WO2010095425A1 - Procédé pour produire des cristaux de dérivé de vitamine d - Google Patents

Procédé pour produire des cristaux de dérivé de vitamine d Download PDF

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Publication number
WO2010095425A1
WO2010095425A1 PCT/JP2010/000985 JP2010000985W WO2010095425A1 WO 2010095425 A1 WO2010095425 A1 WO 2010095425A1 JP 2010000985 W JP2010000985 W JP 2010000985W WO 2010095425 A1 WO2010095425 A1 WO 2010095425A1
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WIPO (PCT)
Prior art keywords
vitamin
crystals
derivative
formula
carboxylic acid
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PCT/JP2010/000985
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English (en)
Japanese (ja)
Inventor
ジョージ ナガ ワンヨイケ
貴秀 重山
葉月 永井
麻子 豊田
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メルシャン株式会社
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Application filed by メルシャン株式会社 filed Critical メルシャン株式会社
Publication of WO2010095425A1 publication Critical patent/WO2010095425A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4

Definitions

  • the present invention relates to a method for producing crystals of paricalcitol which is a vitamin D derivative useful as a pharmaceutical product.
  • Vitamin D derivatives particularly 1-hydroxy-19-norvitamin D derivatives are known to exhibit various physiological activities.
  • paricalcitol represented by the formula (I) has been found as a compound showing differentiation inducing activity of malignant cells (see Patent Document 1, Non-Patent Documents 1 and 2), and at present, Widely used as a treatment for hyperthyroidism in patients with chronic renal failure.
  • Patent Document 4 As a purification method by crystallization, a crystallization method in an organic solvent such as an ether having 2 to 6 carbon atoms, an ester having 2 to 4 carbon atoms, or a ketone having 3 to 5 carbon atoms is known (Patent Document 4). reference).
  • This method includes steps of dissolving a vitamin D derivative represented by the formula (I) in an organic solvent, concentrating, further cooling crystallization, and collecting by filtration.
  • operations such as solvent concentration and apparatus cooling require a long time.
  • the minimum time required for obtaining crystals after starting work is a minimum of one day for the concentration step, one day for the cooling step, and one day for the filtration step. Including the drying process of the target product, 4 days are required.
  • JP-T-3-505330 (WO90 / 10620) US Patent 5,086,191, US Patent 5,281,731 US Patent Publication No. 2007/0093458
  • Patent Documents 1 to 4 and Non-Patent Documents 1 to 2 are specifically incorporated herein by reference.
  • the present invention provides a method for producing a crystal of a vitamin D derivative represented by the formula (I), which can be carried out in a shorter time and can be carried out economically.
  • the inventors of the present invention have been diligently researching to solve the above-mentioned problems.
  • the vitamin D derivative represented by the formula (I) is dissolved in a carboxylic acid, and a high purity crystal is obtained by adding an appropriate poor solvent. It was found that can be obtained with good yield. That is, the present invention includes the following [1] to [11].
  • the carboxylic acid is acetic acid, propionic acid, or a mixture thereof.
  • the method of [1], wherein the hydrocarbon is an alkane.
  • the target product can be obtained in good yield, 2) The target product can be manufactured in a short time because there are few steps, 3) The cost can be reduced because it can be performed in a short time, and 4) Therefore, it is possible to suppress the occurrence of operational troubles. 5) No special equipment such as HPLC is required.
  • the present invention is an efficient purification method that can be implemented industrially and that can complete the work in a very short time.
  • a feature of the present invention is that a high purity crystal of the vitamin D derivative is obtained by dissolving a crude product of the vitamin D derivative represented by the formula (I) in a carboxylic acid and then adding hydrocarbon or water as a poor solvent. It is to obtain with good yield.
  • a crude product of the vitamin D derivative represented by the formula (I) that can be used as a raw material in the present invention can be prepared by a known method disclosed in patents, literatures, etc., and its purity is 70-99.5%. The degree may be sufficient and may be appropriately selected according to the purity of the target crystal.
  • a crystal having a purity of about 99% can be obtained from a raw material having a purity of about 95%.
  • the purity of the vitamin D derivative represented by the formula (I) is measured by the following method.
  • a sample to be measured is dissolved in methanol to prepare a 1 mg / ml solution, and this solution is analyzed by an HPLC analysis method in which conditions and the like are described in Examples.
  • the purity obtained by dividing the area of the target peak on the HPLC chart by the total total area of all the peaks included in the elution time (analysis time) from 0 to 75 minutes is taken as the percentage.
  • the carboxylic acid that can be used in the present invention can be a carboxylic acid having 2 to 6 carbon atoms, preferably acetic acid, propionic acid, or a mixture thereof.
  • the hydrocarbon can be an alkane, preferably a hydrocarbon having 6 to 7 carbon atoms or a mixture thereof.
  • Preferred examples include n-hexane and n-heptane.
  • the carboxylic acid can be used, for example, in an amount of 10 to 50 ml, preferably 22 to 40 ml, based on 1 g of the crude vitamin D derivative represented by the formula (I).
  • the hydrocarbon can be used, for example, in an amount of 50 to 200 ml, preferably 68 to 156 ml, based on 1 g of the crude product.
  • 5 to 100 ml of water can be used with respect to 1 g of the crude product, preferably 13 to 46 ml.
  • the temperature at which the crude body of the vitamin D derivative represented by the formula (I) is dissolved and the temperature at which the crystals are precipitated may be room temperature. No special heating, cooling and / or concentration operations are used in the step of dissolving the crude vitamin D derivative and the step of precipitating crystals.
  • room temperature means, for example, a range of 5 to 40 ° C., and preferably a range of 10 to 30 ° C.
  • the melting temperature and the crystal precipitation temperature can be the same temperature.
  • the time for precipitating the crystals is about 10 to 120 minutes, but it is preferably 45 minutes to 1 hour.
  • the crystals thus precipitated can be isolated by a commonly used solid-liquid separation method. For example, it can be isolated by filtration using a Kiriyama funnel or a Buchner funnel.
  • the obtained crystals can be subjected to a step of washing with a solvent.
  • the solvent used for washing is not particularly limited as long as it does not react with the crystals and has a low ability to dissolve, but the hydrocarbon or water used in the crystallization step is preferable. Since the solubility of crystals is high, washing with a solvent containing a carboxylic acid is not preferable.
  • the washed crystal is dried under reduced pressure of a vacuum pump. Drying is sufficient for 6 to 30 hours, preferably 10 to 25 hours.
  • the drying temperature may be room temperature. As described above, in the method of the present invention, it can be completed in 1 to 2 days from the start of the operation until the crystal is obtained.
  • Example 1 (Example) Acetic acid was used as a dissolving solvent and n-heptane was used as a poor solvent, and the vitamin D derivative represented by the formula (I) was crystallized as follows. A crude product of vitamin D derivative represented by the formula (I) (50 mg, purity 95.4%) was dissolved in acetic acid (1.15 ml). Add n-heptane (4.8 ml) with stirring. After stirring for 45 minutes, the precipitated crystals were collected by filtration with a Kiriyama funnel (21 mm ⁇ , using No. 5c filter paper). The crystals were washed with n-heptane (1 ml ⁇ 2). The dissolution, precipitation and washing of the crude product were performed at room temperature (23 ° C.). At room temperature, the crystals were dried for 20 hours under vacuum pump vacuum. White powder (27.5 mg, yield 55.0%). Purity 98.6% by HPLC.
  • Example 2 (Example) Acetic acid was used as a dissolving solvent and n-hexane was used as a poor solvent, and the vitamin D derivative represented by the formula (I) was crystallized as follows. A crude product of vitamin D derivative represented by the formula (I) (50 mg, purity 95.4%) was dissolved in acetic acid (1.15 ml). Add n-hexane (4.6 ml) with stirring. After stirring for 45 minutes, the precipitated crystals were collected by filtration with a Kiriyama funnel (21 mm ⁇ , using No. 5c filter paper). The crystals were washed with n-hexane (1 ml ⁇ 2). The dissolution, precipitation and washing of the crude product were performed at room temperature (23 ° C.). The crystals were dried at room temperature for 20 hours under vacuum pump vacuum. White powder (25.7 mg, yield 51.5%). Purity 98.7% by HPLC.
  • Example 3 (Example) Acetic acid was used as a dissolving solvent and water was used as a poor solvent, and the vitamin D derivative represented by the formula (I) was crystallized as follows. A crude product of vitamin D derivative represented by the formula (I) (50 mg, purity 95.4%) was dissolved in acetic acid (1.15 ml). Purified water (0.65 ml) is added with stirring. After stirring for 45 minutes, the precipitated crystals were collected by filtration with a Kiriyama funnel (21 mm ⁇ , using No. 5c filter paper). The crystals were washed with purified water (1 ml ⁇ 2). The dissolution, precipitation and washing of the crude product were performed at room temperature (23 ° C.). The crystals were dried at room temperature for 25 hours under vacuum pump vacuum. White powder (37.1 mg, 74.3% yield). Purity 97.9% by HPLC.
  • Example 4 Using propionic acid as the dissolving solvent and n-heptane as the poor solvent, the vitamin D derivative represented by the formula (I) was crystallized as follows. A crude product of vitamin D derivative represented by the formula (I) (50 mg, purity 95.0%) was dissolved in propionic acid (1.4 ml). Add n-heptane (3.4 ml) with stirring. After stirring for 45 minutes, the precipitated crystals were collected by filtration with a Kiriyama funnel (21 mm ⁇ , using No. 5c filter paper). The crystals were washed with n-heptane (1 ml ⁇ 2). The dissolution, precipitation and washing of the crude product were performed at room temperature (23 ° C.). The crystals were dried at room temperature for 17 hours under vacuum pump vacuum. White powder (32.1 mg, 64.1% yield). Purity 98.2% by HPLC.
  • Example 5 Using propionic acid as the dissolving solvent and water as the poor solvent, the vitamin D derivative represented by the formula (I) was crystallized as follows. A crude product of vitamin D derivative represented by the formula (I) (50 mg, purity 95.0%) was dissolved in propionic acid (1.4 ml). While stirring, purified water (2.3 ml) is added. After stirring for 45 minutes, the precipitated crystals were collected by filtration with a Kiriyama funnel (21 mm ⁇ , using No. 5c filter paper). The crystals were washed with purified water (1 ml ⁇ 2). The dissolution, precipitation and washing of the crude product were performed at room temperature (23 ° C.). The crystals were dried at room temperature for 17 hours under vacuum pump vacuum. White powder (39.6 mg, yield 79.2%). Purity 97.7% by HPLC.
  • Example 6 (Example) Acetic acid was used as a dissolving solvent and n-heptane was used as a poor solvent, and the vitamin D derivative represented by the formula (I) was crystallized as follows. A crude product of vitamin D derivative represented by the formula (I) (50 mg, purity 98.2%) was dissolved in acetic acid (1.1 ml). Add n-heptane (5.1 ml) with stirring. After stirring for 55 minutes, the precipitated crystals were collected by filtration with a Kiriyama funnel (21 mm ⁇ , using No. 5c filter paper). The crystals were washed with n-heptane (1 ml ⁇ 2). The dissolution, precipitation and washing of the crude product were performed at room temperature (23 ° C.). The crystals were dried at room temperature for 20 hours under vacuum pump vacuum. White powder (32.5 mg, yield 65.0%). Purity 99.4% by HPLC.
  • Example 7 (Example) Acetic acid was used as a dissolving solvent and n-hexane was used as a poor solvent, and the vitamin D derivative represented by the formula (I) was crystallized as follows. A crude product of vitamin D derivative represented by the formula (I) (50 mg, purity 98.2%) was dissolved in acetic acid (1.1 ml). Add n-hexane (7.8 ml) with stirring. After stirring for 45 minutes, the precipitated crystals were collected by filtration with a Kiriyama funnel (21 mm ⁇ , using No. 5c filter paper). The dissolution, precipitation and washing of the crude product were performed at room temperature (23 ° C.). The crystals were washed with n-hexane (1 ml ⁇ 2). The crystals were dried at room temperature for 17 hours under vacuum pump vacuum. White powder (39.6 mg, yield 79.2%). Purity 99.3% by HPLC.
  • Example 8 (reference example) Acetone was used as the dissolving solvent and water was used as the poor solvent, respectively, and the following procedure was performed according to the method described in Example 1 of Patent Document 4.
  • Acetone (7.5 ml) was added to a crude product of vitamin D derivative represented by the formula (I) (50 mg, purity 95.4%) and dissolved by applying ultrasonic waves for 15 minutes. This was filtered to remove insolubles, and purified water (0.75 ml) was added. Dissolution of the crude product and addition of purified water were performed at room temperature (23 ° C.). This was concentrated under reduced pressure until the liquid volume became 5 ml and allowed to stand at ⁇ 13 ° C. for 17 hours. The produced crystals were collected by filtration and washed with cold acetone (1.8 ml). The crystals were dried at room temperature for 18 hours under vacuum pump vacuum. White needle crystal (19.0 mg, yield 38.0%). Purity 98.3% by HPLC.
  • Example 9 (reference example) Acetone was used as the dissolving solvent and water was used as the poor solvent, respectively, and the following procedure was performed according to the method described in Example 1 of Patent Document 4.
  • Acetone (15 ml) was added to a crude vitamin D derivative represented by the formula (I) (100 mg, purity 98.7%), and dissolved by applying ultrasonic waves for 15 minutes. This was filtered to remove insolubles, and purified water (1.5 ml) was added. Dissolution of the crude product and addition of purified water were performed at room temperature (23 ° C.). This was concentrated under reduced pressure until the liquid volume reached 10 ml and allowed to stand at ⁇ 13 ° C. for 17 hours. The produced crystals were collected by filtration and washed with cold acetone (3.7 ml). The crystals were dried at room temperature for 13 hours under vacuum pump vacuum. White needle crystal (32.5 mg, yield 32.5%). Purity 99.1% by HPLC.
  • Example 10 (Example) Acetic acid was used as a dissolving solvent and water was used as a poor solvent, and the vitamin D derivative represented by the formula (I) was crystallized as follows. A crude product (200 mg, purity 99.3%) of the vitamin D derivative represented by the formula (I) was dissolved in acetic acid (6.6 ml). Purified water (7.0 ml) was added with stirring. After stirring for 60 minutes, the precipitated crystals were collected by filtration with a Kiriyama funnel (21 mm ⁇ , using No. 5c filter paper). The crystals were washed with purified water (2 ml ⁇ 3). The dissolution, precipitation and washing of the crude product were performed at room temperature (23 ° C.). The crystals were dried at room temperature for 17 hours under vacuum pump vacuum. White powder (192.2 mg, 96.1% yield). Purity 99.6% by HPLC.
  • Table 1 summarizes the results of Examples 1-10.
  • the crystal form was determined by comparison with the powder X-ray crystallographic data described in Patent Document 4.

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  • Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne un procédé pour produire des cristaux d'un dérivé de vitamine D représenté par la formule (I), avec lequel la production peut être effectuée de manière économique en un temps plus court que les procédés conventionnels. Un matériau brut du dérivé de vitamine D représenté par la formule (I) est dissous à température ambiante dans un acide carboxylique (acide acétique ou acide propionique), où 10 à 50 ml de l'acide carboxylique sont utilisés par gramme du matériau brut, et en outre un solvant faible approprié (un hydrocarbure ou l'eau) est ajouté à celui-ci, de manière à précipiter des cristaux du dérivé de vitamine D. Ensuite, les cristaux précipités sont séparés par filtration et séchés, de manière à obtenir des cristaux de pureté élevée du dérivé de vitamine D. Les cristaux cibles peuvent être obtenus à un rendement élevé en un temps plus court que les procédés conventionnels.
PCT/JP2010/000985 2009-02-17 2010-02-17 Procédé pour produire des cristaux de dérivé de vitamine d WO2010095425A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2009033489A JP2012096996A (ja) 2009-02-17 2009-02-17 ビタミンｄ誘導体の結晶化方法
JP2009-033489 2009-02-17

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5115609A (en) * 1974-07-27 1976-02-07 Eisai Co Ltd 5 66 toransuubitamin d noketsushokaho
JPS59104358A (ja) * 1982-12-03 1984-06-16 Teijin Ltd １α，２４−ジヒドロキシコレカルシフエロ−ルの一水塩及びその製造法
US20070093458A1 (en) * 2005-07-18 2007-04-26 Anchel Schwartz Preparation of paricalcitol and crystalline forms thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5115609A (en) * 1974-07-27 1976-02-07 Eisai Co Ltd 5 66 toransuubitamin d noketsushokaho
JPS59104358A (ja) * 1982-12-03 1984-06-16 Teijin Ltd １α，２４−ジヒドロキシコレカルシフエロ−ルの一水塩及びその製造法
US20070093458A1 (en) * 2005-07-18 2007-04-26 Anchel Schwartz Preparation of paricalcitol and crystalline forms thereof

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