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Preparation method of trans-2-(substituted phenyl)-3-hydroxymethyl morpholine

A technology of reaction and bromination, applied in the direction of organic chemistry, etc., to achieve the effect of reducing side reactions, improving reaction yield and mild reaction conditions

Active Publication Date: 2022-03-22
SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The compound PDE12-IN-1 has been successful in the market, but there are no literature or patent reports on the synthesis of this compound

Method used

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  • Preparation method of trans-2-(substituted phenyl)-3-hydroxymethyl morpholine
  • Preparation method of trans-2-(substituted phenyl)-3-hydroxymethyl morpholine
  • Preparation method of trans-2-(substituted phenyl)-3-hydroxymethyl morpholine

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preparation example Construction

[0041] In order to solve the above-mentioned technical problems, the invention provides a kind of preparation method of compound VI, comprises the following steps:

[0042] Step 1: compound I reacts with phosphorus ylide to obtain compound II;

[0043]

[0044] Step 2: Addition reaction of compound II with compound III and brominated reagent to obtain compound IV;

[0045]

[0046] Step 3: Compound IV is deprotected and ring-closed to obtain Compound V;

[0047]

[0048] Step 4: Preparation of Compound VI

[0049]

[0050] The R 1 selected from halogen, hydrogen, C 1～6 Substituted or unsubstituted alkyl; said halogen is selected from fluorine, chlorine, bromine, iodine;

[0051] The R2 It is selected from tert-butoxycarbonyl, fluorenylmethoxycarbonyl, and benzyloxycarbonyl.

[0052] In a preferred embodiment, the preparation method of step 1 includes the following steps: mixing compound I, phosphorus ylide and an organic solvent, and reacting at room temperatu...

Embodiment 1

[0082] Embodiment 1, the preparation of compound II-1

[0083]

[0084] Compound I-1 (20g, 161mmol), methoxycarbonylmethylene triphenyl orthophosphorus (56.1g, 161mmol) and DCM (200mL) were mixed and reacted at room temperature for 3h; LCMS detection, after the reaction was completed, silica gel was added The sample was mixed and purified by column chromatography (PE:EA=10:1-8:1-6:1-5:1-3:1) to obtain compound II-1 (27.26 g, 94%).

Embodiment 2

[0085] Embodiment 2, the preparation of compound IV-1

[0086]

[0087] Compound II-1 (13g, 72.1mmol), compound III-1 (58g, 360.7mmol), NBS (39g, 216.3mmol) were dissolved in DCE (150mL), and reacted at 60°C for 70h; after the reaction was detected by LCMS, Add water (300mL) to the reaction solution, extract with DCE (100mL×3), combine the organic phases, wash with saturated sodium chloride (100mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product; add the crude product to silica gel and mix The sample was purified by column chromatography (PE:EA=10:1-8:1-6:1-5:1-3:1) to obtain compound IV-1 (12.12 g, 40%).

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Abstract

The invention relates to a preparation method of trans-2-(substituted phenyl)-3-hydroxymethyl morpholine. The defects of low analogue yield and difficulty in purification in the prior art are overcome, and the overall yield and atom economy of the route are effectively improved; especially for synthesis of a compound IV, reaction conditions are optimized, side reactions are reduced, the post-treatment difficulty can be reduced, and the reaction yield is further effectively improved; the synthesis method is mild in reaction condition, simple and convenient to operate, suitable for small-amount preparation in a laboratory and suitable for industrial large-scale production.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a preparation method of trans-2-(-substituted phenyl)-3-hydroxymethylmorpholine. Background technique [0002] PDE12-IN-1 (CAS#2259620-80-7, named trans 3-(5-bromo-6-((2S*,3S*)-2-(4-fluorophenyl)-3-(hydroxy Methyl)morpholine-4-carbonyl)-1-methyl-1H-benzo[d]imidazol-2-yl)-1-ethyl-1H-indole-6-carbonitrile) is a potent PDE12 Inhibitor, pIC 50 is 9.1. PDE12-IN-1 increases the levels of 2′,5-linked adenylate polymers (2-5A), pEC 50 The value is 7.7. PDE12-IN-1 exhibits antiviral activity. The literature Journal of Biological Chemistry, 2015, 290(32): 19681-19696 and the patent US20190002585A1 only disclose the structure of PDE12-IN-1, but do not disclose the preparation method of the product. (trans-2-(4-fluorophenyl)morpholin-3-yl)methanol (compound A) and its salts can be used to synthesize PDE12-IN-1, but again, there is no prior art disclosing this chirality Synth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D265/30
CPCC07D265/30Y02P20/55
Inventor 蒋贵兰张宏伟周治国高强郑保富
Owner SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD