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Synthesis method of linagliptin chlorinated intermediate

A synthesis method and intermediate technology are applied in the field of synthesis of linagliptin intermediates, and can solve the problems of long routes and low yields.

Inactive Publication Date: 2021-06-04
JIANGSU QINGJIANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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 linagliptin chlorinated intermediate
  • Synthesis method of linagliptin chlorinated intermediate
  • Synthesis method of linagliptin chlorinated intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0025] In a 5 0m L one-mouth bottle, add 1-methyluracil (1 .26g, 1 0m mol) and urea (1 .20g,

[0026] 20mmol), NCS (2.6g, 20mmol), TBHP (70%, 2.83g, 22mmol), sulfuric acid (concentration 98wt%, 49mg, 0.5mmol), the dioxane of 20mL, then raise temperature to 75 ℃, 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 2.6 g of compound A with a yield of 82% and a purity of 99%.

Embodiment 2

[0027] Embodiment 2, the preparation of compound B

[0028] [In a 100mL single-necked bottle, sequentially add the compound of formula (2.6g, about 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 a crude product as a light yellow solid. The crude product was recrystallized with dichloromethane and cyclohexane to obtain 3.58 g of compound B with a yield of 96% and a purity of 99%. %.

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Abstract

The invention discloses a synthesis method of a linagliptin intermediate. The method comprises the following steps: reacting 1-methyl uracil, urea, NCS and the like with an oxidizing agent under the combined effect of acid catalysis and a high-pressure mercury lamp to obtain a compound A; and then carrying out substitution reaction on the compound A and 1-bromo-2-butyne to obtain a compound B, namely the linagliptin intermediate. The method provided by the invention has the advantages of easily available raw materials, fewer steps, high yield and mild reaction conditions, and is suitable for industrial production.

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 caused by the absolute or relative insufficiency of insulin, which leads to elevated blood sugar and causes metabolic disorders in the body. [0003] chaos. 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, hyp...

Claims

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Application Information

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IPC IPC(8): C07D473/04
CPCC07D473/04
Inventor 叶俊涛
Owner JIANGSU QINGJIANG PHARMA
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