Synthesis method of canrenone

A synthetic method, the technology of canrenone, applied in the field of chemical synthesis, can solve the problems such as difficult to complete the reaction, long reaction time, and dangerous reaction, and achieve the effect of improving experimental operability, short time, and less side reactions

CN113461767APending Publication Date: 2021-10-01TIANJIN PHARMA GROUP CORP
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Patent Information

Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Publication Date
2021-10-01

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Abstract

The invention provides a synthesis method of canrenone, and relates to the technical field of chemical synthesis. The synthesis method of canrenone comprises the following steps: (a) adding a compound in a formula 1 into an organic solvent to obtain a solution containing the compound in the formula 1; and (b) introducing the solution in the step (a) into a micro-channel reactor, and carrying out a decarboxylation reaction to obtain canrenone. The method can completely react within a short time, reduces side reactions caused by long-time high temperature, can continuously react in the microchannel reactor, has the advantages of high mass transfer efficiency, fast reaction, short time and less side reactions, greatly improves the experiment operability, has the yield equivalent to that of the original process, and solves the problems of slow reaction and dangerous and tedious operation, and improves the production applicability of the reaction.
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Description

technical field

[0001] The invention relates to the technical field of chemical synthesis, in particular to a synthesis method of canrenone. Background technique

[0002] Canrenone, chemical name: 17β-hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid-γ-lactone. It is a commonly used diuretic and an important intermediate in the synthesis of aldosterone receptor antagonists, spironolactone and eplerenone. Since 1957, spironolactone has been used clinically to treat hypertension and congestive heart failure; and eplerenone is the first approved and selective aldosterone receptor antagonist with similar efficacy to spironolactone. But almost no endocrine side effects of spironolactone, with better tolerance. Therefore, the research on the synthesis process of canrenone has high application value.

[0003] The synthetic route reported in the patent US3919198: using 4-androstenedione as a substrate, canrenone is obtained through the following reaction:

[0004] . [...

Examples

Embodiment 1

[0047]

[0048] Material preparation:

[0049] Add 100g of compound 1, 500mL of ethylene glycol and 25mL of water into a 2L plastic beaker, mix them evenly, and stir to dissolve them.

[0050] System preparation:

[0051] Turn on the microchannel reaction system, set the temperature of the heat transfer oil in the preheating zone to 50°C, set the temperature of the reaction module in the reaction zone to 90°C, set the temperature of the heat transfer oil in the cooling zone to 20°C, and wait for the temperature to balance.

[0052] Preparation of canrenone:

[0053] After the temperature of the heat transfer oil is stable, use a convection pump to inject the prepared solution into the microchannel system at a rate of 10g / min. When the material flows out from the outlet of the cooling zone of the microchannel system, the residence time of the material is 5min after the system is stabilized. , carry out liquid chromatographic analysis on the outlet liquid of the reactor. Af...

Embodiment 2

[0055]

[0056] Material preparation:

[0057] Add 100g of compound 1, 800mL of DMSO and 50mL of water into a 2L plastic beaker, mix them evenly, and stir to dissolve them.

[0058] System preparation:

[0059] Turn on the microchannel reaction system, set the temperature of the heat transfer oil in the preheating zone: 30°C, set the temperature of the reaction module in the reaction zone to 120°C, set the temperature of the heat transfer oil in the cooling zone to 40°C, and wait for the temperature to balance.

[0060] Preparation of canrenone:

[0061] After the temperature of the heat transfer oil is stable, use a convection pump to inject the prepared solution into the microchannel system at a rate of 30g / min. When the material flows out from the outlet of the cooling zone of the microchannel system, the residence time of the material is 8 minutes after the system is stabilized. , carry out liquid chromatographic analysis on the outlet liquid of the reactor. After the...

Embodiment 3

[0063]

[0064] Material preparation:

[0065] Add 100g of compound 1, 1000mL of NMP and 100mL of water into a 2L plastic beaker, mix them evenly, and stir to dissolve them.

[0066] System preparation:

[0067] Turn on the microchannel reaction system, set the temperature of the heat transfer oil in the preheating zone to 25°C, set the temperature of the reaction module in the reaction zone to 140°C, set the temperature of the heat transfer oil in the cooling zone to 20°C, and wait for the temperature to balance.

[0068] Preparation of canrenone:

[0069] After the temperature of the heat transfer oil is stable, the prepared solution is pumped into the micro-channel system at a rate of 50g / min with an advection pump. When the material flows out from the outlet of the cooling zone of the micro-channel system, the residence time of the material is 1min after the system is stabilized. , carry out liquid chromatographic analysis on the outlet liquid of the reactor. After th...