Set of intermediate compounds used for synthesis of Ivabradine, and applications thereof

A technology for ivabradine and a compound, which is applied to the application field of ivabradine synthesis, can solve the problems of high preparation cost of ivabradine, difficult to obtain starting materials, large production pollution, etc., and achieves reasonable reaction sequence, The effect of simple reaction and low production cost

Active Publication Date: 2015-08-12
江苏宇田医药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0019] This route is CN102633720A patent (Seville, France), which is an optimization and improvement of the third route of the method. The reaction principle is simple, easy to operate, and avoids the use of toxic reagents in the cyclization step, but the reducing agent for the first step of reductive amination reaction is selected Since sodium triacetoxyborohydride, sodium cyanoborohydride, and catalysts such as palladium, platinum, nickel, nails, germanium and their compo

Method used

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  • Set of intermediate compounds used for synthesis of Ivabradine, and applications thereof
  • Set of intermediate compounds used for synthesis of Ivabradine, and applications thereof
  • Set of intermediate compounds used for synthesis of Ivabradine, and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Embodiment 1: the preparation of compound II

[0049] Add 10.9mL (0.1mol) of aminoacetaldehyde dimethyl acetal, 16.6mL (0.12mol) of triethylamine, and 100mL of dichloromethane into the reaction flask and place it in an ice-water bath. Add 15.8g of 1,3-bromochloropropane ( 0.1mol) was dissolved in 50mL of dichloromethane to form a dropwise solution, and the dropwise solution was dropped into the aforementioned reaction solution placed in an ice bath, stirred and reacted for 1h, washed with 100ml of saturated sodium bicarbonate solution, washed with 100mL of water, and separated layer, the dichloromethane layer was collected, dried, and concentrated under reduced pressure to obtain 17.2 g of a colorless to light yellow oily substance (Compound II), with a yield of 95%.

Embodiment 2

[0050] Embodiment 2: the preparation of compound III

[0051] Add 17.2g (0.095mol) of compound II, 14.5ml (0.105mol) of triethylamine, and 100ml of dichloromethane into the reaction flask and place it in an ice-water bath. Add 21.4g of 3,4-dimethoxy-phenylacetyl chloride (0.1mol) was dissolved in 100mL of dichloromethane to form a dropwise solution, and the dropwise solution was dropped into the aforementioned reaction solution placed in an ice bath, stirred and reacted for 1h, washed with 100ml of saturated sodium bicarbonate solution, and washed with 100mL of water, The layers were separated, and the dichloromethane layer was collected, dried, and concentrated under reduced pressure to obtain 32.7 g of a brown-yellow oily substance (Compound III), with a yield of 96%.

Embodiment 3

[0052] Embodiment 3: the preparation of compound IV

[0053] Take compound III 10.8g (0.03mol), (1S)-4,5-dimethoxy-1-[(methylamino)methyl]benzocyclobutane hydrochloride 6.1g (0.025mol), carbonic acid Potassium 8.7g (0.063mol) and 1.50g sodium iodide 3.75g (0.025mol) were refluxed in 50mL methyl isobutyl ketone for 6h, cooled, added 50mL of 1N hydrochloric acid, separated into layers, collected the water layer, and used Sodium hydroxide was adjusted to pH = 10, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated to dryness to obtain 12.1 g of compound IV with a yield of 91%.

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Abstract

The invention provides a set of intermediate compounds used for synthesis of Ivabradine and a preparation method thereof, and also provides a method used for synthesizing Ivabradine from the intermediate compounds. According to the method, the set of intermediate compounds are subjected to a plurality of N alkylation or N acylation so as to obtain a compound IV; and Ivabradine is directly synthesized from the compound IV. The method is short in synthesis route; raw materials are simple and easily available; reaction sequence is reasonable; operation is simple and high in efficiency; the method is green and friendly to the environment; synthesis difficulty of Ivabradine is reduced greatly; cost is low; product yield is high; and the method is suitable for industrialization production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a group of novel compounds and their application in the synthesis of ivabradine. Background technique [0002] Ivabradine, chemical name: 7,8-dimethoxy-3-(3-[[(1S)(4,5-dimethoxybenzocyclobutan-1-yl)methyl] -methylamino]propyl)-1,3,4,5-tetrahydro-2H-benzazepin-2-one, its structure is shown in the following formula: [0003] [0004] Ivabradine and its pharmaceutically acceptable acid addition salts, especially the hydrochloride, have very important pharmacological and therapeutic properties, especially heart rate slowing properties, which make these compounds useful for prophylactic or therapeutic Various clinical myocardial ischemic conditions, such as angina, myocardial infarction and related rhythm disturbances, represent a very promising new generation of cardiovascular drugs. [0005] At present, the synthesis of ivabradine mainly includes the f...

Claims

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Application Information

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IPC IPC(8): C07C217/40C07C213/00C07C235/34C07C231/02C07D223/16
Inventor 张超朱连清李祥陆强李其荣李奉春刘德龙
Owner 江苏宇田医药有限公司
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