Preparation method of carfilzomib intermediate

A technology for carfilzomib and intermediates, which is applied in the field of preparation of carfilzomib intermediates, can solve the problems of difficult acquisition, difficult purification, low yield, etc., to reduce the number of times of protection and deprotection, and process routes The effect of simplicity and reduction of preparation steps

Active Publication Date: 2014-05-21
铜陵尚东高新科创有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Its shortcoming is that the protection and deprotection of the amino acid nitrogen end are repeated many times, which makes the whole process cumbersome, the overall yield is not high, and the purification is difficult
However, this method cannot fundamentally solve the problems of cumbersome process, low yield and difficult purification. At the same time, intermediates (III) and (IV) are atypical intermediates and are difficult to obtain, which limits its industrial application.

Method used

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  • Preparation method of carfilzomib intermediate
  • Preparation method of carfilzomib intermediate
  • Preparation method of carfilzomib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Add 2-(4-morpholinyl)acetic acid (V) (1.74g, 12mmol), 4-phenylbutyric acid methyl ester (VI) (1.93g, 10mmol), diisopropyl Ethylamine (DIEA) (6.43g, 50mmol) and N,N-dimethylformamide (DMF) 30mL were stirred to dissolve and cooled to 0°C. Add benzotriazol-1-yloxy tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (6.7g, 15mmol), rise to room temperature after 1 hour and react for 12 hours, TLC detects that the reaction is complete . The reaction solution was poured into brine, extracted three times with ethyl acetate, the organic phases were combined, washed with water, saturated sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was recovered under reduced pressure to obtain 2.7 g of oily product (αS)-[2-(4-morpholinyl)acetamido]benzenebutyric acid methyl ester (VII), with a yield of 84.4%.

Embodiment 2

[0031] At 0-5°C, add (αS)-[2-(4-morpholinyl)acetamido]benzenebutyric acid methyl ester (VII) (3.2 g, 10 mmol), lithium hydroxide ( 0.24g, 10mmol), methanol 120mL and water 30mL, stirred and reacted at this temperature for 10 hours, and TLC detected that the reaction was complete. Adjust the pH to 3 with 1N hydrochloric acid, extract three times with dichloromethane, combine the organic phases, and dry over anhydrous magnesium sulfate. Dichloromethane was recovered under reduced pressure, and the residue was recrystallized from ethyl acetate and n-hexane (1 / 2) to obtain off-white solid (αS)-[2-(4-morpholinyl)acetamido]benzenebutyric acid ( VII-1) 2.65g, yield 86.6%.

Embodiment 3

[0033] Add (αS)-[2-(4-morpholinyl)acetamido]benzenebutyric acid (VII-1) (3.06g, 10mmol), L-leucine methyl ester (VIII) into the dry reaction flask (1.45g, 10mmol), diisopropylethylamine (DIEA) (6.43g, 50mmol), N-hydroxybenzotriazole (HOBt) (2.7g, 20mmol) and N,N-dimethylformamide (DMF) 30mL, stir to dissolve and cool to 0°C. Add benzotriazol-1-yloxy tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (6.7g, 15mmol), rise to room temperature after 1 hour and react for 13 hours, TLC detects that the reaction is complete . The reaction solution was poured into brine, extracted three times with ethyl acetate, the organic phases were combined, washed with water, saturated sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was recovered under reduced pressure to obtain 3.2 g of oil (αS)-[[2-(4-morpholinyl)acetamido]phenylbutyryl]-L-leucine methyl ester (IX), with a yield of 73.9%.

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Abstract

The invention discloses a preparation method of a carfilzomib intermediate (alpha S)-[[2-(4-morpholinyl)acetamido]phenylbutyryl]-L-leucyl-L-phenylalanine (I), which comprises the following steps: with 2-(4-morpholinyl)acetic acid (V), 4-phenyl homophenylalanine ester (VI), L-leucine ester (VIII) and L-phenylalanine ester (X) as raw materials, performing an amidation reaction and a hydrolysis reaction to generate (alpha S)-[[2-(4-morpholinyl)acetamido]phenylbutyryl]-L-leucyl-L-phenylalanine (I). Compared with the prior art, the preparation method has the advantages of simple process, easily available raw materials and few side reactions, adapts to industrial production and promotes the economic and technological development of the raw medicine.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a preparation method of a carfilzomib intermediate. Background technique [0002] Carfilzomib is a new generation proteasome inhibitor developed by Onyx Pharmaceuticals. Since the compound does not have a standard Chinese translation name, the applicant here transliterates it as "carfilzomib". Carfilzomib injection was approved by the U.S. Food and Drug Administration (FDA) in July 2012, and its trade name is Kyprolis. The drug selectively targets the proteasome in hematological tumor cells, avoiding the toxic side effects of inhibiting the constitutive proteasome in non-malignant cells. It is clinically used for patients with relapsed or refractory myeloma who have not responded to at least two existing therapies (one of which must be bortezomib). [0003] Carfilzomib is a tetrapeptide compo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/117
Inventor 许学农
Owner 铜陵尚东高新科创有限公司
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