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1. 发明申请

US20080214876A1 Process for Preparation of Pharmaceutically Pure Anhydrous Calcipotriol 失效
标题翻译：药物纯无水二硫代三醇的制备方法
公开(公告)号：US20080214876A1
公开(公告)日：2008-09-04
申请号：US11813211
申请日：2005-12-29
申请人： Andrzej Kutner , Michal Chodynski , Teresa Ryznar , Hanna Fitak , Jerzy Winiarski , Bartlomiej Gorecki , Agnieszka Burzynska , Wieslaw Szelejewski
发明人： Andrzej Kutner , Michal Chodynski , Teresa Ryznar , Hanna Fitak , Jerzy Winiarski , Bartlomiej Gorecki , Agnieszka Burzynska , Wieslaw Szelejewski
IPC分类号： C07C39/12
CPC分类号： C07C401/00
摘要： A process for the preparation of a pharmaceutical-grade anhydrous calcipotriol comprising: (a) dissolving crude calcipotriol having a water content of X % by weight in a first solvent or in a mixture of two or more first solvents, said first solvent or said mixture of two or more first solvents forming an azeotropic system with water, to obtain a solution of crude calcipotriol; (b) obtaining an intermediate calcipotriol by (i) placing said solution of crude calcipotriol under a reduced pressure and evaporating, if X is greater than or equal to 1, or (ii) crystallizing, if X is lower than 1; and (c) re-dissolving said intermediate calcipotriol in a second solvent or a mixture of two or more second solvents, said second solvent being anhydrous, and crystallizing at least once to obtain pharmaceutical-grade anhydrous calcipotriol.
摘要翻译：一种制备药物级无水卡泊三醇的方法，包括：（a）将水含量为X重量％的粗卡泊三醇溶于第一溶剂或两种或更多种第一溶剂的混合物中，所述第一溶剂或所述混合物的两种或更多种与水形成共沸系统的第一溶剂，以获得粗卡泊三醇的溶液; （b）通过以下步骤获得中间体卡泊三醇：（i）如果X大于或等于1，则放置所述粗卡泊三醇溶液并蒸发，如果X低于1，则（ii）结晶; 和（c）将所述中间体卡泊三醇再溶解在第二溶剂或两种或更多种第二溶剂的混合物中，所述第二溶剂是无水的，并结晶至少一次以获得药物级无水卡泊三醇。

2. 发明申请

US20080255380A1 Process and Intermediates for the Preparation of Sulfonyl Derivatives of Cholecalciferol 审中-公开
标题翻译：制备胆钙化醇磺酰衍生物的方法和中间体
公开(公告)号：US20080255380A1
公开(公告)日：2008-10-16
申请号：US11568977
申请日：2005-05-13
申请人： Michal Chodynski , Malgorzata Krupa , Hanna Fitak , Jerzy Winiarski , Teresa Ryznar , Bartlomiej Gorecki , Wieslaw Szelejewski , Andrzej Kutner
发明人： Michal Chodynski , Malgorzata Krupa , Hanna Fitak , Jerzy Winiarski , Teresa Ryznar , Bartlomiej Gorecki , Wieslaw Szelejewski , Andrzej Kutner
IPC分类号： C07C401/00
CPC分类号： C07C401/00 , Y02P20/55
摘要： Preparation of sulfonyl derivatives of cholecalciferol of Formula 1, wherein R1 is a protective group, preferably a t-butyl(dimethyl)silyl, and R2 is a heterocyclic group, such as a 2-thiazolyl, a 2-benzothiazolyl, a 1-phenyl-1H-tetrazo-5-yl, a 2-pyridyl, a 2-pyrimidynyl, a 1-isochinolinyl, a 1-methyl-2-imidazyl, or a 4-alkyl-1,2,4-triazo-3-yl, comprises the conversion of the hydroxyl derivative of cholecalciferol into the corresponding sulfide followed by its oxidation to the respective sulfone characterized by the use of a hydroxyl derivative of cholecalciferol as a starting material, in which the triene system is protected as a Diels-Alder adduct, and in particular as an adduct with sulfur dioxide of the Formula 2a. Novel are also the derivatives of Formula 3a and 4a, isolated in the process provided by the invention.
摘要翻译：制备式1的胆钙化甾醇的磺酰基衍生物，其中R 1是保护基，优选叔丁基（二甲基）甲硅烷基，R 2是杂环基，例如2-噻唑基，2-苯并噻唑基，1-苯基-1H-双偶氮-5-基，2-吡啶基，2-嘧啶基，1-异辛基，1-甲基-2-咪唑基或 4-烷基-1,2,4-三唑-3-基包括将胆钙化甾醇的羟基衍生物转化成相应的硫化物，然后氧化成相应的砜，其特征在于使用胆钙化醇的羟基衍生物作为起始材料，其中三烯体系被保护为狄尔斯 - 阿尔德加合物，特别是作为与式2a的二氧化硫的加合物。新颖的也是在本发明提供的方法中分离的式3a和4a的衍生物。

3. 发明授权

US07700580B2 Process for preparation of pharmaceutically pure anhydrous calcipotriol 失效
标题翻译：制备药学纯无水卡泊三醇的方法
公开(公告)号：US07700580B2
公开(公告)日：2010-04-20
申请号：US11813211
申请日：2005-12-29
申请人： Andrzej Kutner , Michal Chodyński , Teresa Ryznar , Hanna Fitak , Jerzy Winiarski , Bartlomiej Górecki , Agnieszka Burzyńska , Wieslaw Szelejewski
发明人： Andrzej Kutner , Michal Chodyński , Teresa Ryznar , Hanna Fitak , Jerzy Winiarski , Bartlomiej Górecki , Agnieszka Burzyńska , Wieslaw Szelejewski
IPC分类号： A01N37/36
CPC分类号： C07C401/00
摘要： A process for the preparation of a pharmaceutical-grade anhydrous calcipotriol comprising: (a) dissolving crude calcipotriol having a water content of X% by weight in a first solvent or in a mixture of two or more first solvents, said first solvent or said mixture of two or more first solvents forming an azeotropic system with water, to obtain a solution of crude calcipotriol; (b) obtaining an intermediate calcipotriol by (i) placing said solution of crude calcipotriol under a reduced pressure and evaporating, if X is greater than or equal to 1, or (ii) crystallizing, if X is lower than 1; and (c) re-dissolving said intermediate calcipotriol in a second solvent or a mixture of two or more second solvents, said second solvent being anhydrous, and crystallizing at least once to obtain pharmaceutical-grade anhydrous calcipotriol.
摘要翻译：一种制备药物级无水卡泊三醇的方法，包括：（a）将水含量为X重量％的粗卡泊三醇溶于第一溶剂或两种或更多种第一溶剂的混合物中，所述第一溶剂或所述混合物的两种或更多种与水形成共沸系统的第一溶剂，以获得粗卡泊三醇的溶液; （b）通过以下步骤获得中间体卡泊三醇：（i）如果X大于或等于1，则放置所述粗卡泊三醇溶液并蒸发，如果X低于1，则（ii）结晶; 和（c）将所述中间体卡泊三醇再溶解在第二溶剂或两种或更多种第二溶剂的混合物中，所述第二溶剂是无水的，并结晶至少一次以获得药物级无水卡泊三醇。

4. 发明申请

US20050119241A1 Preparation of 24 alkyl analogs of cholecalciferol and non-racemic compounds 有权
标题翻译：胆钙化醇和非外消旋化合物的24个烷基类似物的制备
公开(公告)号：US20050119241A1
公开(公告)日：2005-06-02
申请号：US10962873
申请日：2004-10-08
申请人： Andrzej Kutner , Jacek Martynow , Michal Chodynski , Wieslaw Szelejewski , Hanna Fitak , Malgorzata Krupa
发明人： Andrzej Kutner , Jacek Martynow , Michal Chodynski , Wieslaw Szelejewski , Hanna Fitak , Malgorzata Krupa
IPC分类号： C07C31/133 , C07C309/73 , C07C401/00 , C07F7/18 , A61K31/59
CPC分类号： C07C31/1333 , C07C309/73 , C07C401/00 , C07C2601/02 , C07F7/1892
摘要： Disclosed is a process for the preparation of 24-alkyl analogs of cholecalcyferol of Formula 1 having a (5E) or (5Z) configuration, wherein X represents a hydrogen atom, a hydroxy group or an OR1 group, where R1, R2 and R3 may be the same or different and represent groups suitable for hydroxyl protection, and R4 is a C1-6 alkyl chain or a C1-6 cykloalkyl group, optionally substituted with C1-3 alkyl groups, especially for calcipotriol. The invention also provides new intermediates and non-racemic compounds being valuable synthones for the synthesis of pharmacologically active substances.
摘要翻译：公开了制备具有（5E）或（5Z）构型的式1的胆碱酯的24-烷基类似物的方法，其中X表示氢原子，羟基或OR 1个基团其中R 1，R 2和R 3可以相同或不同，并且代表适用于羟基保护的基团，并且R 1， R 4是C 1-6烷基链或C 1-6烷基烷基，任选被C 1-3 - 烷基，特别是卡泊三醇。本发明还提供了新的中间体和非外消旋化合物，作为合成药物活性物质的有价值的合成物。

5. 发明授权

US07829746B2 Process for the preparation of calcipotriol 有权
标题翻译：卡泊三醇的制备方法
公开(公告)号：US07829746B2
公开(公告)日：2010-11-09
申请号：US12685256
申请日：2010-01-11
申请人： Andrzej Kutner , Michal Chodynski , Kinga Leszczynska , Wieslaw Szelejewski , Hanna Fitak
发明人： Andrzej Kutner , Michal Chodynski , Kinga Leszczynska , Wieslaw Szelejewski , Hanna Fitak
IPC分类号： C07C35/00
CPC分类号： C07C401/00 , C07C2601/02 , Y02P20/55
摘要： A process for the preparation of calcipotriol at least including: (a) reacting a C-22 phenylsulfonyl derivative of cholecalciferol of Formula 2, wherein R1 and R2 are the same or different and represent hydroxyl protecting groups, with a silyl derivative of alfa-hydroxy aldehyde of Formula 3, wherein R3 represents silyl group of formula Si(R4)(R5)(R6), where R4-R6 are the same or different and represent C1-6 alkyl or phenyl groups, in the presence of a strong organic base in an aprotic solvent, followed by reductive desulfonation of the obtained diastereomeric mixture of alfa-hydroxysulfones with sodium amalgam, removal of the hydroxyl protecting groups, and purification of the product. The process leads to the formation of calcipotriol containing less than 0.3% of the (22Z)-isomer. The obtained calcipotriol is free of mercury traces.
摘要翻译：一种制备卡泊三醇的方法，至少包括：（a）使式2的胆钙化甾醇的C-22苯基磺酰基衍生物与其中R 1和R 2相同或不同并代表羟基保护基，与α-羟基的甲硅烷基衍生物醛，其中R 3表示式Si（R 4）（R 5）（R 6）的甲硅烷基，其中R 4 -R 6相同或不同，表示C 1-6烷基或苯基，在强有机碱存在下在非质子溶剂中，然后将所得到的α-羟基磺酰胺与汞齐汞合物的非对映异构体混合物还原脱磺化，除去羟基保护基团并纯化产物。该方法导致含有小于0.3％的（22Z）异构体的卡泊三醇的形成。得到的卡泊三醇没有汞痕迹。

6. 发明申请

US20060111332A1 Process and intermediates to prepare17beta-hydroxy-7alpha-methyl-19-nor-17alpha-pregn -5(10)-en-20-yn-3-one 审中-公开
标题翻译：制备17β-羟基-7α-甲基-19-去甲-17α-孕-5（10）-en-20-炔-3-酮的方法和中间体
公开(公告)号：US20060111332A1
公开(公告)日：2006-05-25
申请号：US10530139
申请日：2003-10-01
申请人： Jacek Martynow , Andrzej Kutner , Wieslaw Szelejewski , Wanda Wojciechowska , Hanna Fitak
发明人： Jacek Martynow , Andrzej Kutner , Wieslaw Szelejewski , Wanda Wojciechowska , Hanna Fitak
IPC分类号： A61K31/56 , C07J7/00
CPC分类号： C07J75/00 , C07J21/00
摘要： The present invention is a process for the preparation of 17β-hydroxy-7α-methyl-19-nor-17α-pregn-5(10)-en-20-yn-3-one (17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estren-3-one, tibolone) of formula 1, which comprises hydrolysis of 17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estrene 3,3-cyclic ketals of formula 2, where groups R1, R2, R3 and R4 are hydrogen atoms or alkyl groups, or R1 and R3, taken together with the carbon atoms within the dioxolane ring to which they are attached, form an alicyclic ring fused to the dioxolane ring, with R2 and R4 being hydrogen atoms, or R1 and R3 together with the carbon atoms to which they are attached form an aromatic ring fused to the dioxolane ring, where R2 and R4, taken together, form a chemical bond within said aromatic ring. In addition, the present invention includes an intermediate, compound of formula 2 and two processes to prepare 17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estrene 3,3-cyclic ketals of formula 2: (a) by contacting 17α-ethynyl-17β-hydroxy-7α-methyl-4-estren-3-one with vicinal diols in the presence of a protic acid, and (b) by contacting 7α-methyl-5(10)-estrene-17-one 3,3-cyclic ketals of formula 4, where R1-R4 are defined as above, with metal acetylides, in inert solvents.
摘要翻译：本发明是制备17β-羟基-7α-甲基-19-去甲-17α-孕-5（10）-en-20-炔-3-酮（17α-乙炔基-17β-羟基-7α - 甲基-5（10） - 雌酚-3-酮，替勃龙酮），其包括式17α-乙炔基-17β-羟基-7α-甲基-5（10） - 雌甾3,3-环缩酮的式 2，其中基团R 1，R 2，R 3和R 4是氢原子或烷基，或R 1和R 3与它们所连接的二氧杂环戊烷环内的碳原子一起形成稠合到二氧戊环的脂环， R 2和R 4均为氢原子，或者R 1和R 3与它们所在的碳原子一起连接形成与二氧杂环戊烷环稠合的芳环，其中R 2和R 4一起在所述芳环中形成化学键。另外，本发明包括中间体式2化合物和两种制备式2的17α-乙炔基-17β-羟基-7α-甲基-5（10） - 雌甾3,3-环缩酮的方法：（a）通过在质子酸存在下将17α-乙炔基-17β-羟基-7α-甲基-4-雌酮-3-酮与邻位二醇接触，和（b）通过使7α-甲基-5（10） - 雌二醇-17 - 一种式4的3,3-环缩酮，其中R 1 -R 4定义如上，与金属乙炔化物在惰性溶剂中。

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