- Real-Time Monitoring of Solid-Liquid Slurries: Optimized Synthesis of Tetrabenazine
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Solid-liquid slurries are vital and increasingly prevalent in the pharmaceutical and chemical industries. Despite the importance of these heterogeneous systems, process control and optimization are fundamentally hindered by a lack of compatible real-time analytical techniques. We present herein an online HPLC monitoring platform enabling access to real-time compositional information on slurries. We demonstrate the system by investigating the heterogeneous synthesis reaction of tetrabenazine. Furthermore, we integrated our online HPLC platform with the orthogonal monitoring techniques of a pH probe and a microscopic imaging probe to provide additional mechanistic insight. These combined insights enable the optimization of tetrabenazine synthesis in terms of reaction time, byproduct formation, and diastereomeric purity of the final product.
- Sato, Yusuke,Liu, Junliang,Kukor, Andrew J.,Culhane, Jeffrey C.,Tucker, John L.,Kucera, David J.,Cochran, Brian M.,Hein, Jason E.
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p. 14069 - 14078
(2021/07/26)
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- Synthetic method 3 - [(dimethylamino) methyl] -5 -methyl -2 - hexanone (by machine translation)
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The invention provides a synthetic method, 3 - [(dimethylamino) methyl] -5 -methyl -2 - hexanone. Belong to organic synthesis technical field. To the synthesis method, 5 - methyl -3 -hexene -2 - ketone is subjected to addition reaction under the conditions of a hydrogenation copper triphenylphosphine complex as a catalyst to obtain the intermediate 6; and the obtained intermediate 6 and N, N - dimethyl methylene iodide are reacted, namely, 3 - [(dimethylamino) methyl] -5 - methyl -2 - hexanone as crude product. Finally, the obtained crude product is subjected to distillation and purification to obtain a product fine product. The synthesis method provided by the invention is good in selectivity, and the content of the 1% reaction-generated isomer by-product is no unitz ?; the 99.3% purity of the finally prepared product of the synthetic 60 - 70% process can reach (by machine translation)
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Paragraph 0056-0109
(2019/08/30)
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- The synthesis of precursor of FP- (+) DTBZ
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A synthetic route to the precursor of FP- (+) DTBZ was disclosed, in which 3-hydroxy-4-methoxybenzaldehyde was employed as a starting material. In the method, the benzyl-protecting protocol and the in-situ Diels-Alder reaction made the procedure more practical because of the mild conditions for selectively deprotection and the accelerated reaction process.
- Wu, Caijiao,Li, Hui,Sun, Feiyang,Bao, Changshun,Bao, Xuefei,Chen, Guoliang
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supporting information
p. 3218 - 3225
(2019/09/13)
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- BENZOQUINOLINE INHIBITORS OF VESICULAR MONOAMINE TRANSPORTER 2
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The present invention relates to new benzoquinoline inhibitors of vesicular monoamine transporter 2 (VMAT2), pharmaceutical compositions thereof, and methods of use thereof.
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Paragraph 0228; 0229
(2018/07/05)
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- Synthetic method for tetrabenazine and intermediate of tetrabenazine
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The invention discloses a simple and effective method for synthesizing tetrabenazine (cis-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-3-isobutyl-2H-benzo[a]quinolizin-2-one) and an intermediate of the tetrabenazine. The method comprises the following steps: firstly, paraformaldehyde, dimethylamine hydrochloride and 5-methyl-2-hexanone are taken as raw materials to synthesize a key intermediate 3-dimethylaminomethyl-5-methyl-2-hexanone; secondly, a crude product is effectively optimized by using simple chemical purification operation to obtain a key intermediate with higher purity; and finally, water is taken as a solvent, under the action of a catalyst, the purified key intermediate and 6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride are subjected to condensation to obtain a tetrabenazine crude product, and recrystallization is performed to obtain the tetrabenazine product, wherein the HPLC purity is greater than 99.5%. According to the method provided by the invention, the key intermediate with higher purity can be obtained by the simple chemical raw materials through synthesis and purification, and therefore the tetrabenazine product with good purity is further obtained; and the raw materials used in the method are easy to obtain, the operation is simple, special equipment is not needed, the yield is higher, and the obtained tetrabenazine has higher purity.
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Paragraph 0018
(2018/03/26)
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- SYNTHETIC METHODS FOR PREPARATION OF (S)-(2R,3R,11bR)-3-ISOBUTYL-9,10-DIMETHOXY-2,3,4,6,7,11b-HEXAHYDRO-1H-PYRIDO[2,1-a]ISOQUINOLIN-2-YL 2-AMINO-3-METHYLBUTANOATE DI(4-METHYLBENZENESULFONATE)
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Provided herein are processes for the preparation of (S)-(2R,3R,11bR-3-isobuty-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or a solvate, hydrate, or polymorph thereof.
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Paragraph 0162; 0163
(2017/07/14)
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- BENZOQUINOLINE INHIBITORS OF VESICULAR MONOAMINE TRANSPORTER 2
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The present invention relates to new benzoquinoline inhibitors of vesicular monoamine transporter 2 (VMAT2), pharmaceutical compositions thereof, and methods of use thereof. (Formula (I))
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Paragraph 00198
(2015/08/06)
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- METHODS OF MANUFACTURING BENZOQUINOLINE COMPOUNDS
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The present invention relates to new methods of manufacturing benzoquinoline inhibitors of vesicular monoamine transporter 2 (VMAT2), and intermediates thereof.
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Paragraph 0251; 0252
(2015/06/10)
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- METHODS OF TREATING ABNORMAL MUSCULAR ACTIVITY
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Methods for treating abnormal muscular activity are disclosed. The methods may be performed remotely and permit monitoring of a subject outside a healthcare provider's office.
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Paragraph 0199
(2015/06/08)
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- BENZOQUINOLINE INHIBITORS OF VESICULAR MONOAMINE TRANSPORTER 2
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The present invention relates to new benzoquinoline inhibitors of vesicular monoamine transporter 2 (VMAT2), pharmaceutical compositions thereof, and methods of use thereof. (I)
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Paragraph 00167
(2015/06/08)
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- (+)-9-Benzyloxy-α-dihydrotetrabenazine as an important intermediate for the VMAT2 imaging agents: Absolute configuration and chiral recognition
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This article reports, for the first time, on the absolute configuration of (+)-9-benzyloxy-α-dihydrotetrabenazine (8), as determined from the perspective of X-ray crystallography. Compound 8 was prepared by a six-step reaction using 3-benzyloxy-4-methoxybenzaldehyde (1) as a starting material. The X-ray crystal diffraction structure of two compounds, racemic 9-benzyloxy-tetrabenazine (5) and the diastereomeric salt of compound 8, is also described for the first time in this article. The X-ray results and the chiral HPLC helped elucidate that compound 8 has an absolute configuration as 2R,3R,11bR. The crystal structure of racemic compound 5 contains two symmetry- independent molecules in the unit cell. Interestingly, while they are structural isomers, they are enantiomers, too, i.e., in solution, because they are not mirror images of each other in the crystal lattice. In order to elucidate the intermolecular interaction mechanism of the diastereomeric salt of compound 8, its crystal packing was investigated with regard to the weak interactions, such as salt bridge, OH.O and CH.O hydrogen bonds, and intermolecular CH.π interaction. The results showed that the carbonyl-assisted salt bridges and the OH.O hydrogen bonds formed polar columns in the crystal structure of the diastereomeric salt of compound 8, resembling butterflies with open wings as viewed along the c-axis. These polar columns were extended to three-dimensional network by intermolecular CH.O hydrogen bonds and intermolecular CH.π interactions. Chirality, 2013. 2013 Wiley Periodicals, Inc. Copyright
- Liu, Chunyi,Chen, Zhengping,Li, Xiaomin,Tang, Jie,Qin, Xiaofeng
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p. 215 - 223
(2013/08/22)
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- PROCESS FOR PREPARING TETRABENAZINE
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A substantially pure crystalline form A of tetrabenazine compound of structural formula I and processes for the preparation thereof is provided.
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Page/Page column 26-27
(2012/06/30)
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- Synthesis of 3H-labeled Tetrabenazine (TBZ)
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Tetrabenazine (TBZ) (1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2- methylpropyl)-2H-benzo[a]quinolin-2-one), a vesicular monamine transporter 2 inhibitor, was prepared as a tritium-labeled compound with high specific activity and radiochemical purity. Catalytic hydrogenation of a precursor with the terminal double bond was used to introduce the tritium. This method provides tritium-labeled TBZ with high specific activity and radiochemical purity, which allow the further investigation of a TBZ in the neurological field.
- Rhee, Sung-Whi,Ryan, Kenneth J.,Tanga, Mary J.
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experimental part
p. 367 - 370
(2012/06/01)
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- BENZOQUINOLONE INHIBITORS OF VMAT2
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The present invention relates to new benzoquinolone inhibitors of VMAT2, pharmaceutical compositions thereof, and methods of use thereof. Formula (I)
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Page/Page column 44
(2011/12/14)
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- Preparation and characterization of tetrabenazine enantiomers against vesicular monoamine transporter 2
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As a clinical medication for the treatment of hyperkinetic movement disorders, in conditions such as Huntington's disease, tetrabenazine (TBZ) has always been used in its racemic form. To establish whether or not its beneficial therapeutic actions are enantiospecific, a practical total synthetic route was developed to yield each enantiomeric form to allow their chemical and pharmacological characterization. We briefly summarize the total synthesis of TBZ and report a detailed procedure for resolution of TBZ into its enantiomers, (+)-TBZ and (-)-TBZ. This allowed determination of the optical rotation and absolute configurations of each TBZ enantiomer, based on X-ray crystallographic analysis, together with characterization of their inhibitory action at the vesicular monoamine transporter 2, where (+)-TBZ proved 3-fold more active than (-)-TBZ.
- Yu, Qian-Sheng,Luo, Weiming,Deschamps, Jeffery,Holloway, Harold W.,Kopajtic, Theresa,Katz, Jonathan L.,Brossi, Arnold,Greig, Nigel H.
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scheme or table
p. 105 - 109
(2010/11/18)
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- BENZOQUINOLINE INHIBITORS OF VESICULAR MONOAMINE TRANSPORTER 2
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The present invention relates to new benzoquinoline inhibitors of vesicular monoamine transporter 2 (VMAT2), pharmaceutical compositions thereof, and methods of use thereof.
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Page/Page column 28
(2010/04/30)
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- SUBSTITUTED 3-ISOBUTYL-9, 10-DIMETHOXY-1,3,4,6,7,11B-HEXAHYDRO-2H-PYRIDO[2,1-A] ISOQUINOLIN-2-OL COMPOUNDS AND METHODS RELATING THERETO
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Substituted 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol compounds are disclosed that are inhibitors of the vesicular monoamine transporter 2 (VMAT2). The compounds of this invention have the structure (I): wherein R1 is as defined herein, including stereoisomers and pharmaceutically acceptable salts and solvates thereof. Also disclosed are compositions containing a compound of this invention in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use in a subject in need thereof.
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Page/Page column 13
(2008/12/05)
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