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Preparation method of loteprednol etabonate intermediate

A technique of loteprednol etabonate and intermediates, applied in the field of preparation of loteprednol etabonate intermediates, can solve problems such as high cost of raw materials, long process routes, complicated operations, etc., and achieves low cost and shortened process routes. , the effect of simple operation

Inactive Publication Date: 2021-07-13
HENAN LIHUA PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Its synthetic process all is to use 17β carboxylic acid (seeing formula VI) as main intermediate, and traditional process route is to be starting material with prednisolone, obtains 17β carboxylic acid through periodate oxidation, and this method raw material cost is relatively low. high
[0006] Chinese patent CN111072743A relates to a new method for preparing 17β carboxylic acid, which uses cheap 11α-hydroxyl-ADD as a substrate to carry out a series of functional group transformations to synthesize 17β carboxylic acid. The process route is long, the operation is complicated, and the types of excipients used Various, the purity is only about 97%, and the yield is low

Method used

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  • Preparation method of loteprednol etabonate intermediate
  • Preparation method of loteprednol etabonate intermediate
  • Preparation method of loteprednol etabonate intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0032] Add 250ml of tetrahydrofuran and 50g of 11α-hydroxyl-ADD (compound I) into the reaction flask under the protection of nitrogen. 10g, each interval of 20 minutes, control the temperature at -40°C after adding, react for 5h, then control the temperature at 10°C, slowly add 50ml of drinking water to stop the reaction, slowly add 150ml of 30% sodium hydroxide solution dropwise, adjust the pH of the system to Between 6 and 7, control the temperature at 25°C, let the layers stand for 30 minutes, wash the water layer with 100ml of tetrahydrofuran, stir for 10 minutes, let stand for 30 minutes to separate layers, combine the tetrahydrofuran layers, concentrate under reduced pressure, recover the solvent, and pour into 50ml of methanol Tetrahydrofuran was entrained, filtered, and dried for 10 hours to obtain 45.1 g of compound II with a mass yield of 90.2% and a purity of 98.5% as determined by high performance liquid chromatography.

[0033] Add 40g of compound II to 150ml of a...

Embodiment 2

[0038]Add 200ml of dichloromethane and 50g of compound I into the reaction flask under the protection of nitrogen, cool down to -50°C, add 50g of phosphorus pentachloride in 5 times, 10g each time, each time at an interval of 20 minutes, and control the temperature after adding - 40°C, react for 5 hours, then control the temperature at 10°C, slowly add 50ml of drinking water to stop the reaction, slowly add 150ml of 30% sodium hydroxide solution dropwise, adjust the pH of the system to 6-7, control the temperature at 25°C, and statically Separate the layers for 30 minutes, wash the water layer with 100 ml of dichloromethane, stir for 10 minutes, let stand for 30 minutes to separate layers, combine the dichloromethane layers, concentrate under reduced pressure, recover the solvent, pour into 50 ml of methanol to entrain the dichloromethane, filter, and dry for 10 42.5 g of compound II was obtained, with a mass yield of 85.0%, and a purity of 97.8% as determined by high performan...

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Abstract

The invention provides a preparation method of a loteprednol etabonate intermediate. The preparation method comprises the following steps: carrying out dehydration reaction on 11 alpha-hydroxyl-ADD and a dehydrating agent in an organic solvent to obtain a compound II; carrying out a first addition reaction on the compound II and a halogenating reagent in an organic solvent in the presence of an acid catalyst, and adding a quenching agent to carry out a quenching reaction after the reaction is finished, so as to obtain a compound III; carrying out reduction reaction on the compound III and a metal reducing agent in an organic solvent in the presence of an acid catalyst to obtain a compound IV; carrying out secondary addition reaction on the compound IV and a cyaniding reagent in an organic solvent in the presence of a basic catalyst to obtain a compound V; and carrying out hydrolysis reaction on thecompound V and an acid reagent in an organic solvent to obtain a compound VI, wherein the compound VI is the loteprednol etabonate intermediate. The preparation method saves energy, reduces consumption, and is easy to operate, high in yield and good in purity.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a preparation method of a loteprednol etabonate intermediate. Background technique [0002] Loteprednol etabonate is a novel glucocorticoid indicated for the treatment of corticosteroid-sensitive inflammatory conditions such as eyelid and bulbar conjunctivitis, uveitis, and inflammation of the cornea and anterior segment. This product can be quickly metabolized into inactive products after eye drops, which reduces systemic toxicity and minimizes the adverse reactions of glucocorticoids. Its anti-inflammatory effect is stronger than that of prednisolone. [0003] The structural formula is: [0004] [0005] Its synthetic process all is to use 17β carboxylic acid (see formula VI) as main intermediate, and traditional process route is to be starting material with prednisolone, obtains 17β carboxylic acid through periodate oxidation, and this method raw material cost ...

Claims

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Application Information

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IPC IPC(8): C07J3/00
CPCC07J3/005
Inventor 王海波刘娜娜王瑞玲魏志奎李合兴
Owner HENAN LIHUA PHARMA
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