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Preparation method of larotinib intermediate, and intermediate compound

A larotrectinib and compound technology, which is applied in the preparation of larotrectinib intermediates and the field of intermediate compounds, can solve the problems of unsuitability for industrial production, high price and high production cost

Pending Publication Date: 2020-10-20
钟桂发
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The route condenses 2,5-difluorobenzaldehyde with (R)-2-tert-butylsulfonamide to form an imine, followed by addition of (1,3-dioxolane-2-ethyl)magnesium bromide Synthesis reaction, then through cyclization and reduction to obtain (R)-2-(2,5-difluorophenyl)pyrrolidine, used expensive Grignard reagents in the preparation process, the production cost is higher, and it is not suitable for industrialization Production

Method used

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  • Preparation method of larotinib intermediate, and intermediate compound
  • Preparation method of larotinib intermediate, and intermediate compound
  • Preparation method of larotinib intermediate, and intermediate compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1 Synthesis of intermediate I (Ia, Ib)

[0040]

[0041]Synthesis of Ia: In a 500mL three-necked flask, add 19.3g (0.1mol) of p-2,5-difluorobromobenzene and 160ml of tetrahydrofuran, cool to 0 degrees, start to drop 60ml of isopropylmagnesium chloride (2M THF solution, 0.12 mol), after the dropwise addition, continue to react for 2h; then dropwise add 25.7g (0.1mol) tetrahydrofuran 80ml solution of N-tert-butoxycarbonyl-L-pyroglutamic acid ethyl ester, after the dropwise addition, react at 0 degree for 4h, TLC showed the reaction was complete. Add 50ml of 2N hydrochloric acid solution dropwise to the reaction mixture, stir for 20 minutes, separate the layers, extract the aqueous phase twice with 120ml of methyl tert-butyl ether, combine the organic phases, wash with 60ml of saturated saline, and dry over anhydrous sodium sulfate , filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain 35.2 g of oily substan...

Embodiment 2

[0047] Example 2 Synthesis of Intermediate II (IIa, IIb)

[0048]

[0049] Synthesis of IIa: In a 250ml flask, 18.6g (0.05mol) of compound Ia and 15ml of dichloromethane were added, cooled to 0°C, and 15ml (0.2mol) of trifluoroacetic acid was added dropwise. After the dropwise addition, the reaction was stirred at 0°C, and the reaction was tracked by TLC until the raw material of compound Ia disappeared. Then use 10% sodium hydroxide solution to adjust the pH value to 8, add 80ml of dichloromethane to separate layers, extract the aqueous layer twice with dichloromethane, 50ml each time, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure , separated by silica gel column chromatography to obtain IIa11.6g with a yield of 92% and a purity of 98.3%.

[0050] 1 HNMR (400Hz, CDCl 3 )δ: 7.72-7.81 (m, 1H), 7.05-7.17 (m, 2H), 4.85-4.95 (m, 1H), 4.25 (q, 2H), 3.14-3.26 (m, 1H), 3.00-3.12 ( m, 1H), 2.31-2.45(m, 1H), 2.15-2.32(m, 1H...

Embodiment 3

[0055] Example 3 Synthesis of Intermediate IV

[0056]

[0057] method one:

[0058] Add 10 g (0.04 mol) of compound IIa, 1 g of 10% palladium on carbon and 150 ml of methanol in a hydrogenation reactor to hydrogenate to 5 atmospheres, react at room temperature for 5 h, follow the reaction by TLC until the raw material disappears. It was filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain 9.7 g of III with a yield of 95% and a purity of 99%.

[0059] Alternatively prepare III by:

[0060] In a 250ml flask, 5.0g (0.02mol) of compound IIa, 50ml of methanol and 20ml of acetic acid were added, cooled to -40°C, and 1.52g (0.04mol) of sodium borohydride was added in batches. After the dropwise addition was completed, stirred for 1 h, raised to 0°C and stirred for 2 h, and followed the reaction by TLC until the raw material of compound IIa disappeared. Then it was quenched with 10% sodium carbonate solution, concentrated un...

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PUM

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Abstract

The invention discloses a preparation method of a larotinib intermediate represented by V, and an intermediate compound. The method comprises the following steps: taking 2,5-difluorobromobenzene and N-tert-butoxycarbonyl-L-pyroglutamate as initial raw materials, and carrying out coupling, deprotection group cyclization, reduction and decarboxylation to obtain a compound represented by a formula V.According to the invention, the preparation method has the advantages of novelty, low cost, cheap and easily available raw materials and high yield, and is suitable for large-scale industrial production.

Description

technical field [0001] The present invention specifically relates to a preparation method of a larotrectinib intermediate and an intermediate compound. Background technique [0002] Larotrectinib is an orally available, selective, and ATP-competitive potent inhibitor of tropomyosin receptor kinase TRK, which was approved by the US Food and Drug Administration (FDA) in November 2018 , for the treatment of solid tumors in adults or children with NTRK fusion genes. This means that larotrectinib can not only be used to treat tumors in a specific site, but can be used to treat a type of tumor with a certain genetic signature or a certain biomarker, including colon, lung, pancreas, It is effective for 17 kinds of cancers including thyroid, saliva and gastrointestinal cancer. It has now become the first cancer drug to receive FDA approval for a major breakthrough therapy. [0003] [0004] (R)-2-(2,5-difluorophenyl)pyrrolidine is the key intermediate of lorlatinib. At present...

Claims

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Application Information

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IPC IPC(8): C07D207/08C07D207/16C07D207/22C07C271/22C07C269/06
CPCC07D207/08C07D207/16C07D207/22C07C271/22C07C269/06Y02P20/55
Inventor 钟桂发
Owner 钟桂发
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