CN102464669A - Amorphous everolimus and preparation method thereof - Google Patents

Amorphous everolimus and preparation method thereof Download PDF

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CN102464669A
CN102464669A CN 201010546471 CN201010546471A CN102464669A CN 102464669 A CN102464669 A CN 102464669A CN 201010546471 CN201010546471 CN 201010546471 CN 201010546471 A CN201010546471 A CN 201010546471A CN 102464669 A CN102464669 A CN 102464669A
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everolimus
ether
method according
alkane
cycloalkane
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CN 201010546471
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CN102464669B (en )
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刘自兵
吴忠伟
郭红军
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浙江海正药业股份有限公司
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Abstract

The invention relates to an everolimus amorphous solid and a preparation process thereof. The preparation process comprises the following steps of: dissolving everolimus into ester; and dropwise adding alkane or cyclane for separating an amorphous solid out.

Description

无定形依维莫司及其制备方法 Amorphous everolimus and preparation method

技术领域 FIELD

[0001] 本发明涉及一种依维莫司无定形固体及其制备工艺。 [0001] The present invention relates to an amorphous solid everolimus and its preparation process. 背景技术 Background technique

[0002] 雷帕霉素是由吸水链霉菌产生的大环三烯抗生素,发现它具有体外和体内抗真菌活性,特别是抗白色念珠菌[C. Vezina 等人,J. Antibiot. 28,721 (1975) ;SN Sehgal 等人,J. Antibiot. 28,727(1975) ;HA Baker 等人,J. Antibiot. 31,539(1978);美国专利3,929,992 和美国专利3,993,749]。 [0002] Rapamycin is produced by Streptomyces hygroscopicus macrocyclic triene antibiotic found to have in vitro and in vivo antifungal activity, particularly against Candida albicans [C. Vezina et al., J. Antibiot. 28,721 (1975);.. SN Sehgal et al., J Antibiot 28,727 (1975);.. HA Baker et al., J Antibiot 31,539 (1978); U.S. Patent No. 3,929,992 and U.S. Patent No. 3,993,749].

[0003] 雷帕霉素具有抗肿瘤(美国专利4,885,171和4,401,653)和免疫抑制作用[FASEB 3,3411(1989)],其用途包括预防或治疗系统性红斑疮[美国专利5,078,999], 肺炎[美国专利5,080,899],胰岛素依赖型糖尿病[炎性疾病研究协会第五次国际会议(Fifth Int. Conf. Inflamm. Res. Assoc.) 121 (摘要),(1990)],平滑肌细胞增生及血管损伤引起的内膜变厚[Morris, RJ心肺移植(Heart Lung Transplant) 11 (pt. 2); 197(1992)],成年人T细胞白血病/淋巴瘤[EP525,960A1]和眼炎[EP532,862A1]。 [0003] Rapamycin has antitumor (U.S. Patent No. 4,885,171 and 4,401,653) and immunosuppressive effects [FASEB 3,3411 (1989)], which uses include prevention or treatment of systemic lupus erythematosus sores [ US Patent 5,078,999] and pneumonia [US Patent 5,080,899], [fifth international Conference insulin-dependent diabetes, inflammatory diseases Research Association (fifth Int. Conf. Inflamm. Res. Assoc.) 121 ( Abstract), (1990)], smooth muscle cell proliferation and intimal vascular injury caused by thickening [Morris, RJ Heart and Lung transplantation (Heart Lung transplant) 11 (pt 2);. 197 (1992)], adult T-cell leukemia / lymphoma [EP525,960A1] and ocular inflammation [EP532,862A1]. 雷帕霉 Rapamycin

素和雷帕霉素衍生物包括依维莫司(结构式I) 一直被研究用于治疗这些以及其它疾病。 Hormone and rapamycin derivatives include everolimus (Formula I) has been investigated for treatment of these and other diseases.

[0004] [0004]

^Js. ^J"…'UIUIioy^ I ^ Js. ^ J "... 'UIUIioy ^ I

[0005] 依维莫司又名40-0-(2-羟基)乙基雷帕霉素,英文名everolimus,是雷帕霉素的衍生物,其合成描述于美国专利NO. 5,665,772和国际专利公开NO. W094/09010中。 [0005] Everolimus, also known as 40-0- (2-hydroxy) ethyl rapamycin, English name of everolimus, is a derivative of rapamycin, their synthesis is described in U.S. Patent NO. 5,665, 772 and international Patent Publication NO. in W094 / 09010. 其精制纯化专利描述于美国专利N0. 6,605,613B2,用乙酸乙酯和正己烷精制得到晶型固体。 Which was purified purified Patent described in US Patent N0. 6,605,613B2, to give a crystalline solid from ethyl acetate and n-hexane purified.

发明内容 SUMMARY

[0006] 本发明的目的在于研究了一种依维莫司无定形固体及其制备工艺。 [0006] The object of the present invention studied a everolimus amorphous solid and its preparation process.

[0007] 本发明的一方面,涉及一种依维莫司的无定形固体。 [0007] In one aspect the present invention relates to a everolimus amorphous solid. 本发明进一步涉及具有附图1所示的X射线衍射谱图的依维莫司无定形固体。 The present invention further relates to an amorphous solid everolimus having an X-ray diffraction spectrum is shown in the drawings.

[0008] 在本发明的另一方面中,涉及制备依维莫司(everolimus)无定形固体的方法,其特征在于将依维莫司溶于醚类,向其中滴加烷烃或环烷烃,析出无定形固体,若将此含固体的结晶液减压浓缩至1/3〜1/2体积,收率也将相应的提高。 [0008] In another aspect of the present invention relates to the preparation of everolimus (of everolimus) amorphous solid, characterized in that everolimus was dissolved in ether, added dropwise alkane or cycloalkane, precipitated amorphous solid, crystalline solids of this solution if concentrated to 1 / 3~1 / 2 will yield the corresponding volume increase under reduced pressure.

[0009] 在本发明的优选实施方案中,所述的醚优选C4〜C16对称或不对称醚,更优选乙醚、丙醚、异丙醚和/或甲基叔丁基醚。 [0009] In a preferred embodiment of the present invention, preferably the ether C4~C16 a symmetrical or asymmetrical ether, more preferably diethyl ether, dipropyl ether, diisopropyl ether and / or methyl tert-butyl ether.

[0010] 优选其所述的烷烃或环烷烃是C5〜C12的烷烃或环烷烃,更优选正己烷、正庚烷、 环己烷等烷烃或环烷烃类。 [0010] preferably the alkane or cycloalkane is C5~C12 alkane or cycloalkane, and more preferably n-hexane, n-heptane, cyclohexane, alkanes or cycloalkanes.

[0011] 在本发明的优选实施方案中,优选所述依维莫司与醚的比例(质量:体积)是1 : 5〜1 : 100,更优选是1 : 10〜1 : 50 ;优选所述依维莫司与烷烃或环烷烃的比例(质量:体积)是1 : 10〜1 : 100,更优选是1 : 10〜1 : 50。 [0011] In a preferred embodiment of the present invention, preferably, the ratio by everolimus with ether: is (mass volume) of 1: 5~1: 100, more preferably 1: 10~1: 50; preferably the and said ratio of everolimus alkane or cycloalkane (mass: volume) is 1: 10~1: 100, more preferably 1: 10~1: 50. 本发明所涉及的质量与体积的比例单位为g/ml。 Mass to volume ratio of the present invention is in units of g / ml.

[0012] 本发明的实施方案中,涉及精制母液可回收再精制,即将析出固体之后的母液浓缩至原来的约1/3体积,再根据依维莫司粗品的质量加入约1体积醚及约10体积的烷烃或环烷烃,再浓缩此精制溶液即可从母液中再精制出依维莫司。 [0012] In embodiments of the present invention relates to recyclable refined liquor purified mother liquor was concentrated to precipitate a solid after coming to about 1/3 original volume, then add 1 volume of ether about everolimus The mass of crude product and about 10 volumes of alkane or cycloalkane, and then this solution was concentrated to purification from the mother liquor and then purified everolimus.

[0013] 依维莫司合成描述于美国专利NO. 5,665,772和国际专利公开NO. W094/09010,以 [0013] The synthesis of everolimus is described in U.S. Patent NO. 5,665,772 and International Patent Publication NO. W094 / 09010, in

雷帕霉素为起始原料,在二氯甲烷中在二异丙基乙胺存在下与三氟甲磺酸叔丁基二甲基硅氧基乙基酯反应、经水解通过常规处理得到依维莫司产物。 Rapamycin as a starting material, the reaction in methylene chloride with trifluoroacetic acid tert-butyldimethylsilyloxy ethyl ester in the presence of diisopropylethylamine, to give after hydrolysis by treatment by a conventional everolimus product.

[0014] 本发明方法操作方便;处理的样品量大,便于工业化;母液可以回收再精制,可最大程度上减少损失,提高产品的收率。 [0014] The method of the present invention is easy to operate; large sample processing, easy industrialization; purification mother liquor can be recycled, the loss can be reduced to the maximum extent, improve the product yield.

附图说明 BRIEF DESCRIPTION

[0015] 附图1 :实施例1方法纯化得到的无定形依维莫司 [0015] Figure 1: Purification method of Example 1 to give amorphous everolimus

[0016] 其中,横坐标是2 θ角,纵坐标是峰强度。 [0016] wherein the abscissa is the angle 2 θ, and the ordinate is the peak intensity.

具体实施例 Specific Example

[0017] 附图1所示谱图的仪器、操作方法 Spectra shown in the instrument, the operation method of [0017] Figure 1

[0018] 仪器:Rigaku D/max-2200 [0018] Instrument: Rigaku D / max-2200

[0019] 操作方法:Cu靶连续扫描扫描速度:4° /分钟 [0019] Operation: Cu target continuous scan scanning speed: 4 ° / min

[0020] 扫描范围:3°〜40° [0020] Scanning range: 3 ° ~40 °

[0021] 实施例1 : [0021] Example 1:

[0022] 将Ig依维莫司粗品溶于20ml甲基叔丁基醚,室温搅拌,缓慢滴加40ml正己烷,析出固体,过滤,真空干燥得0. 46g类白色无定形依维莫司,纯度>99%,其X射线衍射光谱如附图1所示。 [0022] The Ig everolimus crude product was dissolved in 20ml t-butyl methyl ether, stirring at room temperature, was slowly added dropwise 40ml of n-hexane, and the precipitated solid was filtered and dried in vacuo to give 0. 46g white amorphous everolimus, purity> 99% X-ray diffraction spectrum as shown in Figure 1.

[0023] 实施例2 : [0023] Example 2:

[0024] 将Ig依维莫司粗品溶于40ml甲基叔丁基醚,室温搅拌,缓慢滴加40ml正庚烷,减压浓缩至约原来的2/5体积,析出大量固体,过滤,真空干燥得0. Sg类白色无定形依维莫司,纯度>99%。 [0024] The Ig everolimus crude product was dissolved in 40ml t-butyl methyl ether, stirred at room temperature, was slowly added dropwise 40ml of n-heptane, and concentrated under reduced pressure to about 2/5 the original volume, the precipitated solid was filtered in vacuo 0. Sg dried to give an off-white amorphous everolimus, purity> 99%. 所得产品的谱图同实施例1。 Spectrum of the product obtained in Example 1.

[0025] 实施例3 : [0025] Example 3:

[0026] 将IOg依维莫司粗品溶于200ml甲基叔丁基醚,室温搅拌,缓慢滴加400ml正己烷,析出固体,过滤,母液浓缩至三分之一体积,加入IOOml正己烷、IOml甲基叔丁基醚,再浓缩至三分之一体积,过滤,真空干燥得总共8. 2g类白色无定形依维莫司,纯度> 99%,其X射线衍射光谱如附图1所示。 [0026] The IOg everolimus crude product was dissolved in 200ml of MTBE, stirring at room temperature, was slowly added dropwise 400ml of n-hexane, and the precipitated solid was filtered, mother liquor was concentrated to one third volume, n-hexane was added IOOml, IOml methyl tert-butyl ether, and concentrated to one third volume, filtered, and dried in vacuo to give a total of 8. 2g white amorphous everolimus, purity> 99%, of its X-ray diffraction spectrum as shown in Figure 1 .

[0027] 实施例4 : [0027] Example 4:

[0028] 根据实施例2将甲基叔丁基醚替换成异丙醚,得类白色无定形依维莫司,纯度> 99%。 [0028] According to Example 2 to replace MTBE diisopropyl ether to give white amorphous everolimus, purity> 99%. 所得产品的谱图同实施例1。 Spectrum of the product obtained in Example 1.

[0029] 实施例5 : [0029] Example 5:

[0030] 根据实施例1将甲基叔丁基醚替换成乙醚,得类白色无定形依维莫司,纯度> 99%。 [0030] According to Example 1 replacing methyl tertiary butyl ether into diethyl ether to yield an off-white amorphous everolimus, purity> 99%. 所得产品的谱图同实施例1。 Spectrum of the product obtained in Example 1.

[0031] 实施例6: [0031] Example 6:

[0032] 根据实施例2将甲基叔丁基醚替换成丙醚,得类白色无定形依维莫司,纯度> 99%。 [0032] According to Example 2 to replace MTBE propyl ether to give white amorphous everolimus, purity> 99%. 所得产品的谱图同实施例1。 Spectrum of the product obtained in Example 1.

[0033] 实施例7 : [0033] Example 7:

[0034] 根据实施例2将正庚烷替换成环己烷,得类白色无定形依维莫司,纯度> 99 %。 [0034] Example 2 according to the alternative n-heptane to cyclohexane to give white amorphous everolimus, purity> 99%. 所得产品的谱图同实施例1。 Spectrum of the product obtained in Example 1.

Claims (12)

  1. 1. 一种依维莫司无定形固体,其特征在于具有如附图1所示的XPRD图谱。 An amorphous solid everolimus, characterized in that the XPRD pattern 1 shown in the figures.
  2. 2. 一种制备如权利要求1所述的依维莫司无定形固体的方法,包括,将依维莫司溶于醚中,向其中滴加烷烃或环烷烃,析出无定形固体。 A process for preparing an amorphous solid as claimed in claim everolimus method of claim 1, comprising, everolimus was dissolved in ether, added dropwise alkane or cycloalkane, the precipitated amorphous solid.
  3. 3.根据权利要求2所述的方法,其中所述的醚是指C4〜C16对称或不对称醚。 3. The method according to claim 2, wherein said ether is a symmetrical or asymmetrical ether C4~C16.
  4. 4.根据权利要求3所述的方法,其中所述的醚选自乙醚、丙醚、异丙醚和/或甲基叔丁基醚。 4. The method according to claim 3, wherein the ether is selected from diethyl ether, dipropyl ether, diisopropyl ether and / or methyl tert-butyl ether.
  5. 5.根据权利要求2-4任一项所述的方法,其中所述的烷烃或环烷烃是指C5〜C12的烷烃或环烷烃。 The method of any of claims 2-4, wherein said alkane or cycloalkane refers C5~C12 alkane or cycloalkane.
  6. 6.根据权利要求5所述的方法,其所述的烷烃或环烷烃选自正己烷、正庚烷或环己烷。 6. The method according to claim 5, in which the alkane or cycloalkane is selected from n-hexane, n-heptane or cyclohexane.
  7. 7.根据权利要求2-6任一项所述的方法,其所述依维莫司与醚的比例(质量:体积) 是1 : 5 〜1 : 100。 The method according to any of claims 2-6, which is the ratio of everolimus with ether (mass: volume) is 1: 5 ~ 1: 100.
  8. 8.根据权利要求2-7任一项所述的方法,其所述依维莫司与醚的比例(质量:体积) 是1 : 10 〜1 : 50。 8. A method according to any one of claims 2-7, which is the ratio of everolimus with ether (mass: volume) is 1:10 ~ 1: 50.
  9. 9.根据权利要求2-8任一项所述的方法,其所述依维莫司与烷烃或环烷烃的比例(质量:体积)是1 : 5〜1 : 100。 9. The method according to any one of claims 2-8, which is the ratio of everolimus with alkane or cycloalkane (mass: volume) is 1: 5~1: 100.
  10. 10.根据权利要求9所述的方法,其所述依维莫司与烷烃或环烷烃的比例(质量:体积)是1 : 10 〜1 : 50。 10. The method according to claim 9, which is the ratio of everolimus with alkane or cycloalkane (mass: volume) is 1:10 ~ 1: 50.
  11. 11.根据权利要求2所述的方法,其特征在于,在滴加烷烃或者环烷烃之后,对得到的结晶液进行减压浓缩除去部分溶剂。 11. The method according to claim 2, characterized in that, after the dropwise addition of an alkane or cycloalkane, of the crystallization solution was subjected to solvent was partially removed under reduced pressure and concentrated.
  12. 12.根据权利要求2所述的方法,其特征在于,析出固体之后剩余的精制母液可回收再精制。 12. The method according to claim 2, characterized in that, after precipitation of the remaining mother liquor was purified solid was purified recyclable.
CN 201010546471 2010-11-17 2010-11-17 Amorphous everolimus and preparation method thereof CN102464669B (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104892632A (en) * 2015-06-03 2015-09-09 道中道(菏泽)制药有限公司 Everolimus in crystal form and preparation method thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994009010A1 (en) * 1992-10-09 1994-04-28 Sandoz Ltd. O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants
US20020128470A1 (en) * 1996-09-11 2002-09-12 Peter Fuenfschilling Purification process
WO2003090684A2 (en) * 2002-04-24 2003-11-06 Sun Biomedical, Ltd. Polymer compositions containing a macrocyclic triene compound
CN1768066A (en) * 2003-03-31 2006-05-03 特瓦药厂有限公司 Crystallization and purification of macrolides
CN1856500A (en) * 2003-07-24 2006-11-01 特瓦药厂私人有限公司 Method of purifying macrolides

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994009010A1 (en) * 1992-10-09 1994-04-28 Sandoz Ltd. O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants
US20020128470A1 (en) * 1996-09-11 2002-09-12 Peter Fuenfschilling Purification process
WO2003090684A2 (en) * 2002-04-24 2003-11-06 Sun Biomedical, Ltd. Polymer compositions containing a macrocyclic triene compound
CN1768066A (en) * 2003-03-31 2006-05-03 特瓦药厂有限公司 Crystallization and purification of macrolides
CN1856500A (en) * 2003-07-24 2006-11-01 特瓦药厂私人有限公司 Method of purifying macrolides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
王博: "依维莫司(everolimus)", 《中国药物化学杂志》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104892632A (en) * 2015-06-03 2015-09-09 道中道(菏泽)制药有限公司 Everolimus in crystal form and preparation method thereof
CN104892632B (en) * 2015-06-03 2017-12-26 道中道(菏泽)制药有限公司 A crystal form and preparation method everolimus

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