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A kind of synthetic method of fluticasone derivative

A technology of fluticasone and a synthesis method, applied in the field of synthesis of fluticasone derivatives, can solve the problems of high price of bromofluoromethane, complex organic carriers, low temperature requirements, etc., and achieve the effects of short reaction time, good reaction selectivity and little environmental pollution

Active Publication Date: 2016-04-13
ZHEJIANG UNIV OF TECH +1
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Problems solved by technology

[0003] The traditional method for preparing fluticasone (furoate) propionate (furoate) is generally obtained by condensation of formula (Ⅲ) through bromofluoromethane. The yield of this method is relatively ideal, but bromofluoromethane is expensive and highly toxic, and its damage to ozone is severely restricted by international conventions , another route is to condense with (Ⅲ) BrCHC1, which is cheap and has relatively little impact on ozone, and then use AgF, KI / KF for halogen exchange, but the yield is low
[0004] There are also many research reports on how to synthesize fluticasone propionate (furoate) from (Ⅲ) at present: the world patent (WO2004 / 052912) utilizes a novel fluorinating agent to prepare fluticasone propionate, and a new Fluorine is added to the method, first (Ⅲ) is condensed with formaldehyde, and then hydroxy fluoride is carried out, which is convenient for feeding compared with halofluoromethane, but the temperature requirement is very low, and the price is expensive and the yield is low; Chinese patent (CN100549022C) Reported the use of ionic liquids for the exchange of fluorine atoms, the yield is relatively ideal; the world patent (WO2011 / 151625A1) reported the use of XeF 2 or BrF 3 Fluticasone propionate (furoate) was prepared by decarboxylation and fluorination, but XeF 2 Extremely expensive, little production value, BrF 3 Strong activity, high toxicity, dangerous operation; world patent (WO2011 / 151624A1), using organic salt carrier containing S, N, P to directly add CH 2 F group, the yield has not been reported, but the synthesis of the organic carrier is more complicated

Method used

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  • A kind of synthetic method of fluticasone derivative
  • A kind of synthetic method of fluticasone derivative
  • A kind of synthetic method of fluticasone derivative

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037]

[0038] Add formula (Ⅲ-A) 1.0g (2.1mmol), triethylamine 0.45ml (3.15mmol), bromoacetic acid 0.32g (2.31mmol) in a 100ml three-necked flask equipped with a thermometer, add 10ml acetone and 2ml water to dissolve Clarify, react at room temperature, track and detect by TLC until the end of the reaction, adjust the pH to 2-3 with hydrochloric acid, add 30ml of water to precipitate a white solid, filter, and dry to obtain 1.05g (II-A), yield 95%.

[0039] 1 HNMR (400MHz, CDCl 3), δ: 0.99(d, J=7.2Hz, 3H), 1.10(s, 3H), 1.13(t, J=7.4Hz, 3H), 1.32-1.38(m, 1H), 1.52(s, 3H) ,1.73-1.91(m,3H),2.17-2.39(m,7H),3.34(m,1H),3.76(s,2H),4.36(d,J=9.2Hz,1H),5.31-5.44(m ,1H),6.36(dd,J 1 =10.0Hz,J 2 =1.6Hz,1H),6.42(s,1H),7.10(d,J=10.0Hz,1H); MS(ESI-)m / z525(M-H) + .

Embodiment 2

[0041]

[0042] Add (II-A) 1.0g (1.9mmol), silver nitrate 0.1g (0.58mmol) and selective fluorination reagent Selectfluor (Aladdin Chemical Reagent Co., Ltd., the same below) 1.5 to a 100ml three-necked flask equipped with a thermometer. g (4.2mmol), add 30ml acetone and 15ml water to dissolve and clarify, react at 45°C, TLC follow-up detection, after 10 hours of reaction, add dichloromethane for extraction, take the organic phase, wash with water, dry over anhydrous sodium sulfate, spin dry 0.4 g of the target product (I-A) was obtained with a yield of 42%.

[0043] 1 HNMR (400MHz, CDCl 3 ), δ: 0.98(d, J=7.0Hz, 3H), 1.12(s, 3H), 1.12(t, J=7.4Hz, 3H), 1.32-1.37(m, 1H), 1.52(s, 3H) ,1.76-1.91(m,3H),2.25-2.44(m,7H),3.39(m,1H),4.42(d,J=8.8Hz,1H),5.31-5.44(m,1H),5.73-5.96 (m,2H),6.36(dd,J 1 =10.0Hz,J 2 =1.6Hz,1H),6.42(s,1H),7.10(d,J=10.0Hz,1H); MS(ESI-)m / z500(M) + .

Embodiment 3

[0045] In a 100ml three-necked flask equipped with a thermometer, add (II-A) 1.0g (1.9mmol), silver nitrate 0.1g (0.58mmol), selective fluorination reagent Selectfluor 3.0g (8.4mmol), add 40ml acetone and 20ml Dissolved in water and clarified, reacted at 45°C, followed by TLC detection, and reacted for 8 hours. After the reaction was completed, dichloromethane was added for extraction, and the organic phase was washed with water, dried over anhydrous sodium sulfate, and spin-dried to obtain 0.81 g of the target product, with a yield of 85%.

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Abstract

The invention discloses a synthesis method of a fluticasone derivative shown as a formula (I). The synthesis method comprises the following steps: under actions of a monovalent metal silver salt catalyst and a selective fluorinating reagent, performing decarboxylation and fluorine substitution reaction on a compound shown as a formula (II) to prepare the fluticasone derivative shown as the formula (I). Conventionally, fluticasone propionate (furoate) (I) is generally prepared from a compound shown as a formula (III) through bromofluoromethane condensation, but bromofluoromethane is high in cost, large in toxicity and serious in environment pollution; the reagents used in the synthesis method provided by the invention are relatively cheap and easy to obtain and low in environment pollution; and the synthesis method is mild in reaction condition, good in selectivity and high in reaction yield.

Description

(1) Technical field [0001] The invention relates to a synthesis method of fluticasone derivatives. (2) Background technology [0002] Fluticasone propionate (Fluticasonepropionate) is a new type of glucocorticoid drug developed by Glaxo Wellcome, Germany. Compared with other glucocorticoids, this drug has strong curative effect and weak adverse reactions. Fluticasone furoate (fluticasonefuroate) ), developed by GlaxoSmithKline, a new drug nasal spray listed in the United States in April 2007, with a trade name of Veramyst. Compared with fluticasone propionate, fluticasone furoate has higher receptor affinity and prolonged duration of action. [0003] The traditional method for preparing fluticasone (furoate) propionate (furoate) is generally obtained by condensation of formula (Ⅲ) through bromofluoromethane. The yield of this method is relatively ideal, but bromofluoromethane is expensive and highly toxic, and its damage to ozone is severely restricted by international conv...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J31/00
Inventor 苏为科周嘉第施湘君张汝金张峥斌
Owner ZHEJIANG UNIV OF TECH