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Preparation method of kyprolis

A technology of carfilzomib and compounds, which is applied in the field of preparation of carfilzomib, can solve the problems of inapplicability to large-scale industrial production, complex and diverse reaction conditions, and low yield of final products, and achieve low price and few reaction steps , the effect of reducing production costs

Inactive Publication Date: 2014-06-18
CHONGQING TAIHAO PHARM CO LTD
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  • Description
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Problems solved by technology

This method can finally synthesize carfilzomib, but there are still some problems when it is applied to large-scale production, such as the low yield of sodium iodide chlorine substitution reaction, which not only consumes more starting materials, but also leads to the loss of final product. The yield is low; moreover, there are many types of reactions in this synthetic method, the reaction conditions are complicated and varied, and the controllability is poor, so it is not suitable for large-scale industrial production

Method used

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  • Preparation method of kyprolis
  • Preparation method of kyprolis
  • Preparation method of kyprolis

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preparation example Construction

[0044] The invention provides a kind of preparation method of carfilzomib, comprises the following steps:

[0045] Step 1. Under the action of a condensing agent and an organic base, a condensation reaction occurs between the compound shown in formula (II) and the compound shown in formula (III) to obtain the compound shown in formula (IV), which is then protected by deamination to generate formula (V ) shown in the compound;

[0046]

[0047] Among them, R 1 is a carboxyl protecting group;

[0048] Step 2. Under the action of a condensing agent and an organic base, a condensation reaction occurs between the compound shown in formula (V) and the compound shown in formula (VI) to obtain the compound shown in formula (VII), which is then protected by decarboxylation to generate formula ( IX) the compound indicated;

[0049]

[0050] Step 3, the compound represented by formula (IX) and the compound represented by formula (VIII) undergo a condensation reaction to generate...

Embodiment 1

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

[0091] Under nitrogen protection, add 27.9g (0.10mol) of N-Boc-L-homophenylalanine and 26.0g (0.105mol) of L-leucine methyl ester trifluoroacetate into a 1000mL three-necked flask, and add 500mL Tetrahydrofuran, and 51.7 g (0.4 mol) of DIEA were added thereto, and the mixture was cooled to 0°C while stirring. To this mixture was added HOBT 14.9 g (0.11 mol). The reactant was placed under nitrogen, stirred for 2 h, distilled under reduced pressure, and the residue was dissolved in 300 mL of dichloromethane, and washed twice with saturated sodium bicarbonate, water and saturated saline, each time 150 mL, organic The layer was evaporated to dryness under reduced pressure to obtain 36.5 g of the compound of formula (IV), to which 120 mL of a mixed solution of trifluoroacetic acid: dichloromethane = 4:1 was added, stirred and reacted at 15°C for 7 h, and after concentration, 29.3 g of off-white solid was obtained...

Embodiment 2

[0095] Preparation of compound shown in embodiment 2 formula (V-b)

[0096] Under argon protection, add 27.9g (0.10mol) of N-Boc-L-homophenylalanine and 39.2g (0.2mol) of L-leucine ethyl ester hydrochloride into a 1000mL three-necked flask, and add 600mL of acetonitrile , and 158.2 g (2.0 mol) of pyridine was added thereto, and the mixture was cooled to -5°C while stirring. Add HBTU113.8g (0.3mol) to this mixture, place the reactant under argon, stir the reaction for 18h, distill under reduced pressure, dissolve the residue in 300mL ethyl acetate, wash with saturated sodium bicarbonate, water and saturated salt in sequence Wash twice with water, 150 mL each time, evaporate the organic layer to dryness under reduced pressure to obtain 37.2 g of the compound of formula (IV), add it to HCl-ethyl acetate (about 1.5 mol / L) solution, and react at 20 °C After 10 hours, it was concentrated to dryness, and after purification, 26.6 g of off-white solid was obtained. According to HPLC d...

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Abstract

The invention provides a preparation method of kyprolis, which comprises the steps of carrying out a condensation reaction among N-Boc-L-homophenylalanine shown in a formula (I), L-leucine ester shown in a formula (III) and salt, and carrying out deamination protection so as to obtain a compound shown in a formula (V); carrying out a condensation reaction between the compound shown in the formula (V) and morpholin-4-yl-acetic acid shown in a formula (VI), and carrying out decarboxylation protection so as to obtain a compound shown in a formula (IX); carrying out a condensation reaction between the compound shown in the formula (IX) and a compound shown in a formula (VIII), so that kyprolis is directly generated. According to the invention, a convergent synthesis method is adopted, and condensation and deprotection among amino acids are only involved, so that the reaction steps are less, reaction conditions are mild and controllable, and the yield of kyprolis is increased, therefore, the method is suitable for industrial production. Experimental results show that by using the method provided by the invention, the yield of kyprolis can reach 19.3-30.8%.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical compounds, in particular to a preparation method of carfilzomib. Background technique [0002] Carfilzomib, chemical name (2S)-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxirane-2-yl )-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholineacetamido)-4-phenylbutanylamino )-4-methylpentanamide, the foreign name or common name is Carfilzomib, the trade name is Kyprolis, and the molecular formula is C 19 h 25 BN 4 o 4 , has the structure of formula (I). [0003] [0004] On July 20, 2012, the U.S. Food and Drug Administration (FDA) approved the listing of ONYXPHARMSINC's product carfilzomib (carfilzomib) freeze-dried powder for injection. Carfilzomib can be used to treat at least 2 drugs before treatment, including Multiple myeloma patients treated with bortezomib and immunomodulators. Multiple myeloma is a malignant clonal disease of plasma cells. The incidence rate is increasin...

Claims

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Application Information

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IPC IPC(8): C07K7/06
CPCY02P20/55
Inventor 姚全兴李靖喻威吴进余智奎
Owner CHONGQING TAIHAO PHARM CO LTD
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