WO2020224520A1 - Formes cristallines de 5-oxomilbémycines et leur procédé de préparation - Google Patents

Formes cristallines de 5-oxomilbémycines et leur procédé de préparation Download PDF

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WO2020224520A1
WO2020224520A1 PCT/CN2020/088110 CN2020088110W WO2020224520A1 WO 2020224520 A1 WO2020224520 A1 WO 2020224520A1 CN 2020088110 W CN2020088110 W CN 2020088110W WO 2020224520 A1 WO2020224520 A1 WO 2020224520A1
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ketomilbemycin
crystal form
methanol
ketokimilbemycin
heptane
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PCT/CN2020/088110
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Chinese (zh)
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朱明新
沈敢锋
余贞
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浙江海正药业股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to the field of pharmacy, especially the field of veterinary medicine. More specifically, the present invention relates to 5-ketomibemycin crystal form I and crystal form II and their preparation processes.
  • Milbemycins (milbemycins) is a sixteen-membered ring macrolide anthelmintic produced by Streptomyces. It was discovered by Sankyo Co., Ltd. in 1967. After nearly 20 years of improvement, it was used in 1986 with milbemycin oxime. oxime) was listed. Milbex oxime has a good effect on controlling and preventing most common parasitic diseases. It is usually used to prevent heartworm disease, control dog and cat diseases caused by nematodes and hookworms, and canine whipworm disease. Due to its high insecticidal activity and low toxicity, the LD 50 is more than 2000 times the recommended clinical dosage. At the same time, dogs that are sensitive to abamectin drugs are less toxic, so it has a good market prospect.
  • Milbex oxime is produced by fermentation and semi-synthesis.
  • the milbemycin A3 and A4 obtained by fermentation of Streptomyces are oxidized to obtain intermediate 5-ketomilbemycin A3 and A4, and then the obtained intermediate is subjected to oximation to obtain a mixture of milbemycin A3 and A4.
  • EP and USP have strict limits on the ratio of milbe oxime A3 and milbe oxime A4.
  • 5-keto milbemycin A3 and A4 are key intermediates.
  • CN108586481 discloses the extraction of the fermentation broth of 5-ketomilbemycin and the crystallization process of the mixture of 5-ketomilbemycin A3 and A4, but there is no information about 5-ketomilbemycin A3 and A4. Report on the crystalline forms of the components.
  • the prior art discloses a mixture of 5-ketomilbemycin A3 and A4. This mixture is not yet satisfactory in terms of stability, purity and quality stability of the ratio of A3 and A4. It is very necessary to prepare and study the crystal form of ketomilbemycin A3 and A4. The preparation of high-purity and stable single-component 5-ketokilmbemycin A3 and A4 will lay a solid foundation for the production of milbemycin with a stable ratio of A3 and A4 and high purity.
  • One of the objectives of the present invention is to provide two single-component crystal forms of 5-ketokimirbemycin, namely 5-ketokimirbemycin A3 crystal form I (abbreviated as crystal form I) and 5-ketokimirbemycin Bemycin A4 crystal form II (abbreviated as crystal form II).
  • the 5-ketomilbemycin A3 crystal form I of the present invention uses Cu-K ⁇ radiation, and the X-ray powder diffraction pattern expressed at 2 ⁇ angles has characteristic peaks at the following positions: 4.89 ⁇ 0.20°, 8.69 ⁇ 0.20 °, 13.64 ⁇ 0.20°, 14.71 ⁇ 0.20°, 16.66 ⁇ 0.20°, 19.85 ⁇ 0.20°, 20.90 ⁇ 0.20°.
  • the 5-ketomilbemycin A3 crystal form I of the present invention uses Cu-K ⁇ radiation, and the X-ray powder diffraction pattern expressed at 2 ⁇ angles further has characteristic peaks at the following positions: 14.45 ⁇ 0.20° , 15.33 ⁇ 0.20°, 17.08 ⁇ 0.20°, 17.82 ⁇ 0.20°, 19.24 ⁇ 0.20°, 22.29 ⁇ 0.20°, 23.01 ⁇ 0.20°, 23.51 ⁇ 0.20°.
  • the 5-ketomilbemycin A3 crystal form I of the present invention uses Cu-K ⁇ radiation, and the X-ray powder diffraction pattern expressed at 2 ⁇ angles further has characteristic peaks at the following positions: 12.16 ⁇ 0.20 °, 17.49 ⁇ 0.20°, 22.64 ⁇ 0.20°, 25.70 ⁇ 0.20°, 26.50 ⁇ 0.20°, 28.27 ⁇ 0.20°, 29.29 ⁇ 0.20°, 31.24 ⁇ 0.20°, 33.79 ⁇ 0.20°, 42.62 ⁇ 0.20°.
  • the XRPD pattern of 5-ketomilbemycin A3 crystal form I of the present invention is shown in FIG. 1.
  • the 5-ketomilbemycin A3 crystal form I of the present invention can be characterized by the infrared absorption spectrum measured by KBr tablet. According to the spectrum, it has characteristic peaks at the following positions: 2932cm -1 , 2922cm -1, 1727cm -1, 1677cm -1 , 1367cm -1, 1219cm -1, 1057cm -1, 995cm -1, 909cm -1.
  • the infrared absorption spectrum of 5-ketomilbemycin A3 crystal form I of the present invention also has characteristic peaks at the following positions: 3506cm -1 , 2966cm -1 , 2874cm -1 , 2856cm -1 , 1446cm -1 , 1379cm -1, 1276cm -1, 1180cm -1, 1167cm -1, 1035cm -1, 963cm -1, 887cm -1, 541cm -1, 483cm -1.
  • the differential scanning calorimetry (DSC) spectrum of the 5-ketomilbemycin A3 crystal form I of the present invention has two exothermic peaks at 208°C-212°C and 258°C-262°C.
  • thermogravimetric analysis (TGA) pattern of 5-ketomilbemycin A3 crystal form I of the present invention is shown in FIG. 4.
  • the 5-ketomilbemycin A4 crystal form II of the present invention uses Cu-K ⁇ radiation, and the X-ray powder diffraction pattern expressed at 2 ⁇ angles has characteristic peaks at the following positions: 5.13 ⁇ 0.20°, 9.00 ⁇ 0.20 °, 12.56 ⁇ 0.20°, 15.95 ⁇ 0.20°, 18.73 ⁇ 0.20°, 19.42 ⁇ 0.20°, 20.50 ⁇ 0.20°, 22.78 ⁇ 0.20°.
  • the 5-ketomilbemycin A4 crystal form II of the present invention uses Cu-K ⁇ radiation, and the X-ray powder diffraction pattern expressed at 2 ⁇ angles further has characteristic peaks at the following positions: 14.52 ⁇ 0.20° , 15.11 ⁇ 0.20°, 16.42 ⁇ 0.20°, 22.36 ⁇ 0.20°, 23.30 ⁇ 0.20°, 25.63 ⁇ 0.20°, 26.44 ⁇ 0.20°, 27.24 ⁇ 0.20°.
  • the 5-ketomilbemycin A4 crystal form II of the present invention uses Cu-K ⁇ radiation, and the X-ray powder diffraction pattern expressed at 2 ⁇ angles further has characteristic peaks at the following positions: 28.34 ⁇ 0.20 °, 29.40 ⁇ 0.20°, 30.35 ⁇ 0.20°, 32.15 ⁇ 0.20°, 34.70 ⁇ 0.20°, 41.64 ⁇ 0.20°.
  • the XRPD pattern of 5-ketomilbemycin A4 crystal form II of the present invention is shown in FIG. 5.
  • the 5-ketomilbemycin A4 crystal form II of the present invention can be characterized by the infrared absorption spectrum measured by KBr tablet. According to the spectrum, it has characteristic peaks at the following positions: 3510cm -1 , 2921cm -1 , 1677cm -1 , 1372cm -1 , 1243cm -1 , 1165cm -1 , 990cm -1 .
  • the infrared absorption spectrum of 5-ketomilbemycin A4 crystal form II of the present invention also has characteristic peaks at the following positions: 2956cm -1 , 2873cm -1 , 1459cm -1 , 1436cm -1 , 1334cm -1 , 1103cm -1, 1061cm -1, 964cm -1 , 948cm -1, 907cm -1, 887cm -1, 858cm -1, 820cm -1, 543cm -1, 487cm -1, 459cm -1.
  • the differential scanning calorimetry (DSC) spectrum of the 5-ketomilbemycin A4 crystal form II of the present invention has two exothermic peaks at 218°C-222°C and 258°C-262°C.
  • the DSC chart of 5-ketomilbemycin A4 crystal form II of the present invention is shown in FIG. 7.
  • Another object of the present invention is to provide a method for preparing 5-ketomilbemycin A3 crystal form I and 5-ketomilbemycin A4 crystal form II, which comprises the following steps:
  • Step (1) Load the crude extract of 5-ketomilbemycin on a reversed-phase preparation column, and elute with a methanol solution with a volume concentration of 60%-90% to obtain 5-ketomilbemycin respectively A3 collection solution and 5-ketokimilbemycin A4 collection solution;
  • Step (2) Respectively concentrate the 5-ketomilbemycin A3 and 5-ketomilbemycin A4 of step (1) to a methanol volume concentration of 45%-55% to obtain 5 -Ketomilbemycin A3 methanol concentrate and 5-ketomilbemycin A4 methanol concentrate, and then extracted with n-heptane to obtain 5-ketomilbemycin A3 n-heptane extract and 5 -Ketomilbemycin A4 n-heptane extract, which was concentrated, stirred and crystallized, filtered, and dried to obtain 5-ketokimilbemycin A3 crystal form I and 5-ketokimilbemycin A3 respectively A4 crystal form II.
  • the filler of the reverse phase preparation column in the step (1) is C18 or C8.
  • the crude extract is applied to the column, it is eluted with a methanol solution with a volume concentration of 60%-90%. Collect each fraction according to the peak condition, and then according to the HPLC analysis results of each fraction, combine the high purity parts of 5-ketomilbemycin A3 to obtain 5-ketomilbemycin A3 collection solution. The fractions with high purity of milbemycin A4 are combined to obtain 5-ketokimilbemycin A4 collection solution.
  • the volume ratio of the n-heptane and 5-ketomilbemycin A3 methanol concentrate used in the extraction in the step (2) is 1:1 to 2:1; the extraction in the step (2) is The volume ratio of n-heptane to 5-ketomilbemycin A4 methanol concentrate is 1:1 to 2:1.
  • the 5-ketomilbemycin A3 n-heptane extract is concentrated to a 5-ketomilbemycin A3 concentration of 50g/L ⁇ 150g/L;
  • -Ketomilbemycin A4 n-heptane extract is concentrated to a 5-ketomilbemycin A4 concentration of 50g/L ⁇ 150g/L.
  • the stirring time in the step (2) is 20-30 hours.
  • the temperature of crystallization in the step (2) is 10-30°C
  • the drying temperature in the step (2) is 30-40°C, and the drying time is 2 to 3 hours.
  • the crude 5-ketomilbemycin in step (1) is prepared by the following method:
  • the methanol or ethanol extract of kimilbemycin is concentrated to obtain a 5-ketokimilbemycin concentrate, and the concentrated solution is extracted with n-heptane to obtain a 5-ketokimilbemycin n-heptane extract;
  • the crude 5-ketomilbemycin is dissolved in a methanol aqueous solution with a volume concentration of more than 60% or an ethanol aqueous solution with a volume concentration of more than 60% to obtain a crude 5-ketomilbemycin extract, wherein the 5-
  • the crude ketomilbemycin can be prepared by a conventional synthesis method (for example, the synthesis method disclosed in CN105949217);
  • the 5-ketokimilbemycin fermentation broth in step (a) of the method 1 adopts the method disclosed in CN103789339, using Streptomyces F2-18 (see literature Huang Jun, Lin Jiatan, Zhou Min etc . Streptomyces hygroscopicus HS023 milF gene knockout constructs a genetically engineered strain producing 5-ketokimilbemycin. "Acta Microbiology", 2015, 55(1):107-113).
  • the ratio of the volume concentration of 80%-100% ethanol to mycelium is 4:1-10:1, the unit It is L/Kg, more preferably 5:1.
  • the ratio of the volume concentration of 80%-100% methanol to mycelium is 4:1-10:1, the unit It is L/Kg, more preferably 5:1.
  • the volume concentration of ethanol or methanol in the 5-ketomilbemycin concentrate in step (a) of the method 1 is 45-55%.
  • the volume ratio of n-heptane to 5-ketomilbemycin concentrate is 1:1 to 2:1.
  • the volume concentration of methanol or ethanol used in the method 2 is more than 95%.
  • the concentration of 5-ketokimilbemycin in the crude extract in the method 2 is 20-100 g/L.
  • the concentration in the present invention can be concentrated under reduced pressure, and the negative pressure is 0.08-0.1Mpa.
  • the inventors of the present invention have found that 5-ketokimirbemycin A3 crystal form I and 5-ketokimirbemycin A4 crystal form II after a lot of research fill in the prior art that there is nothing about 5-ketokimirbemycin.
  • the crystal forms I and II of the present invention have good stability, and no crystal conversion phenomenon is found when placed at room temperature for several months. The process is simple and easy to implement industrialization.
  • To produce 5-ketokimilbemycin A3 and A4 single-component crystals it is convenient to use 5-ketokimilbemycin A3 and A4 in accordance with the requirements of the A3 and A4 ratio in the quality standard of the Milbex oxime product.
  • Milbex oxime A3 is mixed in proportion and then oximated to produce a higher quality Milbex oxime with a stable proportion. It is also possible to directly produce milbexime A3 single-component or milbex oxime A4 single-component from 5-ketomilbemycin A3 and A4 single-component crystals as raw materials to adjust the proportion of the components in the Milbex oxime product. , To ensure that the ratio between Milbex oxime A3 and Milbex oxime A4 in the finished product meets the requirements.
  • the 5-ketomilbemycin in the present invention is a sixteen-membered ring macrolide compound containing 5-ketomilbemycin A3 and 5-ketomilbemycin A4, and its structure is as follows:
  • Both normal temperature and room temperature in the present invention refer to 10°C to 30°C.
  • Example 5 is the X-ray powder diffraction pattern of 5-ketomilbemycin A4 crystal form II obtained in Example 10.
  • Example 7 is the DSC chart of 5-ketomilbemycin A4 crystal form II obtained in Example 10.
  • the 5-ketomilbemycin fermentation broth used in the present invention is obtained by fermentation according to Example 1 of Chinese invention patent CN108586481.
  • the X-ray powder diffraction instrument and test conditions involved in the present invention are: X-ray diffraction instrument model Rigaku D/max-2115 Cu target; operation method: scanning speed 3°/min, scanning step width 0.01°.
  • the infrared spectrophotometer and test conditions involved in the present invention are: infrared spectrophotometer model: BRWKER VECTOR 22; operation method: KBr compression method with a scanning range of 400-4000 cm-1.
  • the DSC detector and test conditions involved in the present invention are: the model of the DSC detector is: NETZSCHDSC214; the operation method: the heating rate is 10°C/min, and the temperature range: 25°C to 300°C.
  • TGA detector and test conditions involved in the present invention are: TGA detector model: PerkinElmer TGA400; operation method: heating rate 10°C/min, temperature range: 30°C to 280°C.
  • the percentage concentration (%) of the ethanol or methanol solution in the present invention is the volume percentage concentration.
  • Example 2 Take 20L of the n-heptane extract obtained in Example 1 and concentrate it at 38°C and -0.095Mpa to an oily substance. Then add 0.6L of methanol with a volume concentration of 95% to dissolve and filter to obtain 0.7L of 5-ketokimilbemycin crude extract, which contains 5-ketokimilbemycin A3 and 5-ketokimilbemycin The total concentration of A4 is 50g/L, that is, the total mass of A3 and A4 is 35.15g.
  • Respectively concentrated under reduced pressure A3 mixture was concentrated to 6.2L, methanol content was 51%; A4 mixture was concentrated to 10.5L, methanol content was 47%.
  • a sample was taken for X-ray powder diffraction, DSC, TGA, and infrared analysis, and it was confirmed to be 5-ketomilbemycin A3 crystal form I.
  • the X-ray powder diffraction pattern is shown in Figure 1, and the infrared absorption pattern is shown in Figure 2.
  • the DSC spectrum is shown in Figure 3, and the TGA spectrum is shown in Figure 4.
  • Example 8 Take 6L of the 5-ketomilbemycin A4 n-heptane extract in Example 8 and concentrate it to 98.5mL, where the concentration of 5-ketomilbemycin A4 is 100g/L, stir and crystallize at room temperature for 25 hours, The crystalline liquid was suction filtered, and the wet crystal filter cake was rinsed with n-heptane. The wet crystals obtained were dried at 40°C and a negative pressure of 0.09Mpa for 3 hours to obtain 5.9g of 5-ketomilbemycin A4 crystals. The HPLC chromatographic purity of the crystal was 99.2%.
  • the crystal forms I and II obtained in Examples 9 and 10 were kept in 3 bags of each crystal form, and each bag was divided into 0.1 g, and they were packaged in a double-layer PE bag and an aluminum foil bag. Placed in a drug stability test box (temperature: 40°C, humidity 75%) for accelerated testing. Samples were taken at different time points of the placement cycle for 1 month, 2 months, and 3 months, and tested by XRPD and HPLC. The data are shown in Table 3.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

La présente invention concerne une forme cristalline I et une forme cristalline II de 5-oxomilbémycines. Les deux formes cristallines peuvent être représentées au moyen d'un motif de diffraction de rayons X sur poudre (XRPD), d'un motif de calorimétrie différentielle à balayage (DSC), d'un motif d'absorption infrarouge (IR) et analogues. De plus, la présente invention concerne également un procédé de préparation de la forme cristalline I et de la forme cristalline II de 5-oxomilbémycines. La pureté de la forme cristalline I et de la forme cristalline II de 5-oxomilbémycines qui sont produites au moyen du procédé selon la présente invention atteint jusqu'à 99,2 % ou plus, le rendement est élevé, et la stabilité est bonne.
PCT/CN2020/088110 2019-05-05 2020-04-30 Formes cristallines de 5-oxomilbémycines et leur procédé de préparation WO2020224520A1 (fr)

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CN109970758A (zh) * 2019-05-05 2019-07-05 浙江海正药业股份有限公司 5-酮基米尔贝霉素晶型及其制备方法

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CN104327094A (zh) * 2014-10-30 2015-02-04 湖北宏中药业有限公司 一种米尔贝肟的分离纯化方法
CN105061457A (zh) * 2015-08-20 2015-11-18 湖北宏中药业股份有限公司 一种米尔贝肟的合成方法
CN105254644A (zh) * 2015-11-04 2016-01-20 湖北宏中药业股份有限公司 一种米尔贝肟的制备方法
CN107586301A (zh) * 2016-07-06 2018-01-16 浙江海正药业股份有限公司 米尔贝a3肟晶型a及其制备方法
CN108586481A (zh) * 2018-05-14 2018-09-28 浙江海正药业股份有限公司 5-酮基米尔贝霉素发酵液的提取和结晶工艺
CN109970758A (zh) * 2019-05-05 2019-07-05 浙江海正药业股份有限公司 5-酮基米尔贝霉素晶型及其制备方法

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JPH0631246B2 (ja) * 1988-02-02 1994-04-27 三共株式会社 ５−オキソミルベマイシン誘導体の製造方法
CN105949217A (zh) * 2016-05-25 2016-09-21 浙江海正药业股份有限公司 一种米尔贝肟中间体的制备方法

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Publication number Priority date Publication date Assignee Title
CN104327094A (zh) * 2014-10-30 2015-02-04 湖北宏中药业有限公司 一种米尔贝肟的分离纯化方法
CN105061457A (zh) * 2015-08-20 2015-11-18 湖北宏中药业股份有限公司 一种米尔贝肟的合成方法
CN105254644A (zh) * 2015-11-04 2016-01-20 湖北宏中药业股份有限公司 一种米尔贝肟的制备方法
CN107586301A (zh) * 2016-07-06 2018-01-16 浙江海正药业股份有限公司 米尔贝a3肟晶型a及其制备方法
CN108586481A (zh) * 2018-05-14 2018-09-28 浙江海正药业股份有限公司 5-酮基米尔贝霉素发酵液的提取和结晶工艺
CN109970758A (zh) * 2019-05-05 2019-07-05 浙江海正药业股份有限公司 5-酮基米尔贝霉素晶型及其制备方法

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