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Preparation method of HIF-2alpha inhibitor PT2385

A technology of PT2385 and HIF-2, which is applied in the preparation of organic compounds, sulfide preparation, chemical instruments and methods, etc., can solve the problems of unfavorable amplification reactions, low atom economy, lengthy routes, etc., and achieve simple reaction steps and comprehensive synthesis The route is reasonable and the effect of improving the yield

Active Publication Date: 2021-11-16
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0005] By analyzing the above synthetic route, we found that it has the following obvious defects: the route is tedious, and it takes 14 steps of reaction to obtain the final product, and the total yield is less than 9%; in this route, when intermediate C is synthesized, the reaction temperature is 180 ° C, when synthesizing intermediate E, the reaction temperature is 220 ° C, the temperature of the two-step reaction is high, which is not conducive to the scale-up reaction; in the process of synthesizing intermediate F from intermediate C through two-step reaction, atom economy is low

Method used

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  • Preparation method of HIF-2alpha inhibitor PT2385
  • Preparation method of HIF-2alpha inhibitor PT2385
  • Preparation method of HIF-2alpha inhibitor PT2385

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Embodiment 1 of the present invention provides a kind of preparation method of intermediate II, and its synthetic route is as follows:

[0049]

[0050] Specifically adopt the following method to prepare:

[0051] Compound I (50.0g, 0.44mol), 3-chloropropionyl chloride (55.6g, 0.44mmol) and anhydrous aluminum chloride (116.9g, 0.88mmol) were added into the reaction flask, and then stirred at 120°C for 12h. Return the temperature to room temperature, add water (500mL) and ethyl acetate (500mL) to the reaction flask, separate liquid extraction, dry the organic layer with anhydrous sodium sulfate, filter with suction, and remove the solvent under reduced pressure to obtain 69.8 g of a light yellow solid , yield 94.7%.

[0052] The intermediate II prepared in the present embodiment is identified, and the following results are obtained:

[0053] ESI-MS (m / z): 169.1;

[0054] 1 H NMR (300MHz, CDCl 3 )δ7.32–7.19(m,1H), 7.03–6.96(m,1H), 3.22–3.11(m,2H), 2.83–2.72(m,2H)....

Embodiment 2

[0056] Embodiment 2 of the present invention provides a kind of preparation method of intermediate III, and its synthetic route is as follows:

[0057]

[0058] Specifically adopt the following method to prepare:

[0059] Intermediate II (55.0 g, 0.33 mol) was dissolved in N,N-dimethylformamide (200 mL), and then a 20% aqueous solution of sodium methyl mercaptide (126.1 g, 0.36 mol) was added dropwise at room temperature After reacting for 8h, water (200mL) and ethyl acetate (300mL) were added to the reaction liquid, separated and extracted, the organic layer was dried with anhydrous sodium sulfate, filtered with suction, and the solvent was removed under reduced pressure to obtain 60.3 g of a yellowish-brown solid. The rate is 93.9%.

[0060] The intermediate III prepared in the present embodiment is identified, and the following results are obtained:

[0061] ESI-MS (m / z): 197.2;

[0062] 1 H NMR (300MHz, CDCl 3 )δ7.24(t, J=8.4Hz, 1H), 7.07(dd, J=8.5, 4.0Hz, 1H), 3.1...

Embodiment 3

[0064] Embodiment 3 of the present invention provides a kind of preparation method of intermediate IV, and its synthetic route is as follows:

[0065]

[0066] Intermediate III (60.0 g, 0.31 mol) was dissolved in dichloromethane (300 mL), and m-chloroperoxybenzoic acid with a mass fraction of 85% was added at 0°C, followed by stirring the reaction at 25°C for 18 h, and adding to the reaction solution Add water to the mixture, extract by liquid separation, dry the organic layer with anhydrous sodium sulfate, filter with suction, remove the solvent under reduced pressure, and recrystallize using a mixed solvent of petroleum ether:ethyl acetate (4:1, v:v) to obtain a white solid 61.2 g, yield 87.7%.

[0067] The intermediate IV obtained in the present embodiment is identified, and the following results are obtained:

[0068] ESI-MS (m / z): 229.2;

[0069] 1 H NMR (400MHz, DMSO-d 6 )δ8.10–7.96 (m, 1H), 7.75 (t, J=8.4Hz, 1H), 3.41 (s, 3H), 3.22–3.12 (m, 2H), 2.88–2.76 (m, 2H)...

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Abstract

The invention relates to a preparation method of an HIF-2 alpha inhibitor PT2385. The method comprises the following steps of: performing Friedel-Crafts reaction on p-difluorobenzene serving as a raw material and 3-chloropropionyl chloride to generate an intermediate II, performing substitution reaction on the intermediate II and sodium methyl mercaptide to generate an intermediate III, performing oxidation, reduction and two-step substitution reaction to obtain an intermediate VII, performing oxidation reaction on the intermediate to obtain an intermediate VIII, and reacting the intermediate VIII with n-butylamine to obtain a compound IX, carrying out fluorination reaction and hydrolysis to obtain an intermediate X, and finally carrying out asymmetric reduction reaction to obtain a final product PT2385. Compared with the existing synthesis method, the process route provided by the invention has the obvious advantages that the raw materials are cheap and easy to obtain, the operation is simple and convenient, the number of reaction steps is small, the total yield is up to 47.6%, multi-step high-temperature reaction is avoided, and industrial production is easy.

Description

technical field [0001] The invention relates to the technical field of medicine manufacturing, in particular to a new method for preparing HIF-2α inhibitor PT2385. Background technique [0002] Hypoxia-Inducible Factors (HIF) transcription complex is a key factor in sensing changes in oxygen concentration. HIF consists of two different DNA-binding proteins, HIFα and HIFβ, where HIFα includes HIF-1α, HIF-2α And HIF-3α, HIFβ includes HIF-1β, HIF-2β and HIF-3β. Under normal conditions, HIFα is modified by hydroxylation under the action of prolyl hydroxylase (PHD), and the modified HIFα is degraded by ubiquitination, so that the intracellular HIFα maintains a low expression level. Under hypoxic conditions, HIFα is protected from degradation, binds to HIFβ and specific DNA sequences (HRE) in hypoxia-regulated genes to activate the expression of downstream genes. Studies have shown that abnormal function of HIF-2α is a key factor driving cancers such as clear cell renal carcinom...

Claims

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Application Information

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IPC IPC(8): C07C315/04C07C317/22
CPCC07C315/04C07C315/02C07C319/14C07C45/46C07C2602/08C07C317/22C07C317/24C07C317/36C07C323/22C07C49/697
Inventor 邢峻豪江玉琳窦晓巍张男侠
Owner CHINA PHARM UNIV
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