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Process for the synthesis of intermediates of nebivolol

一种异构体、混合物的技术，应用在合成奈比洛尔的中间体领域，能够解决长时间等问题，达到减少合成步骤的效果

Active Publication Date: 2018-09-28
MENARINI INT OPERATIN S LUXEMBORG SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

These reactions take a long time

Method used

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  • Process for the synthesis of intermediates of nebivolol
  • Process for the synthesis of intermediates of nebivolol
  • Process for the synthesis of intermediates of nebivolol

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0100] Example 1: Synthesis of (R)-2-chloro-1-(6-fluorochroman-2-yl)ethan-1-one

[0101]

[0102] At 0°C under a nitrogen atmosphere, a solution of 1M tBuMgCl in THF (21 l, 21 mol) was mixed with 1.6 Kg (7.2 mol) of carboxylated (R)-ethyl 6-fluorochromanyl A solution of IIa in MTBE (8 L) was simultaneously added dropwise to a suspension of sodium chloroacetate (1.74 Kg, 15.1 mol) in MTBE (8 L). The drop rates of the two solutions were adjusted so that both solutions were dropped simultaneously while ensuring that the temperature remained in the range -3°C / +3°C throughout the addition (1.5 to 2.0 hours). At the end of the addition of the reagents, the solution was kept stirring at a temperature of -3°C / +3°C. After confirming the completion of the reaction by HPLC analysis, the suspension was added dropwise to 50% H 2 SO 4 (5.4Kg) solution, ice (17Kg) and H 2 O (17Kg) in the mixture and kept at -5°C, make sure that the temperature is kept within the range of 0°C / +5°C duri...

example 2

[0104] Example 2: Synthesis of (S)-2-chloro-1-(6-fluorochroman-2-yl)ethan-1-one

[0105] The method described in Example 1 was similarly applied to isomeric carboxylated (S)-ethyl 6-fluorochromanyl IIb to give the corresponding product (S)-6-fluorobenzo Dihydropyranylchloroketone IIb.

example 3

[0106] Example 3: (R)-6-fluoro-2-((S)-oxiran-2-yl)chroman and (S)-6-fluoro-2-((R)-cyclo Synthesis of Oxyethane-2-yl)chroman

[0107]

[0108] in N 2 Under flow, (R)-methyloxazoboridine ((R)-MeCBS) or (S)-methyloxazoboridine ((S)-MeCBS) (35.9 g, 0.129 mol, 3.3%) was added to BH 3 A solution of DEA (0.70 Kg, 4.3 mol) in cyclohexane (8 Kg) and the resulting suspension was stirred at ambient temperature for 15 minutes. Chloroketone IIIa or IIIb (0.9 Kg, 3.9 mol), respectively, was added to this reducing mixture in portions of 45 g / 10 minutes. After 20 minutes after the last addition, HPLC analysis showed almost complete disappearance of the starting product (6-fluoro-chromanyl chloroketone 2 SO 4 (7.5Kg) treatment, then with H 2 O (2×8Kg) was treated, and the solvent was removed under reduced pressure to obtain (R) 6-fluoro-2-(S)oxiranyl chroman (Ib) or (S) 6-fluoro- 2-(R)Oxiranylchroman (Id), yield equal to 90% in two steps.

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Abstract

The present invention relates to a novel process for the synthesis of the intermediate compounds constituted by chromanyl haloketones of formula III and 6-fluoro-2-(oxiran-2-yl) chromans of formula I.The intermediates thus obtained can be used for the synthesis of Nebivolol.

Description

technical field [0001] The present invention relates to a new method for synthesizing chromanyl haloketone and oxiranyl chromanone compounds, which can be used as intermediates for the synthesis of Nebivolol. Background technique [0002] Nebivolol is two enantiomers [2S[2R[R[R]]]]α,α'-[imino-bis(methylene)]bis[6-fluoro-chroman Pyran-2-methanol] and [2R[2S[S[S]]]]α,α'-[imino-bis(methylene)]bis[6-fluoro-chroman-2 -methanol] (Figure 2). [0003] [0004] The molecule of nebivolol contains 4 asymmetric centers, from which 16 possible stereoisomers can theoretically be generated, since the symmetry of the molecule is reduced to 10, which explains the complexity of its structure, and the reasons for its preparation. Many synthetic methods were developed. [0005] As a key intermediate in the synthesis of nebivolol, epoxide (I) has been the subject of many synthetic methods developed for its preparation. [0006] EP0334429 reports the synthesis of epoxides in the form of th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D407/04C07D311/58
CPCC07D407/04C07D311/58
Inventor 桑德拉·鲍尔托利瑟瑞娜·曼纽什阿莱西奥·格里塞利阿莱西奥·斯特凡尼尼
Owner MENARINI INT OPERATIN S LUXEMBORG SA
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