Talnetant intermediate, preparation method and applications thereof

A technology of reaction temperature and acylation reaction, applied in the field of organic drug synthesis, can solve the problems of unfavorable industrialization, harsh reaction conditions, and high labor protection requirements

CN102924375AActive Publication Date: 2013-02-13NHWA PHARMA CORPORATION
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Patent Information

Authority / Receiving Office
CN · China
Current Assignee / Owner
Publication Date
2013-02-13

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Abstract

The present invention discloses a (S)-3-hydroxy-2-phenyl-N-(1-phenylpropyl)quinoline-4-formamide intermediate, a preparation method and applications thereof, wherein the intermediate has a structure represented by a formula I. With the intermediate compound represented by the formula I and for Talnetant preparation, Talnetant can be obtained through one-step hydrogenation. The preparation for the compound represented by the formula I has characteristics of simple production operation, easily available raw materials, low labor protection requirements, high yield and less by-product, and is suitable for industrial mass production.
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Description

technical field

[0001] The invention belongs to the field of organic drug synthesis, and specifically relates to a class of (S)-3-substituted oxy-2-phenyl-N-(1-phenylpropyl)quinoline-4-carboxamide and its preparation method and preparation Use of (S)-3-hydroxy-2-phenyl-N-(1-phenylpropyl)quinoline-4-carboxamide. Background technique

[0002] The chemical name of Talnetant is (S)-3-hydroxy-2-phenyl-N-(1-phenylpropyl)quinoline-4-carboxamide, and its structural formula is shown in the following (I). Talnetant is an orally active selective NK-3 antagonist developed by GlaxoSmithKline for the treatment of central nervous system degeneration, respiratory diseases and irritable bowel syndrome.

[0003]

[0004] In the prior art, the preparation methods of Talnetant mainly contain the following types:

[0005] Documents WO9532948; WO2007016609; J Med Chem.1999, 42, 1053-1065 disclose a synthesis method of Talnetant, and the synthesis route is as follows:

[0006]

[0007] Th...

Examples

Embodiment 1

[0045] (1) 3-(Benzyloxy)-2-phenylquinoline-4-carboxylic acid

[0046] Take 7.64g (0.052mol) of isatin, add 50ml of absolute ethanol, stir in an ice bath, add 3.36g (0.06mol) of potassium hydroxide in batches, stir at room temperature (25°C) for 30 minutes, add dropwise 2- (Benzyloxy)-1-phenylethanone 11.3g (0.05mol) and 100ml of anhydrous ethanol solution, dripped over 1 hour, after completion, the temperature was raised to reflux for 12 hours. After the reaction is complete, cool to room temperature, evaporate the solvent to dryness under reduced pressure, add 200ml of water, adjust the pH to 3-4 with concentrated hydrochloric acid, a large amount of white solid precipitates, leave it for 1h, filter with suction, wash with water, dry in vacuo, and weigh with absolute ethanol 9.12g of crystalline white crystals, yield: 54.4%, melting point: 188-190°C, 1 H (DMSO-d 6 )δ14.30(br,s,1H),8.12(d,1H),8.00(dd,2H),7.79-7.85(m,2H),7.71(t,1H),7.55(t,3H),7.34 -7.36(m,3H),7.18-7.16(m,2H)...

Embodiment 2

[0055] (1) 3-(allyloxy)-2-phenylquinoline-4-carboxylic acid

[0056] Take isatin 7.64g (0.052mol), add 50ml of absolute ethanol, stir under ice bath, add potassium hydroxide 3.36g (0.06mol) in batches, stir at 60°C for 30 minutes, add 2-(allyl Oxygen)-1-phenylethanone 8.8g (0.05mol) and 100ml of absolute ethanol solution, dripped over 1 hour, after completion, heated to reflux for 12h. After the reaction is complete, cool to room temperature, evaporate the solvent to dryness under reduced pressure, add 200ml of water, adjust the pH to 3-4 with concentrated hydrochloric acid, a large amount of white solid precipitates, leave it for 1h, filter with suction, wash with water, dry in vacuo, and weigh with absolute ethanol Crystallized white crystals 10.5g, yield: 69.1%, melting point: 158-160°C, 1 H (DMSO-d 6 ( d,2H).M / Z(ES + )306[M+H] +

[0057] (2) 3-(allyloxy)-2-phenylquinoline-4-formyl chloride

[0058] Dissolve 2.8ml of oxalyl chloride in 60ml of toluene, add 6g of 3-(a...

Embodiment 3

[0065] (1) 3-(Benzyloxy)-2-phenylquinoline-4-carboxylic acid

[0066] Take 7.64g (0.052mol) of isatin, add 50ml of anhydrous isopropanol, stir under ice bath, add 4.08g (0.06mol) of sodium ethylate in batches, stir at -10°C for 30 minutes, add dropwise 2-(benzyl Oxygen)-1-phenylethanone 11.3g (0.05mol) and 100ml absolute ethanol solution, dripped in 1 hour, after completion, heated to reflux for 12h. After the reaction is complete, cool to room temperature, evaporate the solvent to dryness under reduced pressure, add 200ml of water, adjust the pH to 3-4 with concentrated hydrochloric acid, a large amount of white solid precipitates, leave it for 1h, filter with suction, wash with water, dry in vacuo, and weigh with absolute ethanol 9.08g of crystalline white crystals, yield: 54.0%, melting point: 188-190°C, 1 H (DMSO-d 6 )δ14.30(br,s,1H),8.12(d,1H),8.00(dd,2H),7.79-7.85(m,2H),7.71(t,1H),7.55(t,3H),7.34 -7.36(m,3H),7.18-7.16(m,2H),4.68(s,2H).M / Z(ES + )356[M+H] +

[0067] ...