ChemicalBook CAS DataBase List Ivabradine

Ivabradine synthesis

9synthesis methods

Product Name:Ivabradine
CAS Number:155974-00-8
Molecular formula:C27H36N2O5
Molecular Weight:468.59

Ivabradine is a novel medication used for the symptomatic management of stable angina pectoris. Ivabradine acts by reducing the heart rate via specific inhibition of the funny channel, a mechanism different from that of beta blockers and calcium channel blockers, two commonly prescribed antianginal drugs. Ivabradine is a cardiotonic agent. Ivabradine was approved in 2015. Ivabradine acts on the If (f is for "funny", so called because it had unusual properties compared with other current systems known at the time of its discovery) ion current, which is highly expressed in the sinoatrial node. If is a mixed Na+–K+ inward current activated by hyperpolarization and modulated by the autonomic nervous system. It is one of the most important ionic currents for regulating pacemaker activity in the sinoatrial (SA) node. Ivabradine selectively inhibits the pacemaker If current in a dose-dependent manner. Blocking this channel reduces cardiac pacemaker activity, slowing the heart rate and allowing more time for blood to flow to the myocardium. Synthetic Description Reference: Pang, Yalong; Liu, Peihua. Process for preparation of Ivabradine and pharmaceutically acceptable salts. CN 101544605. (Assignee Beijing Shenlanhai Bio-Pharmaceutical Science and Technology Co., Ltd., Peop. Rep. China) Synthetic Description Reference: Lerestif, Jean-Michel; Lecouve, Jean-Pierre; Souvie, Jean-Claude; Brigot, Daniel; Horvath, Stephane; Auguste, Marie-Noelle; Damien, Gerard. Process for the preparation of ivabradine via hydrogenation of oxobenzazepinepropanal acetal derivative and coupling with dimethoxycyclobutabenzenemethanamine. US 20050228177. (nee Les Laboratoires Servier, Fr.) Synthetic Description Reference: Dwivedi, Shriprakash Dhar; Kumar, Rajiv; Patel, Sunil Tribhovandas; Shah, Alpeshkumar Parvin Chandra. Process for preparation of ivabradine hydrochloride. WO 2008065681. (Assignee Cadila Healthcare Limited, India) Synthetic Description Reference: Luo, Junzhi; Yan, Yimin; Tu, Yongrui. Process for preparation of Ivabradine hydrochloride and its stable crystal form. WO 2008125006. (Assignee UTOpharm (Shanghai) Co., Ltd., Peop. Rep. China; Changzhou No.4 Pharmaceutical Factory Co., Ltd.) Synthetic Description Reference: Bose, Prosenjit; Siripalli, Udaya Bhaskara Rao; Kandadai, Appan Srinivas. Process for preparation of ivabradine via resolution of N-[[3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl]-N-methylamine. WO 2010072409. (Assignee Krka, d.d., Slovenia) Synthetic Description Reference: Bose, Prosenjit; Siripalli, Udaya Bhaskara Rao; Kandadai, Appan Srinivas. Process for preparation of ivabradine via resolution of N-[[3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl]-N-methylamine. WO 2010072409. (Assignee Krka, d.d., Slovenia) Synthetic Description Reference: Peglion, Jean-Louis; Caignard, Pascal; Lerestif, Jean-Michel; Lecouve, Jean-Pierre. New methods for the synthesis of ivabradine and its pharmaceutically acceptable acid addition salts via alkylation and catalytic hydrogenation. WO 2011033194. (Assignee Les Laboratoires Servier, Fr.) Synthetic Description Reference: Ujvari, Viktor; Bodi, Jozsef; Farago, Janos; Szoke, Katalin; Faigl, Ferenc; Nemet, Zoltan; Temesvari, Krisztina; Kiss, Robert; Matravolgyi, Bela; Kassai, Ferencne; Kiss-Bartos, Dorottya. Method for preparation of ivabradine salts. WO 2011138625. (Assignee Richter Gedeon Nyrt., Hung.) Synthetic Description Reference: Ioannou, Savvas; Sergides, Christakis; Pitta, Daphne; Pittas, Andreas. preparation of new salt of ivabradine and uses thereof. WO 2018115181. (Assignee Biogena (A.P.I) Ltd, Cyprus) Synthetic Description Reference: Sun, Haiyu; Chen, Dong; Wei, Congcong; Wang, Jianyao; Wang, Xiaobo. Preparation method of high-purity ivabradine hydrochloride. CN 108424390. (Assignee Yangtze River Pharmaceutical Group Beijing Haiyan Pharmaceutical Co., Ltd., Peop. Rep. China; Yangtze River Pharmaceutical Group Co., Ltd.)

Synthetic Routes

ROUTE 1

ROUTE 2

ROUTE 3

ROUTE 4

ROUTE 5

ROUTE 6

ROUTE 7

ROUTE 8

ROUTE 9

ROUTE 10

Reference: Pang, Yalong; Liu, Peihua. Process for preparation of Ivabradine and pharmaceutically acceptable salts. CN 101544605. (Assignee Beijing Shenlanhai Bio-Pharmaceutical Science and Technology Co., Ltd., Peop. Rep. China)

3-[3-[[[(7S)-3,4-DiMethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]Methyl]MethylaMino]propyl]-1,3-dihydro-7,8-diMethoxy-H-3-benzazepin-2-one

1086026-31-4
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$200.00/5mg

155974-00-8
99 suppliers
inquiry

Yield:155974-00-8 96%

Reaction Conditions:

Stage #1: 3-{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-(methyl)amino]propyl}-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-onewith formic acid;palladium 10% on activated carbon;triethylamine in acetonitrile at 50; for 16 h;
Stage #2: with hydrogenchloride in water;acetonitrile at 0 - 5; pH=3 - 3.5;Reagent/catalyst;

Steps:

2 3-3 {- [{[(7S) -3,4-dimethoxybenzocyclobutene-7-] methyl} (methyl) amino-propyl] -7,8- dimethoxy-1,3,4,5-tetrahydro-2-hydrogen-3-benzazepine -2-one hydrochloride} (formic acid and triethylamine)

Under stirring conditions, 46.6 g (0.1 mol) of the oil obtained according to the method of Example 1, 200 ml of acetonitrile, 10 g 10% Pd / C (measured in dry form), 30 g (0.65 mol) of formic acid and 27 g (0.27 mol) of triethylamine were mixed and incubated at 50 ° C for 16 h. The Pd / C was removed by filtration, the volatiles were distilled off under reduced pressure, and then 200 mL of acetonitrile was added, The pH was adjusted to 3.0 to 3.5 by the addition of 36% hydrochloric acid. The mixture was stirred at 0 to 5 ° C for 1 h and then the product was filtered, Dried to obtain 45 g of dry product, HPLC purity of 99.83%, single impurity content of not more than 0.06% The yield was 96%.

References:

CN104788377,2017,B Location in patent:Paragraph 0011; 0026-0027