公开(公告)号：US07446227B2

公开(公告)日：2008-11-04

申请号：US11609075

申请日：2006-12-11

申请人： Satyam Nampalli ,  Brijesh Patel ,  Peter Xavier Tharial ,  Ravishanker Kovi

发明人： Satyam Nampalli ,  Brijesh Patel ,  Peter Xavier Tharial ,  Ravishanker Kovi

IPC分类号： C07C211/00

CPC分类号： C07C29/32 ,  C07C209/22 ,  C07C303/28 ,  C07C2603/32 ,  C07C211/32 ,  C07C309/66 ,  C07C33/38

摘要： A process for preparation of protriptyline hydrochloride from 5-dihydrobenzocycloheptatriene of formula (1) by coupling with chloropropyl alcohol in the presence of excess n-butyl Lithium in tetrahydrofuran under inert atmosphere, followed by preparation of mesylate derivative of formula (3) and finally the nucleophilic displacement of the mesylate group by reacting methylamine solution in methanol to give protriptyline free base of the formula (4). Also the present process reveals the hydrochloride salt formation and purification of the same to give pure pharmaceutical grade protriptyline hydrochloride with impurities less than 0.1% w/w.

摘要翻译： 在惰性气氛下，在四氢呋喃中，在过量的正丁基锂存在下，用氯丙醇与氯丙醇偶合制备式（1）的5-二氢苯并环庚三烯的方法，然后制备式（3）的甲磺酸酯衍生物， 通过使甲胺溶液在甲醇中反应，得到式（4）的无游离碱，从而亲核取代甲磺酸酯基。 此外，本发明方法显示盐酸盐形成和纯化，得到纯度为0.1％w / w的杂质的药物级羟基替康林盐酸盐。

公开(公告)号：US20080242892A1

公开(公告)日：2008-10-02

申请号：US12138924

申请日：2008-06-13

申请人： Satyam Nampalli ,  Brijesh Patel ,  Peter Xavier Tharial ,  Ravishanker Kovi

发明人： Satyam Nampalli ,  Brijesh Patel ,  Peter Xavier Tharial ,  Ravishanker Kovi

IPC分类号： C07C209/16 ,  C07C29/00

CPC分类号： C07C29/32 ,  C07C209/22 ,  C07C303/28 ,  C07C2603/32 ,  C07C211/32 ,  C07C309/66 ,  C07C33/38

摘要： A process for preparation of protriptyline hydrochloride from 5-dihydrobenzocycloheptatriene of formula (1) by coupling with chloropropyl alcohol in the presence of excess n-butyl Lithium in tetrahydrofuran under inert atmosphere, followed by preparation of mesylate derivative of formula (3) and finally the nucleophilic displacement of the mesylate group by reacting methylamine solution in methanol to give protriptyline free base of the formula (4). Also the present process reveals the hydrochloride salt formation and purification of the same to give pure pharmaceutical grade protriptyline hydrochloride with impurities less than 0.1% w/w.

摘要翻译： 在惰性气氛下，在四氢呋喃中，在过量的正丁基锂存在下，用氯丙醇与氯丙醇偶合制备式（1）的5-二氢苯并环庚三烯的方法，然后制备式（3）的甲磺酸酯衍生物， 通过使甲胺溶液在甲醇中反应，得到式（4）的无游离碱，从而亲核取代甲磺酸酯基。 此外，本发明方法显示盐酸盐形成和纯化，得到纯度为0.1％w / w的杂质的药物级羟基替康林盐酸盐。

公开(公告)号：US20080293963A1

公开(公告)日：2008-11-27

申请号：US12180057

申请日：2008-07-25

申请人： Ravishanker Kovi ,  Satyam Nampalli ,  Peter Xavier Tharial

发明人： Ravishanker Kovi ,  Satyam Nampalli ,  Peter Xavier Tharial

IPC分类号： C07C309/46 ,  C07C309/44

CPC分类号： C07C309/46 ,  C07C303/02 ,  C07C303/22 ,  C07C309/52

摘要： A process for the preparation of isosulfan blue (Active Pharmaceutical Ingredient) is provided. A process is also provided for preparation of the intermediate, 2-chlorobenzaldehyde-5-sulfonic acid, sodium salt of formula (2), used in the preparation thereof and a procedure for the isolation of benzaldehyde-2,5-disulfonic acid, di-sodium salt of the formula (3). Also provided is a process for the preparation of an isoleuco acid of formula (4), which upon mild oxidation gives rise to isosulfan blue of pharmaceutical grade which can be used for preparation of pharmaceutical formulations. The isolation and purification procedures provided in the process provide substantially pure isosulfan blue with HPLC purity 99.5% or greater.

摘要翻译： 提供了制备异硫丹蓝（Active Pharmaceutical Ingredient）的方法。 还提供了制备用于其制备的中间体2-氯苯甲醛-5-磺酸，式（2）的钠盐的方法和用于分离苯甲醛-2,5-二磺酸，二 式（3）的钠盐。 还提供了制备式（4）的异亮氨酸的方法，其在轻微氧化时产生可用于制备药物制剂的药物级别的异硫丹蓝。 该方法中提供的分离和纯化方法提供基本上纯的异硫丹蓝，HPLC纯度为99.5％或更高。

公开(公告)号：US20120078007A1

公开(公告)日：2012-03-29

申请号：US13310019

申请日：2011-12-02

申请人： Ravishanker Kovi ,  Satyam Nampalli ,  Peter Xavier Tharial

发明人： Ravishanker Kovi ,  Satyam Nampalli ,  Peter Xavier Tharial

IPC分类号： C07C309/46

CPC分类号： C07C309/46 ,  C07C303/02 ,  C07C303/22 ,  C07C309/52

摘要： A process for the preparation of isosulfan blue (Active Pharmaceutical Ingredient) is provided. A process is also provided for preparation of the intermediate, 2-chlorobenzaldehyde-5-sulfonic acid, sodium salt of formula (2), used in the preparation thereof and a procedure for the isolation of benzaldehyde-2,5-disulfonic acid, di-sodium salt of the formula (3). Also provided is a process for the preparation of an isoleuco acid of formula (4), which upon mild oxidation gives rise to isosulfan blue of pharmaceutical grade which can be used for preparation of pharmaceutical formulations. The isolation and purification procedures provided in the process provide substantially pure isosulfan blue with HPLC purity 99.5% or greater.

摘要翻译： 提供了制备异硫丹蓝（Active Pharmaceutical Ingredient）的方法。 还提供了制备用于其制备的中间体2-氯苯甲醛-5-磺酸，式（2）的钠盐的方法和用于分离苯甲醛-2,5-二磺酸，二 式（3）的钠盐。 还提供了制备式（4）的异亮氨酸的方法，其在轻微氧化时产生可用于制备药物制剂的药物级别的异硫丹蓝。 该方法中提供的分离和纯化方法提供基本上纯的异硫丹蓝，HPLC纯度为99.5％或更高。

公开(公告)号：US20080281127A1

公开(公告)日：2008-11-13

申请号：US11747291

申请日：2007-05-11

申请人： Ravishanker Kovi ,  Satyam Nampalli ,  Peter Xavier Tharial

发明人： Ravishanker Kovi ,  Satyam Nampalli ,  Peter Xavier Tharial

IPC分类号： C07C315/00

CPC分类号： C07C309/46 ,  C07C303/02 ,  C07C303/22 ,  C07C309/52

摘要： A process for the preparation of isosulfan blue (Active Pharmaceutical Ingredient) is provided. A process is also provided for preparation of the intermediate, 2-chlorobenzaldehyde-5-sulfonic acid, sodium salt of formula (2), used in the preparation thereof and a procedure for the isolation of benzaldehyde-2,5-disulfonic acid, di-sodium salt of the formula (3). Also provided is a process for the preparation of an isoleuco acid of formula (4), which upon mild oxidation gives rise to isosulfan blue of pharmaceutical grade which can be used for preparation of pharmaceutical formulations. The isolation and purification procedures provided in the process provide substantially pure isosulfan blue with HPLC purity 99.5% or greater.

摘要翻译： 提供了制备异硫丹蓝（Active Pharmaceutical Ingredient）的方法。 还提供了制备用于其制备的中间体2-氯苯甲醛-5-磺酸，式（2）的钠盐的方法和用于分离苯甲醛-2,5-二磺酸，二 式（3）的钠盐。 还提供了制备式（4）的异亮氨酸的方法，其在轻微氧化时产生可用于制备药物制剂的药物级别的异硫丹蓝。 该方法中提供的分离和纯化方法提供基本上纯的异硫丹蓝，HPLC纯度为99.5％或更高。

公开(公告)号：US07662992B2

公开(公告)日：2010-02-16

申请号：US12180057

申请日：2008-07-25

申请人： Ravishanker Kovi ,  Satyam Nampalli ,  Peter Xavier Tharial

发明人： Ravishanker Kovi ,  Satyam Nampalli ,  Peter Xavier Tharial

IPC分类号： C07C309/00

CPC分类号： C07C309/46 ,  C07C303/02 ,  C07C303/22 ,  C07C309/52

摘要： A process for the preparation of isosulfan blue (Active Pharmaceutical Ingredient) is provided. A process is also provided for preparation of the intermediate, 2-chlorobenzaldehyde-5-sulfonic acid, sodium salt of formula (2), used in the preparation thereof and a procedure for the isolation of benzaldehyde-2,5-disulfonic acid, di-sodium salt of the formula (3). Also provided is a process for the preparation of an isoleuco acid of formula (4), which upon mild oxidation gives rise to isosulfan blue of pharmaceutical grade which can be used for preparation of pharmaceutical formulations. The isolation and purification procedures provided in the process provide substantially pure isosulfan blue with HPLC purity 99.5% or greater.

摘要翻译： 提供了制备异硫丹蓝（Active Pharmaceutical Ingredient）的方法。 还提供了制备用于其制备的中间体2-氯苯甲醛-5-磺酸，式（2）的钠盐的方法和用于分离苯甲醛-2,5-二磺酸，二 式（3）的钠盐。 还提供了制备式（4）的异亮氨酸的方法，其在轻微氧化时产生可用于制备药物制剂的药物级别的异硫丹蓝。 该方法中提供的分离和纯化方法提供基本上纯的异硫丹蓝，HPLC纯度为99.5％或更高。

公开(公告)号：US09353050B2

公开(公告)日：2016-05-31

申请号：US13310019

申请日：2011-12-02

申请人： Ravishanker Kovi ,  Satyam Nampalli ,  Peter Xavier Tharial

发明人： Ravishanker Kovi ,  Satyam Nampalli ,  Peter Xavier Tharial

IPC分类号： C07C303/02 ,  C07C303/22

CPC分类号： C07C309/46 ,  C07C303/02 ,  C07C303/22 ,  C07C309/52

摘要： A process for the preparation of isosulfan blue (Active Pharmaceutical Ingredient) is provided. A process is also provided for preparation of the intermediate, 2-chlorobenzaldehyde-5-sulfonic acid, sodium salt of formula (2), used in the preparation thereof and a procedure for the isolation of benzaldehyde-2,5-disulfonic acid, di-sodium salt of the formula (3). Also provided is a process for the preparation of an isoleuco acid of formula (4), which upon mild oxidation gives rise to isosulfan blue of pharmaceutical grade which can be used for preparation of pharmaceutical formulations. The isolation and purification procedures provided in the process provide substantially pure isosulfan blue with HPLC purity 99.5% or greater.

公开(公告)号：US20130310600A1

公开(公告)日：2013-11-21

申请号：US13951034

申请日：2013-07-25

申请人： Ravishanker Kovi ,  Satyam Nampalli ,  Peter Xavier Tharial

发明人： Ravishanker Kovi ,  Satyam Nampalli ,  Peter Xavier Tharial

IPC分类号： C07C303/02

CPC分类号： C07C309/46 ,  C07C303/02 ,  C07C303/22 ,  C07C309/52

摘要： A process for the preparation of isosulfan blue (Active Pharmaceutical Ingredient) is provided. A process is also provided for preparation of the intermediate, 2-chlorobenzaldehyde-5-sulfonic acid, sodium salt of formula (2), used in the preparation thereof and a procedure for the isolation of benzaldehyde-2,5-disulfonic acid, di-sodium salt of the formula (3). Also provided is a process for the preparation of an isoleuco acid of formula (4), which upon mild oxidation gives rise to isosulfan blue of pharmaceutical grade which can be used for preparation of pharmaceutical formulations. The isolation and purification procedures provided in the process provide substantially pure isosulfan blue with HPLC purity 99.5% or greater.

摘要翻译： 提供了制备异硫丹蓝（Active Pharmaceutical Ingredient）的方法。 还提供了制备用于其制备的中间体2-氯苯甲醛-5-磺酸，式（2）的钠盐的方法和用于分离苯甲醛-2,5-二磺酸，二 式（3）的钠盐。 还提供了制备式（4）的异亮氨酸的方法，其在轻微氧化时产生可用于制备药物制剂的药物级别的异硫丹蓝。 该方法中提供的分离和纯化方法提供基本上纯的异硫丹蓝，HPLC纯度为99.5％或更高。

公开(公告)号：US20080139848A1

公开(公告)日：2008-06-12

申请号：US11609075

申请日：2006-12-11

申请人： Satyam S. Nampalli ,  Brijesh Patel ,  Peter Xavier Tharial ,  Ravishanker Kovi

发明人： Satyam S. Nampalli ,  Brijesh Patel ,  Peter Xavier Tharial ,  Ravishanker Kovi

IPC分类号： C07C33/16 ,  C07C211/31

CPC分类号： C07C29/32 ,  C07C209/22 ,  C07C303/28 ,  C07C2603/32 ,  C07C211/32 ,  C07C309/66 ,  C07C33/38

摘要： A process for preparation of protriptyline hydrochloride from 5-dihydrobenzocycloheptatriene of formula (1) by coupling with chloropropyl alcohol in the presence of excess n-butyl Lithium in tetrahydrofuran under inert atmosphere, followed by preparation of mesylate derivative of formula (3) and finally the nucleophilic displacement of the mesylate group by reacting methylamine solution in methanol to give protriptyline free base of the formula (4). Also the present process reveals the hydrochloride salt formation and purification of the same to give pure pharmaceutical grade protriptyline hydrochloride with impurities less than 0.1% w/w.

摘要翻译： 在惰性气氛下，在四氢呋喃中，在过量的正丁基锂存在下，用氯丙醇与氯丙醇偶合制备式（1）的5-二氢苯并环庚三烯的方法，然后制备式（3）的甲磺酸酯衍生物， 通过使甲胺溶液在甲醇中反应，得到式（4）的无游离碱，从而亲核取代甲磺酸酯基。 此外，本发明方法显示盐酸盐形成和纯化，得到纯度为0.1％w / w的杂质的药物级羟基替康林盐酸盐。

公开(公告)号：US08969616B2

公开(公告)日：2015-03-03

申请号：US13951034

申请日：2013-07-25

申请人： Ravishanker Kovi ,  Satyam S. Nampalli ,  Peter Xavier Tharial

发明人： Ravishanker Kovi ,  Satyam S. Nampalli ,  Peter Xavier Tharial

IPC分类号： C07C309/00 ,  C07C303/02 ,  C07C303/22

CPC分类号： C07C309/46 ,  C07C303/02 ,  C07C303/22 ,  C07C309/52

摘要： A process for the preparation of isosulfan blue (Active Pharmaceutical Ingredient) is provided. A process is also provided for preparation of the intermediate, 2-chlorobenzaldehyde-5-sulfonic acid, sodium salt of formula (2), used in the preparation thereof and a procedure for the isolation of benzaldehyde-2,5-disulfonic acid, di-sodium salt of the formula (3). Also provided is a process for the preparation of an isoleuco acid of formula (4), which upon mild oxidation gives rise to isosulfan blue of pharmaceutical grade which can be used for preparation of pharmaceutical formulations. The isolation and purification procedures provided in the process provide substantially pure isosulfan blue with HPLC purity 99.5% or greater.

摘要翻译： 提供了制备异硫丹蓝（Active Pharmaceutical Ingredient）的方法。 还提供了制备用于其制备的中间体2-氯苯甲醛-5-磺酸，式（2）的钠盐的方法和用于分离苯甲醛-2,5-二磺酸，二 式（3）的钠盐。 还提供了制备式（4）的异亮氨酸的方法，其在轻微氧化时产生可用于制备药物制剂的药物级别的异硫丹蓝。 该方法中提供的分离和纯化方法提供基本上纯的异硫丹蓝，HPLC纯度为99.5％或更高。