Synthesis method of 3,3,4,4-tetrafluoropyrrolidine

A technology of tetrafluoropyrrolidine and tetrafluoropyrrolidine hydrochloride, which is used in the synthesis of 3,3,4,4-tetrafluoropyrrolidine, and synthesizes 3,3,4,4-tetrafluoropyrrole from butanedione In the field of alkane, it can solve the problem of toxic yield of fluorine, and achieve the effect of clean reaction, simple operation and efficient synthesis

Active Publication Date: 2018-04-10
武汉药明康德新药开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Mainly solve the technical problems of toxic fluorine and low yield in the existing synthesis process

Method used

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  • Synthesis method of 3,3,4,4-tetrafluoropyrrolidine
  • Synthesis method of 3,3,4,4-tetrafluoropyrrolidine
  • Synthesis method of 3,3,4,4-tetrafluoropyrrolidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] The first step, the preparation of 1,4-dibromobutanedione

[0027]

[0028] The reaction substrate butanedione (50 g, 0.58 mol) was added to chloroform (500 mL), and liquid bromine (186 g, 1.16 mol) was added dropwise at 20-30°C, then heated to 50°C and stirred for 3 hours. Cool down to 0°C, continue to stir for 0.5 hours, then filter, and wash the solid with water (1000 mL ) to obtain the intermediate 1,4-dibromobutanedione (55 g, 0.23 mol). Yield 39%.

[0029] 1 HNMR (CDCl 3 , 400MHz): δ 4.27(s, 4H).

[0030] The second step, the preparation of 1,4-dibromo-2,2,3,3-tetrafluorobutane

[0031]

[0032] The intermediate 1,4-dibromobutanedione (15 g, 61.5 mmol) was cooled to -78°C, and sulfur tetrafluoride (30 g, 277.6 mmol) was introduced into it, then heated to 60°C and stirred for 3 hours. The reaction solution was dissolved in petroleum ether (100 mL), washed with saturated sodium bicarbonate (200 mL) and brine (100 mL) and spin-dried to obtain the intermed...

Embodiment 2

[0043] The first step, the preparation of 1,4-dibromobutanedione

[0044]

[0045]The reaction substrate diacetyl (50 g, 0.58 mol) was added to chloroform (500 mL), and liquid bromine (186 g, 1.16 mol) was added dropwise at 20-30°C, then heated to 60°C and stirred for 1 hour. Cool down to 0°C, continue to stir for 0.5 hours, then filter, and wash the solid with water (1000 mL ) to obtain the intermediate 1,4-dibromobutanedione (50 g, 0.21 mol). The yield is 35%.

[0046] 1 HNMR (CDCl 3 , 400MHz): δ 4.27(s, 4H).

[0047] The second step, the preparation of 1,4-dibromo-2,2,3,3-tetrafluorobutane

[0048]

[0049] The intermediate 1,4-dibromobutanedione (15 g, 61.5 mmol) was cooled to -78°C, and sulfur tetrafluoride (30 g, 277.6 mmol) was introduced into it, then heated to 80°C and stirred for 1 hour. The reaction solution was dissolved in petroleum ether (100 mL), washed with saturated sodium bicarbonate (200 mL) and brine (100 mL) and spin-dried to obtain the interme...

Embodiment 3

[0060] The first step, the preparation of 1,4-dibromobutanedione

[0061]

[0062] The reaction substrate diacetyl (50 g, 0.58 mol) was added to chloroform (500 mL), and liquid bromine (186 g, 1.16 mol) was added dropwise at 20-30°C, then heated to 70°C and stirred for 1 hour. Cool down to 0°C, continue to stir for 0.5 hours, then filter, and wash the solid with water (1000 mL ) to obtain the intermediate 1,4-dibromobutanedione (50 g, 0.21 mol). The yield is 35%.

[0063] 1 HNMR (CDCl 3 , 400MHz): δ 4.27(s, 4H).

[0064] The second step, the preparation of 1,4-dibromo-2,2,3,3-tetrafluorobutane

[0065]

[0066] The intermediate 1,4-dibromobutanedione (15 g, 61.5 mmol) was cooled to -78°C, and sulfur tetrafluoride (30 g, 277.6 mmol) was introduced into it, then heated to 70°C and stirred for 6 hours. The reaction solution was dissolved in petroleum ether (100 mL), washed with saturated sodium bicarbonate (200 mL) and brine (100 mL) and spin-dried to obtain the inter...

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Abstract

The invention discloses a synthesis method of 3,3,4,4-tetrafluoropyrrolidine and mainly solves the technical problems of poisonous introduced fluorine, relatively long steps and relatively low yield in the existing synthesis process. The synthesis method disclosed by the invention comprises four steps: firstly, mixing butanedione with chloroform, then, carrying out addition on the mixture and bromine to form 1,4-dibromo-2,3-butanedione; secondly, introducing sulfur tetrafluoride into the obtained 1,4-dibromo-2,3-butanedione, and carrying out a reaction to obtain 1,4-dibromo-2,2,3,3-tetrafluorobutane; thirdly, carrying out a high-temperature reaction on 1,4-dibromo-2,2,3,3-tetrafluorobutane and benzylamine to obtain 1-benzyl-3,3,4,4-tetrafluoropyrrolidine hydrochloride; and fourthly, carrying out catalytic hydrogenation debenzylation on 1-benzyl-3,3,4,4-tetrafluoropyrrolidine hydrochloride to obtain 3,3,4,4-tetrafluoropyrrolidine. The invention provides the synthesis method of 3,3,4,4-tetrafluoropyrrolidine which is relatively low in toxicity, low in raw material price, simple in operation and high in yield.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and relates to a method for synthesizing 3,3,4,4-tetrafluoropyrrolidine, in particular to a method for synthesizing 3,3,4,4-tetrafluoropyrrolidine from diacetyl. Background technique [0002] 3,3,4,4-Tetrafluoropyrrolidine can participate in the synthesis of dipeptidyl peptidase-IV (DPP-IV) inhibitor drugs. DPP-IV is a serine protease on the surface of cells in living organisms, which can decompose GLP-1 in the body, a hormone that can stimulate insulin, inhibit glucagon, inhibit gastric emptying and regenerate pancreatic islet cells. . DPP-IV inhibitors can inactivate DPP-IV, thereby increasing the level of GLP-1 and controlling blood sugar. DPP-IV inhibitor drugs are used to treat type 1 and 2 diabetes mellitus, metabolic syndrome (X or insulin resistance syndrome), hyperglycemia, cataract, obesity, hypertension, hyperlipidemia, atherosclerosis, bone Acute coronary syndrome, polycy...

Claims

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Application Information

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IPC IPC(8): C07D207/10
CPCC07D207/10
Inventor 吴荣福刘洲亚马建义张治柳姜鲁勇马汝建
Owner 武汉药明康德新药开发有限公司
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