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Synthesis method of (R)-2-(2, 5-difluorophenyl) pyrrolidine

A technology of difluorophenyl and pyrrolidine, which is applied in the field of preparation of pharmaceutical synthesis intermediates, can solve the problems of unfriendly environment and unsatisfactory stereoselectivity, and achieve the effect of less synthesis steps, low cost and high yield

Pending Publication Date: 2022-05-17
四川依维欣医药科技有限公司
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  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In this route, the use of chiral reducing agent (S)-2-methyl-CBS-oxazoborolane and borane dimethyl sulfide complex for chiral reduction has achieved good results, but the industrialization of borane Unfriendly to the environment, especially thioether compounds, and the stereoselectivity is not ideal

Method used

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  • Synthesis method of (R)-2-(2, 5-difluorophenyl) pyrrolidine
  • Synthesis method of (R)-2-(2, 5-difluorophenyl) pyrrolidine
  • Synthesis method of (R)-2-(2, 5-difluorophenyl) pyrrolidine

Examples

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Embodiment 1

[0027] This example provides a kind of synthetic technique of (R)-2-(2,5-difluorophenyl)pyrrolidine, comprises the steps:

[0028]

[0029] Synthesis of compound 3

[0030] 2,5-Difluorobromobenzene (400g) was added to a 5L reaction flask, 1.3L of tetrahydrofuran was added, the temperature was lowered to 0°C under the protection of argon, and isopropylmagnesium chloride (1L, 2M / L) was added dropwise to control the reaction temperature below 0 degrees, after the dropwise addition, keep warm for 3 hours. Add the tetrahydrofuran solution of BOC-2-pyrrolidone (330g) dropwise, control the reaction temperature below 10°C, return to 20-25°C after the addition, and add HCl dropwise to adjust the pH to 2 after the reaction of the raw materials is completed. Liquid and water phases were extracted with petroleum ether 1L×3, the organic phases were combined, washed with saturated brine 2L, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, c...

Embodiment 2

[0038] This example is used to illustrate the synthesis process of compound 4. The difference from Example 1 is only that in the synthesis of compound 4, the mass ratio of intermediate 3 to yeast wet thallus is 8:1, the reaction temperature is 48 °C, and the rest The steps are the same.

[0039] The intermediate compound 4 obtained in this example was 50.6g, with a yield of 50% and an ee value of 90.1%.

Embodiment 3

[0041] This example is used to illustrate the synthesis process of compound 4, and the only difference from example 1 is that in the synthesis of compound 4, the mass ratio of intermediate 3 to yeast wet thallus is 3:1, the reaction temperature is 20°C, and the rest The steps are the same.

[0042] The intermediate compound 4 obtained in this example was 41.5g, with a yield of 41% and an ee value of 89.7%.

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Abstract

The invention discloses a synthesis method of (R)-2-(2, 5-difluorophenyl) pyrrolidine, and belongs to the technical field of preparation of pharmaceutical synthesis intermediates.The method comprises the steps that 2, 5-difluorobromobenzene and N-Boc-pyrrolidone which are low in price and easy to obtain are used as raw materials, and an intermediate 3 is obtained through coupling after Grignard exchange; performing asymmetric reduction on the intermediate 3 by using baker's yeast as carbonyl reductase to obtain an (S)-chiral alcohol intermediate 4, and finally performing methylsulfonylation ring closure and Boc (t-butyloxycarboryl) removal to obtain a qualified target product. The method has the advantages of mild reaction conditions, high product yield and low cost, and can bring higher economic benefits.

Description

technical field [0001] The invention relates to the technical field of preparation of pharmaceutical synthesis intermediates, in particular to a synthesis method of (R)-2-(2,5-difluorophenyl)pyrrolidine. Background technique [0002] Chiral pyrrolidine plays an important role in pharmaceutical intermediates and can be used to synthesize a variety of anticancer drugs. In recent years, receptor target tropomyosin receptor kinase (Trk) inhibitors have received extensive attention. Chiral pyrrolidine The alkane structure is an essential fragment in many biologically active inhibitors. The new anticancer drug Larotrectinib announced by the American Society of Clinical Oncology in 2017 contains a (R)-2-(2,5-difluorophenyl)pyrrolidine structure. [0003] The synthesis method of chiral pyrrolidine is mainly through chemical resolution and chiral induction synthesis. Chemical resolution is mainly to use a suitable chiral resolving agent to resolve it after chemical synthesis, and fi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/08
CPCC07D207/08C07B2200/07Y02P20/55
Inventor 伍道春蒲东章杭根
Owner 四川依维欣医药科技有限公司
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