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    One pot synthesis of tetrazole derivatives of rapamycin
    1.
    发明授权
    One pot synthesis of tetrazole derivatives of rapamycin 有权
    雷帕霉素四唑衍生物的一锅合成

    公开(公告)号：US08129521B2

    公开(公告)日：2012-03-06

    申请号：US12711072

    申请日：2010-02-23

    申请人： Madhup K. Dhaon ,  Chi-nung Hsiao ,  Subhash R. Patel ,  Peter J. Bonk ,  Sanjay R. Chemburkar ,  Yong Y. Chen

    发明人： Madhup K. Dhaon ,  Chi-nung Hsiao ,  Subhash R. Patel ,  Peter J. Bonk ,  Sanjay R. Chemburkar ,  Yong Y. Chen

    IPC分类号： C07D498/18

    CPC分类号： C07D498/18

    摘要： A single-step, one-pot process to obtain zotarolimus and other rapamycin derivatives on large scale is presented, which improves currently available synthesis schemes. In one embodiment, dried rapamycin is dissolved in isopropylacetate (IPAc). The solution is cooled, and 2,6-Lutidine is added, followed slowly adding triflic anhydride at −30° C. Salts are then removed by filtration. Tetrazole, followed by a tert-base diisopropylethylamine (DIEA) is added to the triflate solution. After incubation at room temperature, the product is concentrated and purified by a silica gel column using THF/heptane as eluant. The fractions containing the product are collected, concentrated, and purified again using an acetone/heptane column. The product containing fractions are concentrated. The product is dissolved in t-BME and precipitated with heptane. The solids are dissolved in acetone, treated with butylated-hydroxy toluene (BHT), and the solution concentrated. The process is repeated twice with acetone to remove solvents. At least one stabilizing agent is added, such as BHT at 0.5% before drying.

    摘要翻译： 提出了大规模获得唑他莫司和其他雷帕霉素衍生物的单步一锅法，改进了现有的合成方案。 在一个实施方案中，将干燥的雷帕霉素溶于乙酸异丙酯（IPAc）中。 将溶液冷却，加入2,6-二甲基吡啶，然后在-30℃下缓慢加入三氟甲磺酸酐。然后通过过滤除去盐。 然后向该三氟甲磺酸酯溶液中加入四唑，然后加入叔丁基二异丙基乙胺（DIEA）。 在室温下孵育后，将产物浓缩并通过硅胶柱纯化，使用THF /庚烷作为洗脱剂。 收集含有产物的级分，浓缩并再次使用丙酮/庚烷柱纯化。 将含产物的级分浓缩。 将产物溶于t-BME中并用庚烷沉淀。 将固体溶解在丙酮中，用丁基化羟基甲苯（BHT）处理，浓缩溶液。 用丙酮重复该过程两次以除去溶剂。 在干燥前加入至少一种稳定剂，例如0.5％的BHT。

    ONE POT SYNTHESIS OF TETRAZOLE DERIVATIVES OF RAPAMYCIN
    2.
    发明申请
    ONE POT SYNTHESIS OF TETRAZOLE DERIVATIVES OF RAPAMYCIN 有权
    一种合成RAPAMYCIN的四唑衍生物的方法

    公开(公告)号：US20100204466A1

    公开(公告)日：2010-08-12

    申请号：US12711072

    申请日：2010-02-23

    申请人： Madhup K. Dhaon ,  Chi-nung Hsiao ,  Subhash R. Patel ,  Peter J. Bonk ,  Sanjay R. Chemburkar ,  Yong Chen

    发明人： Madhup K. Dhaon ,  Chi-nung Hsiao ,  Subhash R. Patel ,  Peter J. Bonk ,  Sanjay R. Chemburkar ,  Yong Chen

    IPC分类号： C07D498/18

    CPC分类号： C07D498/18

    摘要： A single-step, one-pot process to obtain zotarolimus and other rapamycin derivatives on large scale is presented, which improves currently available synthesis schemes. In one embodiment, dried rapamycin is dissolved in isopropylacetate (IPAc). The solution is cooled, and 2,6-Lutidine is added, followed slowly adding triflic anhydride at −30° C. Salts are then removed by filtration. Tetrazole, followed by a tert-base diisopropylethylamine (DIEA) is added to the triflate solution. After incubation at room temperature, the product is concentrated and purified by a silica gel column using THF/heptane as eluant. The fractions containing the product are collected, concentrated, and purified again using an acetone/heptane column. The product containing fractions are concentrated. The product is dissolved in t-BME and precipitated with heptane. The solids are dissolved in acetone, treated with butylated-hydroxy toluene (BHT), and the solution concentrated. The process is repeated twice with acetone to remove solvents. At least one stabilizing agent is added, such as BHT at 0.5% before drying.

    摘要翻译： 提出了大规模获得唑他莫司和其他雷帕霉素衍生物的单步一锅法，改进了现有的合成方案。 在一个实施方案中，将干燥的雷帕霉素溶于乙酸异丙酯（IPAc）中。 将溶液冷却，加入2,6-二甲基吡啶，然后在-30℃下缓慢加入三氟甲磺酸酐。然后通过过滤除去盐。 然后向该三氟甲磺酸酯溶液中加入四唑，然后加入叔丁基二异丙基乙胺（DIEA）。 在室温下孵育后，将产物浓缩并通过硅胶柱纯化，使用THF /庚烷作为洗脱剂。 收集含有产物的级分，浓缩并再次使用丙酮/庚烷柱纯化。 将含产物的级分浓缩。 将产物溶于t-BME中并用庚烷沉淀。 将固体溶解在丙酮中，用丁基化羟基甲苯（BHT）处理，浓缩溶液。 用丙酮重复该过程两次以除去溶剂。 在干燥前加入至少一种稳定剂，例如0.5％的BHT。

    One pot synthesis of tetrazole derivatives of rapamycin
    3.
    发明授权
    One pot synthesis of tetrazole derivatives of rapamycin 有权
    雷帕霉素四唑衍生物的一锅合成

    公开(公告)号：US07700614B2

    公开(公告)日：2010-04-20

    申请号：US11300671

    申请日：2005-12-14

    申请人： Madhup K. Dhaon ,  Chi-nung Hsiao ,  Subhash R. Patel ,  Peter J. Bonk ,  Sanjay R. Chemburkar ,  Yong Chen

    发明人： Madhup K. Dhaon ,  Chi-nung Hsiao ,  Subhash R. Patel ,  Peter J. Bonk ,  Sanjay R. Chemburkar ,  Yong Chen

    IPC分类号： C07D498/18

    CPC分类号： C07D498/18

    摘要： A single-step, one-pot process to obtain zotarolimus and other rapamycin derivatives on large scale is presented, which improves currently available synthesis schemes. In one embodiment, dried rapamycin is dissolved in isopropylacetate (IPAc). The solution is cooled, and 2,6-Lutidine is added, followed slowly adding triflic anhydride at −30° C. Salts are then removed by filtration. Tetrazole, followed by a tert-base diisopropylethylamine (DIEA) is added to the triflate solution. After incubation at room temperature, the product is concentrated and purified by a silica gel column using THF/heptane as eluant. The fractions containing the product are collected, concentrated, and purified again using an acetone/heptane column. The product containing fractions are concentrated. The product is dissolved in t-BME and precipitated with heptane. The solids are dissolved in acetone, treated with butylated-hydroxy toluene (BHT), and the solution concentrated. The process is repeated twice with acetone to remove solvents. At least one stabilizing agent is added, such as BHT at 0.5% before drying.

    摘要翻译： 提出了大规模获得唑他莫司和其他雷帕霉素衍生物的单步一锅法，改进了现有的合成方案。 在一个实施方案中，将干燥的雷帕霉素溶于乙酸异丙酯（IPAc）中。 将溶液冷却，加入2,6-二甲基吡啶，然后在-30℃下缓慢加入三氟甲磺酸酐。然后通过过滤除去盐。 然后向该三氟甲磺酸酯溶液中加入四唑，然后加入叔丁基二异丙基乙胺（DIEA）。 在室温下孵育后，将产物浓缩并通过硅胶柱纯化，使用THF /庚烷作为洗脱剂。 收集含有产物的级分，浓缩并再次使用丙酮/庚烷柱纯化。 将含产物的级分浓缩。 将产物溶于t-BME中并用庚烷沉淀。 将固体溶解在丙酮中，用丁基化羟基甲苯（BHT）处理，浓缩溶液。 用丙酮重复该过程两次以除去溶剂。 在干燥前加入至少一种稳定剂，例如0.5％的BHT。

    One pot synthesis of tetrazole derivatives of sirolimus
    5.
    发明申请
    One pot synthesis of tetrazole derivatives of sirolimus 有权
    一锅合成西罗莫司的四唑衍生物

    公开(公告)号：US20080167335A1

    公开(公告)日：2008-07-10

    申请号：US11300671

    申请日：2005-12-14

    申请人： Madhup K. Dhaon ,  Chi-nung Hsiao ,  Subhash R. Patel ,  Peter J. Bonk ,  Sanjay R. Chemburkar ,  Yong Y. Chen

    发明人： Madhup K. Dhaon ,  Chi-nung Hsiao ,  Subhash R. Patel ,  Peter J. Bonk ,  Sanjay R. Chemburkar ,  Yong Y. Chen

    IPC分类号： A61K31/436 ,  C07D267/00

    CPC分类号： C07D498/18

    摘要： A single-step, one-pot process to obtain zotarolimus and other rapamycin derivatives on large scale is presented, which improves currently available synthesis schemes. In one embodiment, dried rapamycin is dissolved in isopropylacetate (IPAc). The solution is cooled, and 2,6-Lutidine is added, followed slowly adding triflic anhydride at −30° C. Salts are then removed by filtration. Tetrazole, followed by a tert-base diisopropylethylamine (DIEA) is added to the triflate solution. After incubation at room temperature, the product is concentrated and purified by a silica gel column using THF/heptane as eluant. The fractions containing the product are collected, concentrated, and purified again using an acetone/heptane column. The product containing fractions are concentrated. The product is dissolved in t-BME and precipitated with heptane. The solids are dissolved in acetone, treated with butylated-hydroxy toluene (BHT), and the solution concentrated. The process is repeated twice with acetone to remove solvents. At least one stabilizing agent is added, such as BHT at 0.5% before drying.

    摘要翻译： 提出了大规模获得唑他莫司和其他雷帕霉素衍生物的单步一锅法，改进了现有的合成方案。 在一个实施方案中，将干燥的雷帕霉素溶于乙酸异丙酯（IPAc）中。 将溶液冷却，加入2,6-二甲基吡啶，然后在-30℃下缓慢加入三氟甲磺酸酐。然后通过过滤除去盐。 然后向该三氟甲磺酸酯溶液中加入四唑，然后加入叔丁基二异丙基乙胺（DIEA）。 在室温下孵育后，将产物浓缩并通过硅胶柱纯化，使用THF /庚烷作为洗脱剂。 收集含有产物的级分，浓缩并再次使用丙酮/庚烷柱纯化。 将含产物的级分浓缩。 将产物溶于t-BME中并用庚烷沉淀。 将固体溶解在丙酮中，用丁基化羟基甲苯（BHT）处理，浓缩溶液。 用丙酮重复该过程两次以除去溶剂。 在干燥前加入至少一种稳定剂，例如0.5％的BHT。