Preparation method of chiral 4-alkyl-pyrrole-3-formic acid compound

A compound, a technology of benzyloxycarbonylpyrrolidine, which is applied in the field of preparation of 4-alkyl-pyrrole-3-carboxylic acid compounds, can solve problems such as expensive transition metal catalysts, and achieve the effects of reducing production costs and improving safety

Pending Publication Date: 2022-05-20
南京卓康医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Some synthetic routes require the u...

Method used

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  • Preparation method of chiral 4-alkyl-pyrrole-3-formic acid compound
  • Preparation method of chiral 4-alkyl-pyrrole-3-formic acid compound
  • Preparation method of chiral 4-alkyl-pyrrole-3-formic acid compound

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Embodiment 1

[0051] Example 1 Synthesis of Compound 5.

[0052]

[0053] Compound 4 (100g, 0.56mol, 1.0eq.) was dissolved in tetrahydrofuran (500ml), cooled to below -40°C, and 1mol / L tetrahydrofuran solution of lithium bistrimethylsilylamide (677ml, 0.677mol, 1.2 eq.) is added dropwise, and the rate of addition is controlled so that the temperature of the reaction system is not higher than -40°C. After the dropwise addition is completed, stir for 10 minutes, and dissolve compound 3 (154.7g, 0.62mol, 1.1eq.) in tetrahydrofuran (500ml ), drop it into, control the rate of addition, and keep the temperature not higher than -40°C. After completion of the dropwise addition, react at -50 to -40°C for 1 hour, add saturated ammonium chloride solution (550ml), add ethyl acetate (500ml), leave to stand for layers, and use saturated sodium chloride solution (300ml× 3) Wash, concentrate the organic phase to dryness under reduced pressure below 45°C, add ethyl acetate (320ml) to the residue, stir t...

Embodiment 2

[0054] Synthesis of Example 2 Compound 5.

[0055] Compound 4 (100g, 0.56mol, 1.0eq.) was dissolved in 2-methyltetrahydrofuran (500ml), cooled to below -40°C, and 1mol / L tetrahydrofuran solution of lithium bistrimethylsilylamide (564ml, 0.564mol, 1.0eq.) was added dropwise, and the rate of addition was controlled so that the temperature of the reaction system was not higher than -40°C. After the dropwise addition was completed, stir for 10 minutes to dissolve compound 3 (154.7g, 0.62mol, 1.1eq.) Add dropwise into 2-methyltetrahydrofuran (500ml), control the rate of addition, and keep the temperature not higher than -40°C. After completion of the dropwise addition, react at -50 to -40°C for 1 hour, add saturated ammonium chloride solution (450ml), add ethyl acetate (500ml), let stand to separate layers, and use saturated sodium chloride solution (300ml× 3) Wash, concentrate the organic phase to dryness under reduced pressure below 45°C, add ethyl acetate (320ml) to the residue...

Embodiment 3

[0056] Example 3 Synthesis of Compound 5.

[0057] Compound 4 (100g, 0.56mol, 1.0eq.) was dissolved in tetrahydrofuran (500ml), cooled to below -40°C, and 1mol / L tetrahydrofuran solution of lithium bistrimethylsilylamide (790ml, 0.790mol, 1.4 eq.) is added dropwise, and the rate of addition is controlled so that the temperature of the reaction system is not higher than -40°C. After the dropwise addition is completed, stir for 10 minutes, and dissolve compound 3 (140.7g, 0.56mol, 1.0eq.) in tetrahydrofuran (500ml ), drop it into, control the rate of addition, and keep the temperature not higher than -40°C. After completion of the dropwise addition, react at -50 to -40°C for 1 hour, add saturated ammonium chloride solution (640ml), add ethyl acetate (500ml), leave to stand for layers, and use saturated sodium chloride solution (300ml× 3) Wash, concentrate the organic phase to dryness under reduced pressure below 45°C, add ethyl acetate (320ml) to the residue, stir to dissolve, ...

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Abstract

The invention discloses a preparation method of a chiral 4-alkyl-pyrrole-3-formic acid compound, which utilizes the spatial effect of an Evans chiral prothetic group to realize asymmetric hydrogenation reduction through metal catalytic hydrogenation to obtain a chiral target compound. Compared with the prior art, the method has the advantages that the achiral pyrrolidine-3-formic acid with low price can be used as a starting material, so that the production cost is reduced. The use of dangerous reagents such as nitromethane and sodium borohydride is avoided, and the safety of the production process is improved.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and in particular relates to a preparation method of 4-alkyl-pyrrole-3-carboxylic acid compounds. Background technique [0002] Upatinib is a JAK kinase inhibitor approved by the US FDA in 2019 for the treatment of moderate to severe adult rheumatoid arthritis. Its structure is shown in Formula 1. [0003] [0004] In the synthetic route of upadatinib, compound 2 is its important intermediate, and the two chiral centers of upadatinib are brought in by it. [0005] [0006] In Chinese patent application CN108368121A, several preparation methods of compound 2 are disclosed. [0007] Route one looks like this: [0008] [0009] In the route one, with ethyl pent-2-enoate as the starting material, under the action of Lindlar catalyst, it is partially reduced to ethyl Z-pent-2-enoate, and then with N-(methoxymethyl)- Reaction of N-(trimethylsilylmethyl)benzylamine, hydrodebenzylation of the...

Claims

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Application Information

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IPC IPC(8): C07D413/06C07D207/16
CPCC07D413/06C07D207/16C07B2200/07Y02P20/55
Inventor 李强刘华权王春健
Owner 南京卓康医药科技有限公司
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