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Epoxy ketone compound, its preparation method and the preparation method of carfilzomib

A compound, epoxy ketone technology, applied in the field of compounds, can solve the problems of unsuitability for large-scale industrial production, large pollution, poor controllability, etc.

Active Publication Date: 2017-01-11
CHONGQING SINTAHO PHARM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are still some problems when this synthetic method is applied to large-scale production, such as the low reaction yield of the linear synthesis method, and the pollution is relatively large due to the use of chloroacetyl chloride in this synthetic method; in addition, there are many reaction types in this synthetic method , the reaction conditions are complex and diverse, and the controllability is poor, so it is not suitable for large-scale industrial production

Method used

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  • Epoxy ketone compound, its preparation method and the preparation method of carfilzomib
  • Epoxy ketone compound, its preparation method and the preparation method of carfilzomib
  • Epoxy ketone compound, its preparation method and the preparation method of carfilzomib

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preparation example Construction

[0043] The present invention also provides a preparation method of the epoxy ketone compound or its salt as shown in formula (I), comprising the following steps:

[0044] Step 1. In an organic solvent, the compound represented by formula (II) and the compound represented by formula (III) undergo a condensation reaction under the action of a condensing agent and an organic base to obtain a compound represented by formula (IV). After decarboxylation protection, Obtain the compound shown in formula (V);

[0045]

[0046] Among them, R 1 is a carboxyl protecting group;

[0047] Step 2. Under the action of a condensing agent, react the compound represented by formula (V) with N,O-dimethylhydroxylamine hydrochloride to generate the compound represented by formula (VI);

[0048]

[0049] Step 3. In an organic solvent, the compound represented by formula (VI) is converted into the compound represented by formula (VII) under the action of Grignard reagent;

[0050]

[0051] S...

Embodiment 1

[0090] Preparation of the compound shown in embodiment 1 formula (V)

[0091] Under nitrogen protection, add 14.5g (0.10mol) L-leucine methyl ester and 27.8g (0.105mol) N-Boc-L-phenylalanine into a 1000mL three-necked flask, add 500mL acetonitrile, and then add 51.7 g (0.4 mol) of DIEA, the mixture was cooled to 0°C with stirring. To this mixture was added 14.9 g (0.11 mol) of HOBT, followed by three additions of PyBOP totaling 57.3 g (0.11 mol) over five minutes. The reactant was placed under nitrogen, stirred and reacted for 8 hours, distilled under reduced pressure, the residue was dissolved in 300mL ethyl acetate, washed twice with saturated sodium bicarbonate, water and saturated saline respectively, each dosage was 200mL, organic The layer was evaporated to dryness under reduced pressure to obtain 24.7g of the compound of formula (IV-a), which was dissolved in a mixed solution of methanol: water = 3:1, cooled to 0°C, and 12.1g (0.5mol) lithium hydroxide was added to rea...

Embodiment 2

[0094] Preparation of compound shown in embodiment 2 formula (V)

[0095] Add 18.1g (0.10mol) L-leucine methyl ester hydrochloride and 132.6g (0.50mol) N-Boc-L-phenylalanine into a 2000mL three-necked flask, add 600mL DMF, and then add 50.6g ( 0.50mol) triethylamine, the mixture was stirred at 20°C, 64.2g (0.2mol) TBTU was added to the mixture, the reactant was placed under nitrogen, stirred for 24h, distilled under reduced pressure, and the residue was dissolved in 300mL diethylamine Chloromethane was washed twice with saturated sodium bicarbonate, water and saturated brine in sequence, each time the dosage was 150mL, and the organic layer was evaporated to dryness under reduced pressure to obtain 23.7g of the compound represented by formula (IV-a), which was dissolved in In the mixed solution of methanol: water = 5:1, cool to 0°C, add 19.4g (0.8mol) lithium hydroxide to react for 8h, stop the reaction with 200mL saturated ammonium chloride, extract twice with 100mL dichlorom...

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Abstract

The invention discloses an epoxy ketone compound as shown in a formula (I) in the specification, and discloses a preparation method of the compound as shown in the formula (I) in the specification. The preparation method comprises the following steps of: carrying out condensation reaction on L-leucine ester as shown in a formula (II) in the specification or a salt thereof and N-Boc-L-phenylalanine as shown in a formula (III) in the specification, and then carrying out decarboxylation protection to obtain a compound as shown in a formula (V) in the specification; reacting the compound as shown in the formula (V) in the specification and N,O-dimethylhydroxylamine hydrochloride under the action of a condensing agent to generate a compound as shown in a formula (VI) in the specification; transforming the compound as shown in the formula (VI) in the specification into a compound as shown in a formula (VII) in the specification under the action of a Grignard reagent; oxygenizing the compound as shown in the formula (VII) in the specification under the action of an oxidizing agent, and carrying out deamination protection to obtain the compound as shown in the formula (I) in the specification or the salt thereof. The invention also discloses a preparation method of kyprolis. The preparation method comprises the following step of: reacting the epoxy ketone compound as shown in the formula (I) in the specification or the salt thereof and a compound as shown in a formula (9) in the specification for one step to generate the kyprolis.

Description

technical field [0001] The invention belongs to the technical field of compounds, and in particular relates to an epoxy ketone compound, a preparation method thereof and a preparation method of carfilzomib. Background technique [0002] In the past three decades, the incidence of cancer in the world has been increasing at an average annual rate of 3% to 5%, and cancer has become the number one cause of death for human beings. How to effectively prevent and treat cancer has always been a key topic in medical research. Among them, multiple myeloma is a malignant clonal disease of plasma cells. The incidence rate is increasing year by year, ranking second among hematological tumors. With the improvement of treatment level, although the complete remission rate is high, the survival rate is still relatively low. Low, one of the main reasons is recurrence. [0003] On July 20, 2012, the U.S. Food and Drug Administration (FDA) approved ONYX’s product: the listing of Carfilzomib (...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/065C07K7/06
CPCY02P20/55
Inventor 朱小锋李靖姚全兴吴进李娅谢俊俏
Owner CHONGQING SINTAHO PHARM CO LTD
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