to meet this demand, the enantiomer content of the crude valsartan used in the present invention is 0.20% or less, preferably 0.15% or less, more preferably 0.10% or less, and 0.05% or less. Particularly preferred.
  • the lower limit of the enantiomer content of crude valsartan is ideally 0.00% (below the detection limit).
  • the enantiomer content of crude valsartan is preferably 0.01% or more, and more preferably 0.02% or more.
  • Enantiomers in crude valsartan are produced when synthesizing valsartan. This enantiomer can be efficiently reduced by, for example, a purification method in which crystallization is performed using acetic esters which are good solvents.
  • valsartan is synthesized according to the method described in the above-mentioned patent document to obtain a wet body of valsartan. Subsequently, the organic solvent content and the enantiomer content of the wet body of valsartan are adjusted so as to fall within the ranges defined in the present invention.
  • a method for preparing crude valsartan will be described with a specific example.
  • valsartan is synthesized as follows. First, valsartan is synthesize
  • the separated valsartan is crystallized using an organic solvent such as ethyl acetate.
  • the obtained valsartan crystal is a solid wet substance containing an organic solvent used for crystallization.
  • the content of the organic solvent occluded in the wet body of valsartan exceeds 25000 ppm.
  • valsartan is dissolved in ethyl acetate at 50 ° C. Subsequently, valsartan precipitates by cooling to 10 degreeC. Solid-liquid separation is performed to obtain a wet body of valsartan containing ethyl acetate.
  • valsartan with few enantiomers is synthesized by the method described in Patent Document 2, and the valsartan is recrystallized in the same manner as described above to obtain a wet body.
  • the content of the enantiomer of the wet body of valsartan (hereinafter sometimes simply referred to as “wet body”) is preferably 0.20% or less.
  • the content of the enantiomer contained in the wet body is more preferably 0.15% or less, further preferably 0.10% or less, 0.05 % Or less is particularly preferable.
  • a method for bringing the content of the enantiomer of the wet body of valsartan within the above range a method of purification by crystallization in an organic solvent is preferable. By repeating the crystallization, the enantiomer content can be controlled within the above range.
  • the organic solvent used for crystallization is preferably an acetate ester, particularly ethyl acetate.
  • the lower limit of the enantiomeric content of the wet body is preferably the same as the lower limit of the enantiomeric content of the crude valsartan, specifically 0.00% (below the detection limit). . However, considering the case of industrial production, it is desirable that it is 0.01% or more, and further it is desirable that it is 0.02% or more.
  • the purity of valsartan in the wet body is preferably in the same range as the purity of the crude valsartan. Specifically, the purity is preferably 99.50% or more, and more preferably 99.90% or more in consideration of industrial production.
  • the wet body is a solid obtained by crystallization of valsartan in an organic solvent and solid-liquid separation. Therefore, the organic solvent content of the wet body is usually 150,000 ppm or more and 600000 ppm or less. However, the content of the organic solvent becomes 150,000 ppm or more and 500,000 ppm or less if dried or left a little.
  • the wet body it is preferable to induce the wet body to crude valsartan having an organic solvent content of 25000 ppm or less as soon as possible.
  • the wet body obtained by precipitating synthesized valsartan crystals from an organic solvent and separating the organic solvent and the crystals is dried without storage and the organic solvent content is 25000 ppm or less. It is preferable to lead to crude valsartan.
  • FIG. 1 is a graph showing the relationship between the content of organic solvent in crude valsartan and the amount of increase in enantiomer when crude valsartan having different organic solvent contents is dried at 60 ° C. From FIG. 1, it can be seen that when the organic solvent content in the crude valsartan exceeds 25000 ppm, the amount of increase in enantiomer increases rapidly.
  • the crude valsartan can be obtained by reducing the organic solvent without increasing the enantiomer.
  • the drying temperature is preferably 45 ° C. or lower.
  • the lower limit of the drying temperature is not particularly limited, but is preferably 0 ° C. or higher, more preferably 10 ° C. or higher.
  • the drying temperature is preferably 35 ° C. or higher.
  • the said drying temperature is the temperature of the atmosphere at the time of drying a wet body.
  • the organic solvent used for crystal precipitation is preferably an acetate ester, particularly ethyl acetate.
  • the atmosphere is not particularly limited, but it is preferably performed in air or an inert atmosphere, particularly preferably in a nitrogen atmosphere or under reduced pressure. .
  • drying is preferably performed under reduced pressure in order to shorten the period in which the wet body exists and at the same time increase productivity.
  • the drying time is 3 to 100 hours, preferably 8 to 50 hours.
  • the degree of vacuum may be appropriately determined according to the structure of the drying apparatus, the amount of organic solvent contained in the wet body, the drying time (treatment time), and the like, and is usually preferably 0.01 to 100 mmHg.
  • a known dryer may be used as the dryer to obtain the crude valsartan by drying the wet body in the above temperature range under reduced pressure.
  • a conical dryer or a shelf dryer is preferable, and the wet body can be efficiently dried by using this.
  • a crude valsartan having an enantiomer content of valsartan of 0.20% or less and an organic solvent content of 3000 ppm to 25000 ppm as impurities can be efficiently obtained.
  • the purity of the crude valsartan is preferably 99.50% or more as described above.
  • the greatest feature of the present invention is that the above crude valsartan is dried at a temperature of 50 to 65 ° C. Next, a method for drying this crude valsartan will be described.
  • crude valsartan having an enantiomer content of 0.20% or less and an organic solvent content of 3000 ppm to 25000 ppm is dried in a temperature range of 50 to 65 ° C.
  • crude valsartan having an enantiomer content of 0.20% or less the content of enantiomer contained in the finally obtained valsartan (hereinafter sometimes referred to as purified valsartan) can be reduced.
  • crude valsartan having an organic solvent content of 3000 ppm or more and 25000 ppm or less is used and dried at a temperature within a temperature range of 50 to 65 ° C.
  • the organic solvent of crude valsartan is suppressed in a short time while suppressing the increase in enantiomers.
  • the content can be reduced.
  • an increase in the enantiomer content of the purified valsartan cannot be suppressed even if it is dried at a temperature of 50 to 65 ° C.
  • the drying temperature of the crude valsartan is more preferably 55 to 65 ° C, and further preferably 55 to 60 ° C. This drying temperature is the temperature of the atmosphere when the crude valsartan is dried.
  • the atmosphere is not particularly limited, but is preferably under a nitrogen atmosphere and under reduced pressure.
  • the degree of reduced pressure is appropriately determined according to the structure of the drying apparatus, the amount of organic solvent contained in the wet body, the drying time, and the like.
  • the degree of vacuum is preferably 0.01 to 100 mmHg.
  • the drying time may be appropriately determined according to the desired organic solvent content of purified valsartan, but is usually 3 to 100 hours, preferably 3 to 50 hours. is there.
  • a known dryer may be mentioned.
  • a conical dryer or a shelf dryer is preferable. By using this, the crude valsartan can be efficiently dried.
  • the organic solvent content of the purified valsartan obtained by drying as described above is usually 1000 ppm or less, preferably 500 ppm or less.
  • the lower limit of the organic solvent content of purified valsartan is most preferably 0 ppm (below the detection limit).
  • the organic solvent content is usually 20 ppm or more.
  • the enantiomer content of purified valsartan is 0.25% or less, preferably 0.20% or less, particularly preferably 0.10% or less.
  • the lower limit of the enantiomer content of purified valsartan is most preferably 0.00% (below the detection limit). However, in industrial production of valsartan, the enantiomer content is usually 0.01% or more.
  • the purity of the refined valsartan depends on the purity of the crude valsartan used, so it cannot be defined unconditionally. However, according to the production method of the present invention, the purity of the purified valsartan is 99.50% or more, preferably 99.90% or more.
  • the purified valsartan obtained by the production method of the present invention has a low organic solvent content, a very low enantiomeric content, and a high purity.
  • the purified valsartan can be pulverized as necessary, and can be suitably used as an angiotensin II receptor antagonist as a therapeutic agent for hypertension and the like.
  • the organic solvent content was measured by gas chromatography (GC). The organic solvent content was quantified using a calibration curve prepared in advance. The content was expressed in ppm (mass basis).
  • the equipment used and the measurement conditions are described below.
  • the temperature was raised to 230 ° C. at 35 ° C. per minute and maintained for another 3 minutes.
  • the measurement conditions were inlet temperature (200 ° C.), detector temperature (250 ° C.), carrier gas (helium), and split (1/10).
  • the above measurement is performed by dissolving the target valsartan in a solvent.
  • the solvent used for dissolving valsartan may be any solvent that can be separated from the organic solvent to be detected under the above measurement conditions.
  • dimethylformamide was used as a solvent for dissolving valsartan.
  • Valsartan purity was measured using high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • Apparatus 2695 manufactured by Waters Detector: Ultraviolet absorptiometer (Waters 2489) Detection wavelength: 225 nm
  • Column Stainless steel tube column with an inner diameter of 4.6 mm and a length of 15 cm. The filler was 5 ⁇ m 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. The measurement conditions were mobile phase flow rate (1 mL / min) and column temperature (constant temperature around 35 ° C.).
  • the enantiomer content was measured by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • Apparatus 2695 manufactured by Waters Detector: Ultraviolet absorptiometer (Waters 2489) Detection wavelength: 230 nm
  • Column Stainless steel tube column with an inner diameter of 4.6 mm and a length of 25 cm.
  • the filler was silica gel for liquid chromatography coated with 5 ⁇ m cellulose carbamate derivative.
  • Mobile phase a mixed solution of 850 mL of hexane, 150 mL of 2-propanol and 1 mL of trifluoroacetic acid.
  • the measurement conditions were mobile phase flow rate (0.8 mL / min) and column temperature (constant temperature around 35 ° C.).
  • the reaction solution was filtered to remove the Pd—C catalyst, and the filtrate was concentrated.
  • 200 mL of isopropyl alcohol and 800 mL of ion-exchanged water were added, and then the pH was adjusted to 8 with 1350 mL of a 10 mass% aqueous potassium hydroxide solution.
  • extraction operation was performed twice using 750 mL of toluene.
  • 1250 mL of ethyl acetate was added to the aqueous layer, and the pH was adjusted to 1 using 200 mL of concentrated hydrochloric acid.
  • Valsartan had a purity of 99.96% and an enantiomer content of 0.03%.
  • the organic solvent content was confirmed by GC.
  • the content of ethyl acetate was 510350 ppm.
  • Example 1 (Preparation of crude valsartan) 40 g of the valsartan wet body obtained in Production Example 1 was placed in a glass petri dish having an inner diameter of 20 cm, and dried under reduced pressure (10 mmHg) at 40 ° C. for 10 hours with a shelf dryer to prepare crude valsartan.
  • a glass petri dish having an inner diameter of 20 cm
  • reduced pressure 10 mmHg
  • valsartan 99.96%, enantiomeric content 0.03%, and organic solvent content analyzed by GC were ethyl acetate content 10410 ppm.
  • Examples 2-7 Purified valsartan was produced in the same manner as in Example 1 except that the drying temperature and time for preparing the crude valsartan of Example 1 and the drying temperature and time for drying the crude valsartan were changed. The results are shown in Table 1.
  • Valsartan was produced in the same manner as in Example 1 except that the drying temperature and time for preparing the crude valsartan of Example 1 and the drying temperature and time for drying the crude valsartan were changed. The results are shown in Table 2.

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Abstract

L'invention concerne un procédé de fabrication de valsartan ayant une teneur en énantiomère de valsartan de 0,25 % ou moins et une teneur en solvant organique de 1 000 ppm ou moins, qui comprend le séchage de valsartan brut ayant une teneur en énantiomère de valsartan de 0,20 % ou moins et une teneur en solvant organique de 3 000 à 25 000 ppm inclus à une température de 50 à 65 °C. Le valsartan brut est obtenu par exemple par séchage d'une substance humide de valsartan ayant une teneur en énantiomère de valsartan de 0,20 % ou moins et une teneur en solvant organique de 150 000 à 600 000 ppm inclus, obtenue par dépôt de valsartan obtenu par synthèse dans un solvant organique et séparation des cristaux déposés de valsartan à une température inférieure à 50 °C.
PCT/JP2011/064032 2010-06-30 2011-06-20 Procédé de fabrication de valsartan Ceased WO2012002189A1 (fr)

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JP2016141643A (ja) * 2015-02-02 2016-08-08 株式会社トクヤマ バルサルタンの製造方法
CN112603894A (zh) * 2020-12-31 2021-04-06 浙江华海药业股份有限公司 一种缬沙坦颗粒的制备方法

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JP2016141643A (ja) * 2015-02-02 2016-08-08 株式会社トクヤマ バルサルタンの製造方法
CN112603894A (zh) * 2020-12-31 2021-04-06 浙江华海药业股份有限公司 一种缬沙坦颗粒的制备方法

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