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Synthetic route of compound and application thereof in field of preparation of anti-diabetic drugs

A synthesis route and compound technology, applied in the field of pharmaceutical synthesis, can solve the problems of low synthesis yield and complicated purification.

Active Publication Date: 2020-03-31
SHENZHEN LINGLAN BIO PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In view of this, the present invention provides a synthetic route of the compound and its application in the field of preparation of antidiabetic drugs, which are used to solve the technical defects of low synthetic yield and complicated purification of SN158 in the prior art

Method used

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  • Synthetic route of compound and application thereof in field of preparation of anti-diabetic drugs
  • Synthetic route of compound and application thereof in field of preparation of anti-diabetic drugs
  • Synthetic route of compound and application thereof in field of preparation of anti-diabetic drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] This example is a specific example of synthesizing SN158.

[0041] 1.1 Step I—preparation of intermediate product 1 (5-bromo-2,4-hydroxybenzaldehyde)

[0042] 2,4-Dihydroxybenzaldehyde (10 g, 72.4 mmol) was dissolved in acetic acid, and the reaction was placed under an ice bath. Under stirring condition, liquid bromine (3.78ml, 72.4mmol) was slowly added dropwise, and the reaction temperature was slowly raised to room temperature. After reacting for 3 hours, the reaction solution was poured into 100 mL of cold water, filtered, washed with 100 mL of cold water, dried, and recrystallized with 1:1 acetonitrile / toluene to obtain 13.09 g of intermediate product 1 crystals (yield: 83%).

[0043] Structural characterization of intermediate product 1:

[0044] Melting point: 165-168°C.

[0045] 1.2 Step II—Preparation of intermediate product 2 (5-bromo-2-hydroxyl-4-(methoxymethyl)benzaldehyde)

[0046] Intermediate 1 (10.9 g, 50 mmol) and potassium carbonate (20.8 g, 150.3 ...

Embodiment 2

[0099] This example is a specific example for verifying that the prepared SN158 improves blood sugar and glucose tolerance.

[0100] Six-week-old male C57BL / 6JHamSlc-ob / ob was used as the animal model of spontaneous insulin resistance diabetes, and the mice were raised under the conditions of 23±2°C, 55±5% humidity and standard light cycle (12 hours light / dark) .

[0101] The experiment was divided into 4 groups, with 7 mice in each group. Four groups of mice were fed with 30mg / kg of pioglitazone, 30mg / kg of SN158, 100mg / kg of SN158 and normal saline every day for 3 consecutive weeks. Blood samples were collected 1 week, 2 weeks, and 3 weeks after administration, and blood glucose levels were measured. After gavage for 3 weeks, fast overnight, take 2g / kg of D-glucose orally, collect blood from the tail vein at 0 minutes, 30 minutes, 60 minutes, 120 minutes, and 240 minutes respectively, use a blood glucose meter to measure blood glucose, and calculate the area under the bloo...

Embodiment 3

[0104] This embodiment is a specific embodiment for measuring the adverse effects of the prepared SN158.

[0105] After the blood glucose and glucose tolerance test in Example 2, the mice were fasted for 12 hours, and the body weight of the mice was measured. Dissect and separate the mouse liver, weigh the weight, and calculate the percentage of liver weight relative to body weight. For the results, please refer to image 3 with Figure 4 .

[0106] from image 3 with Figure 4 It can be concluded that after administration, unlike pioglitazone, SN158 does not cause adverse reactions such as fractional weight gain and hepatomegaly.

[0107] In summary, the present invention provides a synthetic route of SN158, and the present invention also provides an application of the above synthetic route in the field of preparation of antidiabetic drugs. In the technical scheme provided by the present invention, after the raw material 2,4-dihydroxybenzaldehyde is brominated, the para-...

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Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a synthetic route of a compound and application of the compound in the field of preparation of anti-diabeticdrugs. The invention provides a synthetic route of SN158, and also provides the application of the synthetic route in the field of preparation of anti-diabetic drugs. The synthetic route of the invention comprises the following steps: brominating a raw material, namely 2,4-dihydroxybenzaldehyde; protecting para-hydroxyl groups by using methoxymethyl groups; methylating ortho-hydroxyl groups by using dimethyl sulfate or methyl iodide; and carrying out a Claisen-Schmidt condensation reaction by using a hydrochloric acid ethanol or boron trifluoride diethyl ether solution, with HATU or EDCI andHOBt as coupling agents for an amidation reaction. According to the invention, the yield of the prepared SN158 can reach 60% or above; meanwhile, column chromatographic purification is not needed in the preparation process, and the finally produced compound with a purity of 99% or above can be obtained only through recrystallization; and the method is suitable for large-scale / industrial productionand overcomes the technical defects that SN158 is low in synthesis yield and complex in purification in the prior art.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to a synthetic route of a compound and its application in the field of preparation of antidiabetic drugs. Background technique [0002] Diabetes mellitus is a systemic endocrine and metabolic disease characterized by hyperglycemia due to insulin secretion defects or / and insulin resistance caused by sugar, fat, and protein metabolism disorders. The natural product Licochalcone E has the functions of improving blood sugar level, regulating lipid metabolism and improving insulin resistance, and its derivatives, Hereinafter referred to as SN158, it is a dual partial agonist of PPARα / γ, which can promote the differentiation of 3T3-L1 preadipocytes and stem cells into adipocytes, and up-regulate the lipid transcription factor C / EBPα, adiponectin and glucose transporter 4 (Glucose transporter type 4, GLUT-4); can increase the glucose uptake of C2C12 myoblasts...

Claims

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Application Information

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IPC IPC(8): C07C47/565C07C45/63C07C45/64C07C47/575C07C231/12C07C233/76C07C231/02A61K31/167A61P3/10
CPCC07C45/63C07C45/64C07C231/12C07C231/02A61K31/167A61P3/10C07C47/565C07C47/575C07C233/76Y02P20/55
Inventor 曹永凯张子理千胜勋曹永亮
Owner SHENZHEN LINGLAN BIO PHARMA TECH CO LTD
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