139306-10-8Relevant articles and documents
Purification method of carafine intermediate
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, (2021/10/02)
To 3 - hydroxyacetophenone as a raw material, the intermediate 3 - [1 - (dimethylamino) ethyl] phenol is formed by reaction with dimethylamine, and the intermediate is subjected to resolution and purification by a specific resolution system to obtain S - 3 - [1 - (dimethylamino) ethyl] phenol. Compared with the preparation method of the intermediate prepared by the method, the preparation method has the advantages of low cost, high yield, good effect, less environmental pollution, reduced residue of inorganic salt, and favorability for large-scale industrial production.
SYNTHESIS OF NOVEL INTERMEDIATE(S) FOR PREPARING RIVASTIGMINE
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, (2020/04/10)
The present invention relates to novel intermediate(s), which are useful for the preparation of Rivastigmine compound of formula (I) and its pharmaceutically acceptable salts. The present invention further relates to the processes for the preparation of such novel intermediate(s) and preparation of Rivastigmine using such novel intermediate(s).
Synthetic method of rivastigmine chiral intermediate
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Paragraph 0043; 0050-0052, 0053; 0060-0062,0063; 0070-0072, (2020/07/15)
The invention belongs to the technical field of rivastigmine preparation, and particularly relates to a preparation method of a rivastigmine intermediate. The method comprises the following steps: (1)carrying out asymmetric oxidation on a raw material 3-benzyloxy styrene under the catalytic action of a chiral catalyst (salen) Mn (III) to generate a chiral epoxy compound B; (2) carrying out selective a ring-opening reaction on the chiral epoxy compound B and dimethyl amine to obtain a chiral amino alcohol compound C; (3) generating a methane sulfonate compound D from the compound C and methanesulfonyl chloride under the catalysis of a basic catalyst; and (4) carrying out a reduction reaction on the compound D under the catalysis of a reducing agent to remove methane sulfonic acid and benzyl to obtain the target chiral intermediate. According to the method, the chiral center is obtained through asymmetric epoxidation, the product is high in chiral purity; the post treatment of the intermediate is easy, the intermediate can be purified through simple re-crystallization; and in addition, the yield of each step is high, so that the total yield is high, and the production cost is low.
Biaryl diphosphine ligands and their ruthenium complexes: Preparation and use for catalytic hydrogenation of ketones
Abdur-Rashid, Kamaluddin,Abdur-Rashid, Kareem,Dasgupta, Tara,Jia, Wenli,Lorraine, Shannen,Maragh, Paul
, (2020/07/10)
Procedures for the preparation of the nucleophilic diphosphine ligands (R)-(4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine) ((R)-Ph-Garphos, 2a) and (S)-(4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine) ((S)-Ph-Garphos, 2b) were described. The ligands were used to prepare the ruthenium(II) Ph-Garphos complexes, chloro(p-cymene)(R)-(4,4′,6,6′-tetraamethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine)ruthenium(II) chloride ([RuCl(p-cymene)(R)-Ph-Garphos]Cl (3)) and chloro(p-cymene)(S)-(4,4′,6,6′-tetraamethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine)ruthenium(II) chloride ([RuCl(p-cymene)(S)-Ph-Garphos]Cl (4)). In the presence of the chiral diamine co-ligands (1R,2R)-1,2-diphenylethane-1,2-diamine (R,R-DPEN) and (1S,2S)-1,2-diphenylethane-1,2-diamine (S,S-DPEN), complexes 3 and 4 were found to be catalyst precursors for the enantioselective reduction of aryl ketones under mild conditions (room temperature and 3–4 atm of H2). The chiral alcohols were isolated in moderate to good yields and with enantioselectivities of up to 93percent. The ruthenium complexes chloro(p-cymene)(R)-(4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl)bis(bis(3,5-dimethylphenyl)-phosphine)ruthenium(II) chloride ([RuCl(p-cymene)(R)-Xyl-Garphos]Cl (5)) and chloro(p-cymene)(S)-(4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl)bis(bis(3,5-dimethylphenyl)-phosphine)ruthenium(II) chloride ([RuCl(p-cymene)(S)-Xyl-Garphos]Cl (6)) were also prepared and used as catalyst precursors for the hydrogenation of aryl ketones in the presence of (R,R)-DPEN and (S,S)-DPEN. Significant improvements in the enantioselectivities of the alcohols (up to 98percent ee.) were afforded. A combination of 6 and (S,S)-DPEN afforded (R)-1-(3-methoxyphenyl)ethanol in 89percent yield and with 95percent ee which was shown to be a suitable precursor for the preparation of (S)-rivastigmine.
A chiral three-stage amine compound synthetic methods and use thereof
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Paragraph 0030; 0033; 0034, (2019/05/21)
The present invention provides a chiral three-stage compound synthesis method, the method is asymmetric reductive amination reaction, the use of two-stage [...] iridium catalyst in the hydrogenation reaction under the action of the chiral three levels of amine compounds, the method of preparation and chiral three levels of amine compounds can be used for anti-depression drugs and the like synthetic. The relates to chiral three-stage amides synthetic method, the secondary amine as asymmetric reductive amination of amine source, and not through the other chemical reactions by one step to obtain three levels of chiral amine; the use of phosphoramidite chiral ligand as catalyst, such chiral ligand low price, easy synthesis and expand; additive combined use can greatly improve the yield of the reaction and the enantioselectivity. From the foregoing, the method has simple operation and easy mass production advantages.
Group-assisted Purification (GAP) Chemistry/Technology in synthesizing the chiral intermediate of rivastigmine and its ?-Alkyl benzylamine analogues
Yang, Bing,Zhang, Chun-Yan,Xu, Jing,Zheng, Da-Jun,Wang, Xiao-Ying,Dai, Hong,Shi, Yu-Jun,Zhu, Hai-Liang
, p. 1065 - 1068 (2019/08/21)
Introduction of (S)-configuration is the key step in the synthesis of the anti-dementia drug Rivastigmine. Twenty-one alkylation products were obtained through simple washing with hexane/ethyl acetate (v/v: 10/1) in good yields (>85%) and high diastereoselectivity (up to >99:1 dr). Moreover, the chiral auxiliary could be easily dissociated and readily regenerated. That is, the synthesis was proved to follow group-assisted purification (GAP) chemistry/technology. In addition, the chiral amine produced by this asymmetric alkylation reaction was effectively used in the synthesis of Rivastigmine.
Secondary amines as coupling partners in direct catalytic asymmetric reductive amination
Wu, Zitong,Du, Shaozhi,Gao, Guorui,Yang, Wenkun,Yang, Xiongyu,Huang, Haizhou,Chang, Mingxin
, p. 4509 - 4514 (2019/04/29)
The secondary amine participating asymmetric reductive amination remains an unsolved problem in organic synthesis. Here we show for the first time that secondary amines are capable of effectively serving as N-sources in direct asymmetric reductive amination to afford corresponding tertiary chiral amines with the help of a selected additive set under mild conditions (0-25 °C). The applied chiral phosphoramidite ligands are readily prepared from BINOL and easily modified. Compared with common tertiary chiral amine synthetic methods, this procedure is much more concise and scalable, as exemplified by the facile synthesis of rivastigmine and N-methyl-1-phenylethanamine.
Iridium-catalyzed diastereoselective amination of alcohols with chiral: Tert-butanesulfinamide by the use of a borrowing hydrogen methodology
Xi, Xiaomei,Li, Yongjie,Wang, Guannan,Xu, Guangda,Shang, Lina,Zhang, Yao,Xia, Lixin
supporting information, p. 7651 - 7654 (2019/08/30)
An iridium-catalyzed diastereoselective amination of alcohols with chiral tert-butanesulfinamide was developed under basic conditions, affording the optically active secondary sulfinamides in high yields and diastereoselectivities. The removal of the sulfinyl group from sulfonamides allowed a facile access to a wide range of α-chiral primary amines. This synthetic strategy was further applied in the synthesis of the marketed pharmaceuticals (S)-rivastigmine and NPS R-568.
Preparation method of rivastigmine tartrate
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Paragraph 0079; 0080; 0081; 0082-0084; 0091-0096; 0102-0107, (2017/08/28)
The invention discloses a preparation method of rivastigmine tartrate. The preparation method comprises the following steps: using (R, S)-3-(1-(dimethylamino)ethyl)phenol as a raw material, and carrying out resolution on the raw material by the use of S-(+)-camphorsulfonic acid so as to obtain enantiomerically pure (S)-3-(1-(dimethylamino)ethyl)phenol; letting enantiomerically pure (S)-3-(1-(dimethylamino)ethyl)phenol be in butt-joint with N-ethyl-N-methylcarbamyl chloride to obtain rivastigmine free alkali; and finally letting rivastigmine free alkali react with L-(+)-tartaric acid for salifying so as to obtain rivastigmine tartrate. Through process control such as treatment during the synthetic process of raw materials, acid-base alternative impurity removal during refining of an intermediate and acetone pulping for purification during later period, the preparation method of rivastigmine tartrate is obtained. By the method, purity and yield of the product are both raised, the isomer impurity can be more effectively controlled, and cost is greatly reduced and process is simplified. The preparation method is more suitable for industrial production.
Rivastigmine method for the preparation of intermediates
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, (2017/02/24)
The invention relates to the field of pharmaceutical synthesis, and particularly relates to a method for preparing a rivastigmine intermediate. The method employs hydroxy acetophenone as a raw material to prepare a rivastigmine chiral intermediate compound (R)-3-(1-hydroxyethyl) phenol under the action of a chiral catalyst, alkali and hydrogen. The chiral catalyst is a compound with the following structure; X represents H, C1-C8 alkyl, C1-C8 alkoxy, phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, ceteroary or benzyl; the phenyl substituent is C1-C8 alkyl and alkoxy, and in the number of 1-5; and the ceteroary is furan, thiophene or pyridine. The method for preparing the rivastigmine intermediate provided by the invention applies the chiral catalyst to obtain the rivastigmine intermediate (R)-3-(1-hydroxyethyl) phenol with high purity, and the intermediate has ee value greater than 97% through chiral HPLC analysis. The molar ratio of the catalyst only accounts for 1 / 100000-1 / 1000000 of reactant to achieve the required optical purity, and completely convert the reactant, thereby greatly saving the cost, increasing the yield and saving raw materials.
