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Synthesis method of apattamide, intermediate of apattamide and synthesis method of apattamide

A synthetic method, the technology of apalutamide, applied in the field of drug synthesis, can solve the problem of high cost, achieve the effects of less by-products, good reaction selectivity, and simplified process steps

Pending Publication Date: 2021-11-26
SUZHOU KELUN PHARMA RES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] In this synthetic route, a stoichiometric copper salt needs to be used; and the [4+1] cyclization of the last step needs to use a relatively expensive thiocarbonyl compound, and the cost is relatively high

Method used

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  • Synthesis method of apattamide, intermediate of apattamide and synthesis method of apattamide
  • Synthesis method of apattamide, intermediate of apattamide and synthesis method of apattamide
  • Synthesis method of apattamide, intermediate of apattamide and synthesis method of apattamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] This example discloses a one-pot method for synthesizing N-methyl-4-bromo-2-fluorobenzamide, a compound of formula VII-A, specifically:

[0081]

[0082] The compound of formula VIII-A 4-bromo-2-fluorobenzoic acid (60g, 0.27mol) was dissolved in methanol (180mL), under nitrogen protection, 19.5g of thionyl chloride was added dropwise, and the temperature was raised to 45± 5°C, after the reaction of the raw materials is complete, slowly lower the temperature to 25±5°C, slowly add 100g of methylamine aqueous solution (25~30wt%) dropwise, after the addition, keep warm at 25±5°C, continue the reaction for 2 hours, then slowly drop Add 1000 ml of purified water, and continue stirring for two hours after the dropwise addition. Filtrate, collect filter cake, obtain 62.5g intermediate N-methyl-4-bromo-2-fluorobenzamide (compound of formula VII-A), yield 98%, through HPLC detection, purity is 99.92%, maximum impurity 0.04% by mass.

[0083] Compound of formula VII-A: LC-MS:...

Embodiment 2

[0086] This example discloses a one-pot synthesis method for compound 4-methoxybenzyl-1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)cyclobutyrate of formula IV-A, Specifically:

[0087]

[0088] With 60g formula VII-A compound (1.0eq), 1.1eq formula VI-A formula I compound-aminocyclobutane carboxylic acid (32g), 3eq K 2 CO 3 (107g), 0.05eq CuCl (1.2g), 0.05eq tetramethylethylenediamine (1.5g) were added to 360ml DMF, under nitrogen protection, reacted at 115-130°C for 4-6h, then cooled to 60±5°C, drop Add 1.1eq of formula Ⅴ-A compound 4-methoxybenzyl chloride (40g), react for 1 hour, cool down to room temperature, add 90ml of concentrated ammonia water dropwise, then add 300ml of purified water dropwise, and stir for 1h after dropping. Filter to get filter cake. Heat the filter cake and 300ml of ethyl acetate to 75±5°C to dissolve, stir for 15min, and add 100ml of petroleum ether dropwise at a temperature controlled above 70°C. After the dropwise addition, the temperature...

experiment example 3

[0092] This embodiment discloses a method for synthesizing a compound of formula II from a compound of formula III, specifically:

[0093]

[0094] Dissolve the compound of formula III 5-amino-3-trifluoromethyl-2-cyanopyridine (100g, 1.0eq) in 0.5L acetone, add 1.2eq thiophosgene (74g) dropwise, and react at room temperature for 1-3h , most of the solvent was distilled off under reduced pressure, the residue was added with 1.0L of n-hexane and 50g of neutral alumina, heated to 40±5°C and stirred for 1 hour, filtered and concentrated to obtain 105g of the compound of formula II, off-white solid, 5-iso Thiocyanoyl-3-trifluoromethyl-2-cyanopyridine, the yield is 86%, the purity is 99.10% through HPLC detection, and the maximum impurity amount is 0.68%.

[0095] Compound of formula II

[0096] 1 H NMR (400MHz, DMSO-d 6 )δ9.04(d, J=2.2Hz, 1H), 8.57(d, J=2.3Hz, 1H).

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Abstract

The invention belongs to the technical field of medicine synthesis, discloses a synthesis method of apattamide, an intermediate of apattamide and a synthesis method, and aims to solve the problems that a synthesis process of apattamide is complex in operation, high in production cost, not suitable for industrialization and not environmentally friendly in the prior art. In the invention, a compound shown as a formula VIII generates a compound shown as a formula VII through a one-pot method; the compound shown as the formula VII generates an intermediate compound, shown as formula IV, of apattamide through a one-pot method, and the compound shown as formula IV and a compound shown as formula II are cyclized to obtain a compound shown as formula I. The method has the advantages of simple operation, few procedures, low production cost, and high product yield and purity.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a synthesis method of apalutamide, an intermediate thereof and the synthesis method. Background technique [0002] Apalutamide (Apalutamide), the chemical name is 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thio-5,7-di Azaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide, whose structure is shown in formula I, is a second-generation androgen receptor antagonist developed by Johnson & Johnson for non- Metastatic castration-resistant prostate cancer (M0-CRPC). Apalutamide: [0003] [0004] Apalutamide is a derivative of diaryl thiohydantoin, which is composed of pyridine ring, benzene ring, cyclobutane and thiohydantoin ring system. Its synthesis mainly revolves around the connection of arylamine and The construction of the thiohydantoin ring system is unfolded as follows. [0005] [0006] There are usually two synthetic routes of apalutamid...

Claims

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Application Information

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IPC IPC(8): C07C237/40C07C231/12C07D401/04
Inventor 李军栋卞松童耀金灿吴灵静王晶翼
Owner SUZHOU KELUN PHARMA RES CO LTD