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Synthesis method of propeller alkane derivative

A derivative, pentane technology, applied in the field of synthesis of chloromethyl propane, can solve the problems of difficult preparation, complicated post-processing, low yield, etc.

Active Publication Date: 2022-06-07
SHANGHAI SIMR BIOTECHNOLOGY CO LTD +1
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Problems solved by technology

[0012] In order to solve the problems that the existing synthesis process conditions are not mild enough, the yield is low, the preparation is difficult, and the post-treatment is complicated, the present invention provides a halomethyl propeller alkane derivative (halomethyl bicyclo[1.1.1]pentane Derivatives) synthetic method, the method with bromide and alkyl metal salt (such as methyllithium) as starting materials, after the reaction to obtain [1.1.1]-propeller alkane (tricyclo[1.1.1.0]pentane ), and then add cheap iodide, after simple post-treatment, after crystallization of white solid, reduce with reducing agent to obtain the method of the target compound

Method used

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  • Synthesis method of propeller alkane derivative
  • Synthesis method of propeller alkane derivative
  • Synthesis method of propeller alkane derivative

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preparation example Construction

[0022] The present invention provides a method of preparation of a bicyclic [1.1.1] pentane derivative of the preparative formula (1), comprising the following steps:

[0023]

[0024] Step 1): to As the starting material, the formation of tricyclic [1.1.1.0] pentane ([1.1.1]-propellane);

[0025] Step 2): The tricyclic [1.1.1.0] pentane ([1.1.1]-propellal alkane) obtained in step 1) is reacted with the iodine substitute XICHR to form an iodine substitute of the bicyclic [1.1.1] pentane ；

[0026] Step 3): Step 2) result in a bicyclic [1.1.1] pentane iodine , under the action of the initiator, is reduced by the reducing agent ；

[0027] Among them, R is independently selected from hydrogen and C 1-6 Alkyl and halogen, X is independently selected from halogen and C 1-6 Alkyl.

[0028] Preferably, R is independently selected from hydrogen, methyl and Cl, X is independently selected from Cl and methyl; More preferably, R is independently selected from hydrogen, X is independentl...

Embodiment 1

[0050] Example 1: Methyl tert-butyl ether step-by-step method

[0051] Preparation of tricyclic [1.1.1.0] pentane (TCP) (Compound 3).

[0052] 5 L dried three-mouth bottle, add raw compound 2 (320 g, 1.09 mol), Ar gas protection, double row needle add CaH 2 Dried methyl tert-butyl ether 1.2 L, stirred until dissolved and clarified, dry ice + isopropanol cooled to internal temperature -45 o C～-15 o C, double row needle dropwise plus methyl lithium solution (800 mL, 2.4 mol, diethoxymethane solution, 3 M), drop-by-drop process greater than 1 h, and then ice water bath reaction for 2 h. The product of methyl tert-butyl ether - diethoxymethane solution was distilled into the receiving bottle, the receiving bottle was cooled with an isopropanol dry ice bath to give 2.5L of methyl tert-butyl ether containing TCP (Compound 3) - diethoxymethane solution.

[0053] Preparation of 1-(chloromethyl)-3-iodine bicyclo [1.1.1]pentane (Compound 5).

[0054] CH was added to a methyl tert-butyl ethe...

Embodiment 2

[0055] Example 2: Ether step-by-step method

[0056] Preparation of tricyclic [1.1.1.0] pentane (TCP) (Compound 3).

[0057] 250 mL dried three-port bottle, add compound raw material 2 (20 g, 67.4 mmol), Ar gas protection, double row needle add dried ether 80 mL, dry ice + isopropanol cooled to internal temperature -45 o C～-15 o C, double row needle dropwise add lithium methyl solution (54 mL, 2.4 mol, diethoxymethane solution, 3 M), the drop dosing process is greater than 1 h, and then the ice water bath reaction is 2 h. The ether-diethoxymethane solution of the product is distilled into the receiving bottle, which is cooled down with an isopropanol dry ice bath. To obtain 120 mL of ether containing TCP (Compound 3) - diethoxymethane solution was obtained.

[0058] Preparation of 1-(chloromethyl)-3-iodine bicyclo [1.1.1]pentane (Compound 5).

[0059] CH is added to the ether-diethoxymethane solution (120 mL) containing TCP (Compound 3). 2 ClI (12.2 g, 67.8 mmol), stirred at room ...

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Abstract

The present application relates to a process for the preparation of bicyclo [1.1. 1] pentane derivatives of formula (1), comprising the steps of: step 1): forming tricyclic [1.1. 1.0] pentane from starting materials; the method comprises the following steps: 1) preparing tricyclic [1.1. 1.0] pentane, 2) carrying out a free radical reaction on the tricyclic [1.1. 1.0] pentane obtained in the step 1) and an iodide XICHR to form a bicyclo [1.1. 1] pentane iodide, and 3) reducing the bicyclo [1.1. 1] pentane iodide obtained in the step 2) by a reducing agent under the action of an initiator to form the bicyclo [1.1. 1] pentane represented by a formula (1) wherein R is independently selected from hydrogen, C1-6 alkyl and halogen, and X is independently selected from halogen and C1-6 alkyl.

Description

Technical field [0001] The present invention relates to the technical field of organic synthesis methods of propeller compounds, more particularly, to the synthesis method of chloromethylscrewsalane, the method can meet the needs of large-scale synthesis. Background [0002] Bicyclic [1.1.1]pentane derivative (BCP), as an alternative to aromatic rings, tert-butyl groups and acetyl groups, has been one of the hot topics in medicinal chemistry research in recent years. In addition to maintaining the drug activity in the parent nucleus part, there is a large advantage in the improvement of pharmacokinetics. Bicyclic [1.1.1] pentane derivatives are typically obtained by [1.1.1]-propellane (tricyclic [1.1.1.0] pentane (TCP). However, the synthesis requirements for replacing bicyclic [1.1.1] pentane derivatives are higher, such as metal reagent heating reactions or high-pressure mercury photophoresis reactions. Therefore, the amplification and synthesis of bicyclic [1.1.1] pentane deri...

Claims

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Application Information

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IPC IPC(8): C07C17/32C07C23/24C07C17/23C07C22/00C07C1/28C07C13/605
CPCC07C17/32C07C17/23C07C1/28C07C2602/38C07C2603/62C07C23/24C07C22/00C07C13/605
Inventor 孙勇许树杰
Owner SHANGHAI SIMR BIOTECHNOLOGY CO LTD
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