Synthesis method of aryl alcohol compound and Escitalopram

A synthetic method and compound technology, applied in the preparation of hydroxy compounds, amino hydroxyl compounds, organic chemical methods, etc., can solve the problems of high product yield and ee value

Active Publication Date: 2016-07-06
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The technical problem to be solved by the present invention is to overcome the existing technical problem that the product yield and ee value are relatively high in the intermolecular asymmetric addition of inactive ketones by using aryl boron reagents, and provides A kind of synthetic method of aryl alcohol compound and escitalopram

Method used

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  • Synthesis method of aryl alcohol compound and Escitalopram
  • Synthesis method of aryl alcohol compound and Escitalopram
  • Synthesis method of aryl alcohol compound and Escitalopram

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0092] With acetophenone 1a as substrate, 4-methoxyphenylboronic anhydride 2a as boron reagent, [Rh(C 2 h 4 ) 2 Cl] 2 Chiral diarylalkylmethanols were prepared as metal precursors under different conditions.

[0093]

[0094] Among them, the preparation methods of ligands L1-L4 refer to Angew.Chem.Int.Ed.2013, 52, 4235; Adv.Synth.Catal.2013, 355, 1297.

[0095] The reaction is as follows: Acetophenone (0.1mmol, 1equiv), arylboronic anhydride (0.2mmol, 2equiv), base (0.4mmol, 4equiv), additive (0.035mmol, 35mmol%), ligand (0.0036mmol, 3.6mol%) %) and [Rh(C 2 h 4 ) 2 Cl] 2(0.0015mmol, 1.5mol%) was mixed in a dry reaction tube, and after the nitrogen was replaced three times, 1.5mL of methyl tert-butyl ether was added under the protection of nitrogen, followed by reaction at 60°C or 100°C in an oil bath for 18h. After adding water (3 mL) to quench the reaction, it was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine...

Embodiment 2

[0100] With acetophenone 1a (12mg, 0.1mmol, 1equiv) as substrate, 4-methoxyphenylboronic anhydride 2a (80.4mg, 0.2mmol, 2equiv) as nucleophile, [Rh(C 2 h 4 ) 2 Cl] 2 (0.6mg, 0.0015mmol, 1.5mol%) as transition metal precursor, WingPhos (2.7mg, 0.0036mmol, 3.6mmol%) as ligand, cesium fluoride (45.6mg, 0.3mmol, 3equiv) as base, methyl Tert-butyl ether (1.5 mL) was used as a solvent, magnesium bromide (6.4 mg, 0.035 mmol, 0.35 equiv) was used as an additive, and the reaction was carried out at 100°C. The method for preparing chiral diarylalkylcarbinol described in the present invention is described in detail. The reaction was as follows: acetophenone 1a (12 mg, 0.1 mmol, 1 equiv), 4-methoxyphenylboronic anhydride 2a (80.4 mg, 0.2 mmol, 2 equiv), cesium fluoride (45.6 mg, 0.3 mmol, 3 equiv), bromine Magnesium chloride (6.4mg, 0.035mmol, 0.35equiv), WingPhos (2.7mg, 0.0036mmol, 3.6mmol%) and [Rh(C 2 h 4 ) 2 Cl] 2 (0.6mg, 0.0015mmol, 1.5mol%) were mixed in a dry reaction tube...

Embodiment 3

[0138] Synthesis of (S)-4-chloro-1-(2,4-dichlorophenyl)-1-(4-fluorobenzene)-1-butanol (5).

[0139]

[0140] 4-Chloro-1-(2,4-dichlorophenyl)-1-butanone (4) (50.3mg, 0.20mmol, 1equiv), 4-fluorophenylboronic anhydride (146.3mg, 0.40mmol, 2equiv) , Magnesium Bromide (12.9mg, 0.07mmol, 0.35equiv), Cesium Fluoride (121.5mg, 0.80mmol, 4equiv), (R,R,R,R)-WingPhos (5.4mg, 0.0072mmol, 3.6mol%) and [Rh(C 2 h 4 ) 2 C1] 2(1.2mg, 0.003mmol, 1.5mol%) was placed in a dry reaction tube, the nitrogen was purged three times, and freshly distilled methyl tert-butyl ether (1.5mL) was added. The reaction tube was placed in an oil bath at 80° C. for 10 hours. Then move to room temperature to cool, and add water to quench the reaction. Extracted with dichloromethane, combined organic phases, dried over anhydrous sodium sulfate, concentrated, and column chromatography gave the product (S)-4-chloro-1-(2,4-dichlorophenyl)-1-(4-fluorobenzene )-1-Butanol (5) (48.6 mg, 0.14 mmol, 70% yield, >99%...

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Abstract

The invention discloses a synthesis method of an aryl alcohol compound and Escitalopram. The synthesis method of the aryl alcohol compound comprises the following steps: under gas protection and in an organic solvent and in the presence of transition metal, diphosphine ligand and alkali, the compound of formula 1 reacts with an aryl boron reagent 2. The synthesis method of Escitalopram comprises the following steps: (1) under gas protection and in an organic solvent and in the presence of transition metal, diphosphine ligand and alkali, the compound of formula 4 reacts with the aryl boron reagent 2; (2) under gas protection and in an organic solvent and in the presence of alkali, the compound of formula 5 reacts with dimethylamine or hydrochloride thereof; (3) under gas protection and in an organic solvent and in the presence of organic phosphine ligand and a palladium catalyst, the compound of formula 7 reacts with metal cyanide; and (4) under gas protection and in an organic solvent and in the presence of a reducing agent, the compound of formula 6 reacts. The synthesis method disclosed by the invention has high yield and enantioselectivity.

Description

technical field [0001] The invention relates to a synthesis method of aryl alcohol compounds and escitalopram. Background technique [0002] Chiral diarylalkylcarbinols are structural fragments of many important bioactive molecules or drug molecules (InComprehensiveAsymmetricCatalysis; Springer, Berlin, 1999; Chem.Rev.2001,101,757; Chem.Rev.2003,103,169; Chem.Rev.2003,103,169; .Rev.2003, 103, 2763; Curr.Org.Chem.2006, 10, 1849; Org.Biomo1.Chem.2007, 5, 873; ACSCatal.2012, 2, 95; , 893.), such as the antidepressant escitalopram, the antihistamine clemastine, the centrally acting antitussive drug clophenedol, the broad-spectrum fungicide fuconazole, the multi-AGC kinase inhibitor AT13148 and the wood Lipoprotein hydroxytobain (CNSDrugs2006, 20, 763; Org. Lett. 2010, 12, 2222; Appl. Ther. 1962, 4, 830. Clin. CancerRes. 2012, 18, 3912; Tetrahedron: Asymmetry2008, 19, 1504; J. Chem. Soc. 1963, 1445.). How to efficiently synthesize these chiral diarylalkylcarbinols has attracte...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07B53/00C07B41/02C07D307/87C07D307/42C07D307/58C07C41/26C07C43/23C07C29/38C07C33/46C07C67/293C07C69/76C07C201/12C07C205/35C07C205/19C07C213/02C07C215/32
CPCC07B41/02C07B53/00C07B2200/07C07C29/38C07C41/26C07C67/293C07C201/12C07C213/02C07D307/42C07D307/58C07D307/87C07C43/23C07C33/46C07C69/76C07C205/35C07C205/19C07C215/32
Inventor 汤文军黄林伟朱金斌
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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