Novel methods for preparing silodosin and intermediates thereof

A technology of silodosin and intermediates, applied in the field of medicinal chemistry, can solve the problems of long reaction cycle, cumbersome operation, and low product purity

Active Publication Date: 2016-10-26
QILU PHARMA HAINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Although there are patent documents CN200910194691.2, CN201210199199.6, CN201310340656.3 and journal Tetrahedron etc. to disclose multiple preparation methods at present, greatly improved reaction conditions, but there are still many impurities or side reactions, especially dehydrogenation impurities due to their It is very similar to the intermediate in structure, so it is difficult to effectively remove, and the reaction cycle is long, the operation is cumbersome, the product purity is not high, the yield is low, the cost is high, and it is not suitable for industrial scale production.

Method used

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  • Novel methods for preparing silodosin and intermediates thereof
  • Novel methods for preparing silodosin and intermediates thereof
  • Novel methods for preparing silodosin and intermediates thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] Example 1, tert-butyl-(R)-1-(1-(3-(benzoyloxy)propyl)-7-cyanindoline-5-yl)propyl-2-yl- Carbonate (Compound V) Preparation

[0076]

[0077] 500g 5-[(2R)-2-aminopropyl]-2,3-dihydro-1-[3-(benzoyloxy)propyl]-1H-indole-7-carbonitrile tartrate ( Compound SM1) was added to 3.0L of dichloromethane and stirred, then an aqueous solution (4.0L) of potassium carbonate (1.105kg) was added, and 221g (Boc) 2 O, after the dropwise addition, react at 15~25°C for 5 hours, let stand for liquid separation, wash the dichloromethane phase with 3L of 0.2mol / L HCl solution, 2L of saturated sodium bicarbonate solution, and 2L of saturated brine successively, and then Dry over sodium sulfate, filter, and distill off the solvent from the filtrate under reduced pressure to obtain 457g of compound V, with an HPLC purity of 99.57%;

[0078] MS[M+H] + :464;

[0079] 1 H NMR (400 MHz, DMSO): 8.01-7.99(d,2H), 7.67-7.63(m,1H), 7.52-7.49(m,2H), 7.04(s,1H), 6.95(s,1H), 6.72-6.70(m,1H), 4.37(m,2H...

Embodiment 2

[0080] Example 2, tert-butyl (R)-1-(7-carbonamido-1-(3-hydroxypropyl)indoline-5-yl)propyl-2-yl-carbonate (compound IV) preparation of

[0081]

[0082] Add 178g (0.384mol) of compound V to 1.78L of dimethyl sulfoxide and stir to dissolve, control the temperature at 20~25°C, add dropwise 0.168L (0.84mol) of KOH solution with a concentration of 5mol / L, and dropwise add 217g (1.91 mol) with a mass fraction of 30% H 2 o 2 Aqueous solution, reacted at 15~25°C for 5 hours, added 5.34L 5% sodium sulfite aqueous solution to the reaction solution, stirred to precipitate solid, filtered, the filtrate was extracted with ethyl acetate, washed, dried, and the solvent was distilled off under reduced pressure to obtain 119g of compound IV. The yield is 81.5%, the HPLC purity is 97.43%, and the content of the dehydrogenation impurity Q1 is 1.83%. After determination, its X-RPD spectrum is as follows: figure 1 shown;

[0083] MS[M+H] + :378;

[0084] 1 H NMR (400 MHz, DMSO): 7.64(s,1...

Embodiment 3

[0085] Example 3, Preparation of 5-((R)-2-aminopropyl)-1-(3-hydroxypropyl)indoline-7-carbonamide hydrochloride (compound III)

[0086] Add 30g (54.04 mmol) of compound IV into 300mL of ethanol, stir and cool down to 0~10°C, add dropwise 36.2mL of 2mol / L HCl ethanol solution (72.4 mmol), stir at 15~25°C for 5~6h, filter, Dry, obtain 23.8g compound III, HPLC purity 99.59%, the content of dehydrogenation impurity Q2 is 0.18%, after measuring, its X-RPD collection of illustrative plates is as follows figure 2 shown;

[0087] MS[M-Cl] + :278;

[0088] 1 H NMR (400 MHz, DMSO): 8.04(m,2H), 7.74(s,1H), 7.35(s,1H), 6.94-6.89(d,2H), 4.43(br,1H), 3.42-3.16( m,7H); 2.91-2.50(m,4H), 1.62(m,2H),112-1.10(m,3H).

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Abstract

The invention belongs to the technical field of medical chemistry, and particularly relates to a novel intermediate compound of silodosin, a crystal form of the novel intermediate compound, a method for preparing the same and a novel method for preparing the silodosin by the aid of intermediates. The novel intermediate compound, the crystal form and the methods have the advantages that compounds IV are prepared and transformed into compounds III in hydrochloride forms, accordingly, dehydrogenation impurities can be effectively removed and reduced, and the quality of products can be improved; the methods are easy to implement and high in reaction yield and are safe and controllable, reaction conditions are mild, the products are high in purity, and the novel intermediate compound and the methods are applicable to industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, specifically relates to a new silodosin intermediate and a preparation method, and specifically provides a method for preparing silodosin through the new intermediate. The preparation method has simple operation, mild reaction conditions, safety and controllability, high reaction yield, good product purity and is more suitable for industrial production. Background technique [0002] Silodosin, the chemical name is 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy) Phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide has a chemical structure as shown in formula I, which was developed by Japan's original Tachibana and Japan's first The new generation of α1-adrenergic receptor blockers jointly developed and sold by Sankyo Pharmaceuticals has outstanding selectivity for α1 A-subtype adrenergic receptors, and can selectively relax urethral smooth muscle, while for the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/08
CPCC07D209/08
Inventor 冷传新范传文房玺林栋刘培元
Owner QILU PHARMA HAINAN
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