Unlock instant, AI-driven research and patent intelligence for your innovation.

Synthesis technology for continuously preparing azilsartan in micro-channel reactor

A technology of microchannel reactor and synthesis process, applied in chemistry/physics/physicochemical reactor, organic chemistry, chemical instruments and methods, etc., can solve the problem of low degree of automation and the acquisition of 2-ethylhexyl chloroformate raw materials Difficult, complex steps of the ring-forming reaction, etc., to achieve the effect of shortening the reaction time, lowering the reaction temperature, and reducing the reaction steps

Inactive Publication Date: 2020-02-04
南京恒通医药开发有限公司
View PDF8 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it is difficult to obtain the raw material of 2-ethylhexyl chloroformate used in the preparation of TAK3 in the ring-closing reaction of this route, and the ring-forming reaction steps are relatively complicated, and the reactions are all batch-type reaction processes, with a low degree of automation

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Synthesis technology for continuously preparing azilsartan in micro-channel reactor
  • Synthesis technology for continuously preparing azilsartan in micro-channel reactor
  • Synthesis technology for continuously preparing azilsartan in micro-channel reactor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051]

[0052] 2-Ethoxy-1-[(2'-cyano[1,1'-biphenyl]-4-yl)methyl]-1H-benzimidazole-7-carboxylic acid methyl ester (SM- 1) Add 150g, 240g of 50% aqueous solution of hydroxylamine and 38g of triethylamine to 1500mL of absolute ethanol, heat to 80°C, reflux for 20h, monitor the progress of the reaction by TLC, developer: petroleum ether / ethyl acetate=1:2( Volume ratio). After reacting for 20 hours, stop the reaction, cool and crystallize, suction filter, wash, and air-dry at 50°C to obtain intermediate TAK1, a white solid of 95.2g, with a yield of 70%. The mass spectrum and NMR spectrum are shown in image 3 , Figure 5 .

Embodiment 2

[0053] Example 2: This scheme mainly undergoes two-step reactions, namely the addition reaction of SM-1 and hydroxylamine to synthesize intermediate TAK3, and the hydrolysis reaction of intermediate TAK3 to prepare the target compound azilsartan.

[0054]

[0055] Configure the dioxane solution of intermediate TAK1 and triethylamine in the first raw material storage tank, the molar volume ratio of TAK1, triethylamine and dioxane is 100mmol: 120mmol: 250mL, in the second raw material storage tank A dioxane solution of solid phosgene was configured in the mixture, and the molar volume ratio of solid phosgene and dioxane was 100mmol: 250mL. The solution in the storage tank waits to be pumped into the microstructure mixer and enters the microstructure reactor for reaction. The first reactor is a 1 / 4 stainless steel pipe with a length of 6 meters and a total volume of 100mL.

[0056] The first raw material storage tank (TAK1 and triethylamine dioxane solution) and the second raw...

Embodiment 3

[0061] The dioxane solution of intermediate TAK1 and diethylamine is configured in the first raw material storage tank, and the molar volume ratio of TAK1, diethylamine and dioxane is 100mmol: 120mmol: 250mL; in the second raw material storage tank Configure the dioxane solution of solid phosgene in the middle, the molar volume ratio of solid phosgene and dioxane is 100mmol: 250mL; The molar volume ratio is 0.4mol: 1000mL, the solution in the storage tank is waiting to be pumped into the microstructure mixer, and enters the microstructure reactor for reaction. The second reactor is a 1 / 4 stainless steel pipe with a length of 2 meters, which removes the epitaxial volume and effectively The total volume is 30 mL.

[0062] The first raw material storage tank (TAK1 and triethylamine dioxane solution) and the second raw material storage tank (solid phosgene dioxane solution) are pumped into the microstructure reactor according to the volume flow ratio of 1:1 , at 5°C, keep for 20m...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses a synthesis technology for continuously preparing azilsartan in a micro-channel reactor. The technology comprises the following steps: (1) adding SM-1, an aqueous hydroxylaminesolution and triethylamine into anhydrous ethanol, and performing a reaction to obtain an intermediate TAK1; (2) preparing a homogeneous solution A from the TAK1, triethylamine and dioxane; (3) preparing a homogeneous solution B from solid phosgene and dioxane; (4) dissolving sodium hydroxide in water to prepare a homogeneous solution C; (5) respectively pumping the homogeneous solution A and thehomogeneous solution B into a microstructure mixer I in a micro-channel reaction device at the same time, performing mixing, and introducing the obtained mixed solution into a microstructure reactorI; (6) respectively pumping the homogeneous solution C and the effluent of the microstructure reactor I into a microstructure mixer II in the micro-channel reaction device at the same time while step(5) is carried out, performing mixing, and introducing the obtained mixed solution into a microstructure reactor II; and (7) collecting the effluent of the microstructure reactor II to obtain the product azilsartan.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a synthesis process for continuously preparing azilsartan in a microchannel reactor. Background technique [0002] Azilsartan (ァジルバ板), an angiotensin II receptor antagonist developed by Japan's Takeda Pharmaceutical, has been approved for marketing in Japan. The antihypertensive effect of azilsartan is more obvious than that of the same type of sartan drugs. It can be used alone or in combination with other antihypertensive drugs. It is regarded as the next generation product of candesartan cilexetil. The chemical name is 2-ethoxy-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)[1,1'-link Phenyl]-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid. Azilsartan is white to pale yellow crystals or crystalline powder. Soluble in N,N-dimethylacetamide, slightly soluble in methanol, slightly soluble in ethanol, almost insoluble in water. Azilsartan is a poorly water-soluble drug with a sol...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/10B01J19/00
CPCB01J19/0093C07D413/10
Inventor 杨大龙
Owner 南京恒通医药开发有限公司