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Synthetic method of 2,2-difluorodicarboxylic acid dialkyl ester

A technology of dialkyl difluorodicarboxylate and synthesis method, which is applied in the direction of carboxylic acid ester preparation, chemical instruments and methods, preparation of organic compounds, etc., and can solve the problem of low yield, unfriendly environment and low safety and other problems, to achieve the effect of simple and easy operation of reaction conditions, novel synthetic route and high reaction safety

Active Publication Date: 2020-09-29
江苏尚莱特医药化工材料有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The disadvantages of this route are: (1) Michael addition reaction will compete with 1,2-addition reaction, resulting in low yield; (2) the literature can achieve a yield of more than 95%, which is very likely to be compared with the price Higher tetramethylethylenediamine (TMEDA), which will lead to increased production costs; (3) need to use more copper powder, which is not friendly to the environment and is not suitable for industrial production
[0008] The disadvantages of this route are: (1) the competition of 4-position fluorination inevitably exists in this fluorination reaction, resulting in a low yield of less than 60%; (2) strong fluorine needs to be added at a low temperature of -78 °C chemical reagent SF 4 , not only harsh reaction conditions, but also low safety, also not suitable for industrial production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1）

[0036] In this example, 3,3-difluorocyclopentene was prepared by fluorination after chlorination, as follows:

[0037] Dissolve 6.15g of 2-cyclopenten-1-one (75mmol) in 80mL of anhydrous chlorobenzene, then add dropwise 9.52g of oxalyl chloride (75mmol), keep the internal temperature below 20°C, and after 20min, the reaction system No bubbles were released.

[0038] The above reaction solution was cooled to 0°C, 16.16g of triethylamine (160mmol) and 8.37g of triethylamine trihydrofluoride (52mmol) were added in sequence, and the temperature was raised to 40°C and stirred for 3h after the addition.

[0039] After the reaction, cool the reaction system to 0°C, add 50mL of water to stir, let stand to separate the liquid, wash the organic layer with deionized water, separate the water phase, then dry the organic layer with anhydrous sodium sulfate, filter, and After distillation, the fraction with a boiling point lower than 70°C was collected to obtain 6.86 g of 3,3-difluorocyclo...

Embodiment 2～ Embodiment 5）

[0041] In each example, 3,3-difluorocyclopentene was prepared by chlorination first and then fluorination. The specific method is basically the same as that of Example 1, and the differences are shown in Table 1.

[0042] Table 1

[0043] Example 1 Example 2 Example 3 Example 4 Example 5 2-Cyclopenten-1-one 6.15g / 75mmol 6.15g / 75mmol 6.15g / 75mmol 6.15g / 75mmol 6.15g / 75mmol Chlorinating reagent 9.52g oxalyl chloride / 75mmol 8.93g thionyl chloride / 75mmol 15.64g phosphorus pentachloride / 75mmol 19.05g oxalyl chloride / 150mmol 7.62g oxalyl chloride / 60mmol Triethylamine trihydrofluoride 8.37g / 52mmol 8.37g / 52mmol 8.37g / 52mmol 18.11g / 112.5mmol 7.25g / 45mmol 3,3-Difluorocyclopentene 6.86g 6.65g 6.62g 6.94g 6.40g yield 87.9% 85.3% 84.9% 89.0% 82.1%

Embodiment 6）

[0045] This example prepares 3,3-difluorocyclopentene by direct fluorination, as follows:

[0046] Dissolve 6.15 g of 2-cyclopenten-1-one (75 mmol) in 150 mL of 1,2-dichloroethane, then slowly add 24.15 g of DAST (150 mmol) dropwise, keeping the internal temperature below 20 °C, After dripping, stir the reaction at room temperature for 6h.

[0047] After the reaction, wash with water, let stand to separate the liquid, wash the organic layer with deionized water, separate the water phase, then dry the organic layer with anhydrous sodium sulfate, filter, and distill at atmospheric pressure to collect fractions with a boiling point lower than 70°C , to obtain 5.93 g of colorless transparent liquid 3,3-difluorocyclopentene, with a yield of 76.0%.

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PUM

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Abstract

The invention discloses a synthesis method of dialkyl 2,2-difluorodicarboxylate. The synthesis method comprises the following steps: (A) directly carrying out fluorination on 2-cyclene-1-one shown ina formula I, or firstly carrying out chlorination and then carrying out fluorination on the 2-cyclene-1-one so as to obtain 3,3-difluorocycloolefin shown in a formula II; (B) simultaneously oxidizingand esterifying the 3,3-difluorocycloolefin shown in the formula II, or firstly oxidizing and then esterifying the 3,3-difluorocycloolefin so as to obtain the dialkyl 2,2-difluorodicarboxylate shown in a formula III, wherein a chlorinating agent and a fluorinating agent which are used in the step of firstly carrying out chlorination and then carrying out fluorination are respectively oxalyl chloride and triethylamine trihydrofluoride; a reaction system used in the step of simultaneously oxidizing and esterifying is ozone gas / sodium ethoxide, and the reaction temperature is -75 to -15 DEG C. The synthesis method has the advantages of novel synthetic route, less pollution to the environment, lower production cost, simple reaction conditions, easy operation, higher reaction safety and fewer side reactions, can obtain higher reaction yield especially by selecting proper reaction conditions, and has the highest total yield of 82% or above, thus being suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and in particular relates to a synthesis method of 2,2-difluorodicarboxylic acid dialkyl ester. Background technique [0002] DPP-4 inhibitors, dipeptidyl peptidase 4 inhibitors, are a class of drugs for the treatment of type 2 diabetes, which can inhibit glucagon-like peptide-1 (GLP-1) and glucose-dependent insulin secretion The inactivation of polypeptide (GIP) increases the level of endogenous GLP-1 and GIP, promotes the release of insulin from pancreatic β cells, and at the same time inhibits the secretion of glucagon from pancreatic α cells, thereby increasing insulin levels and lowering blood sugar, and it is not easy to induce hypoglycemia. Blood sugar and weight gain. [0003] Gemigliptin is a new DPP-4 inhibitor developed by South Korean company LG Life Science Ltd. Clinical studies have shown that gemagliptin has good effects whether it is used alone ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C67/00C07C69/63
CPCC07C17/202C07C67/00C07C69/63C07C23/08C07C23/10
Inventor 胡国宜胡锦平俞梦龙李喜龙奚小金
Owner 江苏尚莱特医药化工材料有限公司