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Preparation method of Volasertib and intermediates thereof

A technology for voraxetidine and intermediates, which is applied in the field of preparation of voraxetidine and its intermediates, can solve the problems of increased purification difficulty, reduced total reaction yield and the like, and achieves reduced side reactions, mild conditions, and simple process. Effect

Active Publication Date: 2014-08-27
TONGLING SHANGDONG HI TECH INNOVATION CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Investigate the synthetic route of above-mentioned intermediate (A), (B) and voraseti, because intermediate (A), (B) and the amine functional group exist in many places in the molecular structure of voraceti, thereby carrying out condensation, During amidation and reduction reactions, primary amines in cyclohexylamine, secondary amines on the piperidine ring, and primary amines on the benzene ring will all produce competing side reactions, which will increase the difficulty of purification and reduce the overall yield of the reaction.

Method used

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  • Preparation method of Volasertib and intermediates thereof
  • Preparation method of Volasertib and intermediates thereof
  • Preparation method of Volasertib and intermediates thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0036] Under nitrogen protection, 2-amino-7-ethyl-7,8-dihydro-5-methyl-8-isopropyl-(7R)-6(5H)-pteridone (II ) (1.17g, 5mmol), N-[trans-4-[4-(cyclopropylmethyl)-1-piperazinyl]cyclohexyl]-4-bromo-3-methoxybenzamide ( III) (2.25g, 5mmol), cuprous iodide (142mg, 0.75mmol), 8-hydroxyisoquinoline (220mg, 0.75mmol), potassium carbonate (760mg, 5.5mmol) and 50mL N,N-dimethyl Formamide, heated to 100°C, stirred until dissolved. Add triethylamine (75 mg, 0.75 mmol), continue to heat up to 140° C., react for 15 hours, and TLC detects that the reaction is complete. Cool down to 50-60°C, filter, and wash the filter cake with ethyl acetate. The filtrate was washed with brine and water, concentrated under reduced pressure, and recrystallized from ethyl acetate and n-hexane (2:1) to obtain 2.42 g of voraseti (I) as a pale yellow solid, with a yield of 78.3%.

Embodiment 2

[0038]Under nitrogen protection, 2-amino-7-ethyl-7,8-dihydro-5-methyl-8-isopropyl-(7R)-6(5H)-pteridone (II ) (1.17g, 5mmol), N-[trans-4-[4-(cyclopropylmethyl)-1-piperazinyl]cyclohexyl]-4-iodo-3-methoxybenzamide ( III) (2.48g, 5mmol), cuprous iodide (142mg, 0.75mmol), 8-hydroxyisoquinoline (220mg, 0.75mmol), potassium carbonate (760mg, 5.5mmol) and 50mL N,N-dimethyl Formamide, heated to 100°C, stirred until dissolved. Ethylenediamine (45mg, 0.75mmol) was added, the temperature was continued to rise to 120°C, and the reaction was carried out for 8 hours. TLC detected that the reaction was complete. Cool down to 50-60°C, filter, and wash the filter cake with ethyl acetate. The filtrate was washed with brine and water, concentrated under reduced pressure, and recrystallized from ethyl acetate and n-hexane (2:1) to obtain 2.64 g of off-white solid voraseti (I), with a yield of 85.4%.

Embodiment 3

[0040] Add 2-chloro-7-ethyl-7,8-dihydro-5-methyl-8-isopropyl-(7R)-6(5H)-pteridone (IV) (2.68g , 10mmol) and allylamine 25mL, heated to reflux, reacted for 4 hours, and TLC detected that the reaction of the raw materials was complete. Cool, add 50 mL of pure water, extract 3 times with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, recover the solvent under reduced pressure, and the obtained oil is 2-(N-allyl)amino-7-ethyl- 7,8-dihydro-5-methyl-8-isopropyl-(7R)-6(5H)-pteridinone (V), without treatment, directly dissolved in 50mL ethanol, transferred to a dry three-port reaction Boron trifluoride diethyl ether (0.9g, 1eq) and 5% palladium carbon (0.3g, 10%w / w) were added under a nitrogen atmosphere, heated to ethanol reflux, reacted for 9 hours, and TLC detected that the reaction was complete. The solvent was recovered under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain a light yellow solid 2-amino-7-ethyl-7,8...

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Abstract

The invention discloses a preparation method of Volasertib (I). The preparation method comprises the following step: carrying out a nucleophilic substitution reaction on an intermediate 2-amido-7-ethyl-7,8-dihydro-5-methyl-8-isopropyl-(7R)-6(5H)-pteridinone (II) and an intermediate N-[trans-4-[4-( cyclopropyl methyl)-1-piperazinyl]cyclohexyl]-4-halogen-3-methoxybenzamide (III) to prepare the Volasertib (I). The preparation method disclosed by the invention is simple in process, moderate in condition, less in side reaction and suitable for the requirement on industrialized amplification. Besides, the invention also discloses the intermediate 2-amido-7-ethyl-7,8-dihydro-5-methyl-8-isopropyl-(7R)-6(5H)-pteridinone (II) and intermediate N-[trans-4-[4-( cyclopropyl methyl)-1-piperazinyl]cyclohexyl]-4-halogen-3-methoxybenzamide (III) of the volasertib (I) and a preparation method thereof.

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 volasertib and intermediates thereof. Background technique [0002] Volasertib is an experimental Polo-like kinase (Plk) inhibitor developed by Boehringer Ingelheim, which was launched in September 2013 and April 2014, respectively. Granted Breakthrough Therapy and Orphan Drug status by the FDA and EMEA for the treatment of acute myeloid leukemia (AML) patients aged 65 and over who are not eligible for intensive induction chemotherapy regimens. Because the drug has not been officially launched in my country and has no standard Chinese translation, the applicant hereby transliterates it as "Voraseti". Volasertib is designed to inhibit the activity of the regulatory cell mitotic enzyme Plk1. This inhibition prolongs cell cycle arrest, leading to apoptosis. [0003] Volas...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D475/00C07D295/135
CPCC07D295/135C07D475/00C07D487/04
Inventor 许学农
Owner TONGLING SHANGDONG HI TECH INNOVATION CO LTD
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