Preparation method of ciclesonide

Abstract

The invention provides a new synthetic route for preparation of ciclesonide. The method comprises the steps that used raw materials are cheaper and available, the reaction raw materials are protectedafter hydroxylation, selective oxidation of a five-membered ring double bond is then performed, then, a six-membered ring double bond bromination is conducted, bromine atom is removed by reduction, acarbonyl group and a hydroxyl protecting group are removed, then, an oxidized dihydroxyl group is protected, the six-membered ring double bond is then epoxidized and reacts with cyclohexanecarboxaldehyde and isobutyryl chloride in turn to obtain a ciclesonide product. A reaction process is easy to operate, yield is higher in each step, purity of the obtained product is also higher, generation of by-products is effectively avoided, production cost is reduced, and the new synthetic route for the preparation of the ciclesonide is advantageous to industrial production.

Description

technical field

[0001] The application relates to a preparation method of a glucocorticoid-type asthma treatment drug ciclesonide. Background technique

[0002] Ciclesonide is a new type of inhaled glucocorticoid for asthma treatment, belonging to the adrenal corticosteroid class. Ciclesonide was successfully developed by the German drugmaker Altana Pharmaceuticals. The drug was first approved in Australia on December 15, 2004, and was first listed in the United Kingdom in January 2005. It has now been listed in Germany and Ireland for the treatment of adults. Persistent asthma of all severity levels. In a phase III clinical study in patients with severe, persistent asthma, ciclesonide has novel release and distribution properties that reduce local and systemic adverse effects and maintain high anti-asthmatic activity, thereby significantly reducing patient exposure to oral The need for corticosteroids (OCS) to maintain or improve asthma control. Therefore, it is an appro...

Examples

preparation example Construction

[0033] The invention discloses a preparation method of ciclesonide, and those skilled in the art can learn from the content of this paper and appropriately improve the process parameters to achieve. It should be specially pointed out that all similar substitutions and modifications are obvious to those skilled in the art, they are all considered to be included in the present invention, and relevant persons can obviously do so without departing from the content, spirit and scope of the present invention. The content described herein can be modified or appropriately changed and combined to realize and apply the technology of the present invention.

[0034] In the present invention, unless otherwise specified, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art.

Embodiment 1

[0036] Example 1: Preparation of compound of formula II

[0037]

[0038]At the temperature of -5~5℃, 100mL methanol was used as the solvent, the reaction flask was placed in an ice-water bath to control the low temperature, 5.4g (17.5mmol) of compound I, 4.2g (105mmol) of sodium hydroxide were added to the reaction flask, and stirred for 10~ 30min, under the dark condition, add 8.5g (26.3mmol) iodobenzene diacetate at one time, naturally rise to room temperature and react for 6~8 hours, monitor the reaction progress by TLC, drip 20g (141mmol) iodomethane, continue the reaction, wait for After the reaction, the solvent was removed under reduced pressure, extracted with 100 mL of ethyl acetate and 20 mL of water, the organic phase was washed with water, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 6.3 g (16.3 mmol) of the compound of formula II with a yield of 93 %.

Embodiment 2

[0039] Example 2: Preparation of compound of formula III

[0040]

[0041] 150 mL of acetone was used as a solvent, 7.1 g (18.4 mmol) of the compound of formula II was added, the temperature was lowered to -5 to 5 °C, 2.8 mL of about 3.4 g (73.4 mmol) of formic acid was added as a catalyst, and 5.2 g (33.1 mmol) of potassium permanganate were added. Oxidation reaction, TLC monitoring reaction progress, after the reaction is completed, the excess potassium permanganate is treated with saturated sodium sulfite solution, the insoluble solid is removed by filtration, washed with acetone, decolorized with activated carbon, the solid is removed by filtration, the solvent is removed under reduced pressure, and the pure water is recrystallized to obtain formula III Compound 6.8 g (16.2 mmol), 88% yield.

technical field

[0001] The application relates to a preparation method of a glucocorticoid-type asthma treatment drug ciclesonide. Background technique

[0002] Ciclesonide is a new type of inhaled glucocorticoid for asthma treatment, belonging to the adrenal corticosteroid class. Ciclesonide was successfully developed by the German drugmaker Altana Pharmaceuticals. The drug was first approved in Australia on December 15, 2004, and was first listed in the United Kingdom in January 2005. It has now been listed in Germany and Ireland for the treatment of adults. Persistent asthma of all severity levels. In a phase III clinical study in patients with severe, persistent asthma, ciclesonide has novel release and distribution properties that reduce local and systemic adverse effects and maintain high anti-asthmatic activity, thereby significantly reducing patient exposure to oral The need for corticosteroids (OCS) to maintain or improve asthma control. Therefore, it is an appro...

Examples

preparation example Construction

[0033] The invention discloses a preparation method of ciclesonide, and those skilled in the art can learn from the content of this paper and appropriately improve the process parameters to achieve. It should be specially pointed out that all similar substitutions and modifications are obvious to those skilled in the art, they are all considered to be included in the present invention, and relevant persons can obviously do so without departing from the content, spirit and scope of the present invention. The content described herein can be modified or appropriately changed and combined to realize and apply the technology of the present invention.

[0034] In the present invention, unless otherwise specified, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art.

Embodiment 1

[0036] Example 1: Preparation of compound of formula II

[0037]

[0038]At the temperature of -5~5℃, 100mL methanol was used as the solvent, the reaction flask was placed in an ice-water bath to control the low temperature, 5.4g (17.5mmol) of compound I, 4.2g (105mmol) of sodium hydroxide were added to the reaction flask, and stirred for 10~ 30min, under the dark condition, add 8.5g (26.3mmol) iodobenzene diacetate at one time, naturally rise to room temperature and react for 6~8 hours, monitor the reaction progress by TLC, drip 20g (141mmol) iodomethane, continue the reaction, wait for After the reaction, the solvent was removed under reduced pressure, extracted with 100 mL of ethyl acetate and 20 mL of water, the organic phase was washed with water, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 6.3 g (16.3 mmol) of the compound of formula II with a yield of 93 %.

Embodiment 2

[0039] Example 2: Preparation of compound of formula III

[0040]

[0041] 150 mL of acetone was used as a solvent, 7.1 g (18.4 mmol) of the compound of formula II was added, the temperature was lowered to -5 to 5 °C, 2.8 mL of about 3.4 g (73.4 mmol) of formic acid was added as a catalyst, and 5.2 g (33.1 mmol) of potassium permanganate were added. Oxidation reaction, TLC monitoring reaction progress, after the reaction is completed, the excess potassium permanganate is treated with saturated sodium sulfite solution, the insoluble solid is removed by filtration, washed with acetone, decolorized with activated carbon, the solid is removed by filtration, the solvent is removed under reduced pressure, and the pure water is recrystallized to obtain formula III Compound 6.8 g (16.2 mmol), 88% yield.

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