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Synthesis method of trajenta intermediate

A synthetic method and intermediate technology, which is applied in the field of synthesis of linagliptin intermediates, can solve the problems of long routes and low yields, and achieve the effects of high yields, fewer steps, and mild reaction conditions

Active Publication Date: 2018-04-20
安庆奇创药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method has a long route, and uses explosive nitrous acid compounds, and the yield is not high, which limits the industrial application of this method to a certain extent

Method used

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  • Synthesis method of trajenta intermediate
  • Synthesis method of trajenta intermediate
  • Synthesis method of trajenta intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Embodiment 1, the preparation of formula I compound

[0025]

[0026] In a 50mL single-necked bottle, add successively, 1-methyluracil (1.26g, 10mmol), urea (1.20g, 20mmol), potassium iodide (1.83g, 11mmol), TBHP (70%, 2.83g, 22mmol), Sulfuric acid (concentration 98wt%, 49mg, 0.5mmol), 20mL of dioxane, then raise the temperature to 75°C and stir for 18h. Afterwards, 80 mL of ethyl acetate was added to dilute the mother liquor, washed three times with saturated aqueous sodium sulfite solution, once with saturated aqueous sodium chloride solution, and finally washed once with water, and the ethyl acetate was rotary evaporated under reduced pressure to obtain the crude product. The crude product was recrystallized from dichloromethane and cyclohexane to obtain 2.39 g of compound I with a yield of 82% and a purity of 99%.

Embodiment 2

[0027] Embodiment 2, the preparation of formula II compound

[0028]

[0029] In a 100mL single-necked bottle, add formula I compound (2.92g, 10mmol), N, N-diisopropylethylamine (1.94g, 15mmol), 1-bromo-2-butyne (1.98g, 15mmol) , 30mL of acetone, heated to 50°C, and refluxed for 5h. The reaction was cooled, cooled to room temperature, filtered with suction, and the filter cake was washed with methanol to obtain the crude product as a light yellow solid. The crude product was recrystallized with dichloromethane and cyclohexane to obtain 3.23 g of compound II with a yield of 94% and a purity of 99%. .

[0030] EI-SI m / z: 345[M+H]+

[0031] 1H NMR (500MHz, DMSO-d6) δ11.26(s, 1H), 5.00(d, 2H, J=2.5Hz), 3.31(s, 3H), 1.80(t, 3H, J=2.5Hz).

Embodiment 3

[0032] Embodiment 3, the preparation of formula I compound

[0033] Same as Example 1, the only difference is:

[0034] The iodine source is TBAI; the molar ratio of 1-methyluracil to TBAI is 1.0:1.05. The oxidant is iodine; the molar ratio of 1-methyluracil to iodine is 1.0:2.05. The acid catalyst is hydrochloric acid (concentration 37wt%); the molar ratio of 1-methyluracil to hydrochloric acid is 1.0:0.01. The molar ratio of 1-methyluracil to urea is 1.0:1.05. The reaction solvent is DMF; the reaction temperature is 90°C.

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Abstract

The invention discloses a synthesis method of a trajenta intermediate. The synthesis method comprises the following steps: reacting 1-methyluracil, urea, propiodal and an oxidant under the catalytic action of acid to obtain a compound shown as a formula I; then carrying out substitution reaction on the compound shown as the formula I and 1-bromo-2-butyne to obtain a compound shown as a formula II,namely the trajenta intermediate. The method disclosed by the invention has the advantages of easily-obtained raw materials, few steps, higher yield, mild reaction conditions and suitability for industrial production. (Refer to Description).

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a method for synthesizing a linagliptin intermediate. Background technique [0002] Diabetes is a metabolic disorder in the body caused by an absolute or relative deficiency of insulin, resulting in elevated blood sugar. Nowadays, diabetes has become the third biggest killer of human health after cardiovascular diseases and tumors. Generally, diabetes can be divided into insulin-dependent diabetes (type 1 diabetes) and non-insulin-dependent diabetes (type 2 diabetes). Among them, type 2 diabetes is the most common, accounting for more than 90% of diabetic patients. Anti-sugar drugs currently on the market include insulin, biguanides, sulfonylureas, glycosidase inhibitors and thiazolidinediones. However, the above-mentioned traditional anti-diabetic drugs are generally accompanied by side effects such as weight gain, hypoglycemia, and gradual decrease i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/06
CPCC07D473/06
Inventor 吴学平邢继刚海威陈耀
Owner 安庆奇创药业有限公司
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