Preparation method of Beraprost and its salt

A technology of beraprost and formula, applied in organic chemistry methods, bulk chemical production, organic chemistry, etc., can solve problems not related to the preparation method of beraprost sodium, achieve optimized preparation process route, facilitate scale-up, and stability Good results

Active Publication Date: 2017-03-08
BIOCOMPOUNDS PHARMACEUTICAL INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Chinese Patent Publication No. CN103509044A also only reports the method for preparing beraprost and its sodium salt using the ester of intermediate IV containing protective groups as raw material, but does not involve the preparation method of intermediate IV of beraprost sodium

Method used

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  • Preparation method of Beraprost and its salt
  • Preparation method of Beraprost and its salt
  • Preparation method of Beraprost and its salt

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1I-1

[0071] Embodiment 1.I-1 (R 1 =Bn, X=Cl) preparation

[0072] Add 14 g (40.5 mmol) of II (X=Cl) to a 500 ml three-necked flask, add 140 ml of dry tetrahydrofuran, and cool to -78°C. Under nitrogen protection, 19.5 ml of n-butyl lithium in tetrahydrofuran solution (48.6 mmol) was slowly added dropwise to the bottle. After the addition was complete, stirring was continued at -78°C for 20 minutes. Start to add 10.8g of 4-benzyloxy hydroxybutyraldehyde tetrahydrofuran solution (60.75mmol) dropwise, after the dropwise addition, continue to stir at -78°C for 20 minutes, then rise to -40°C and add 30ml of saturated ammonium chloride solution dropwise, stir, and rise to At room temperature, add water, extract 3 times with ethyl acetate, collect the organic phase, wash the organic phase once with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter the organic phase and concentrate under reduced pressure to obtain the crude product I-1, column chromatography Af...

Embodiment 2

[0073] Embodiment 2.I-1 (R 1 =TBS, X=Cl) preparation

[0074] Add 5.4 g (15.6 mmol) of II (X=Cl) into a 250 ml three-necked flask, add 54 ml of dry tetrahydrofuran, and cool to -78°C. Under nitrogen protection, 7.5 ml of a tetrahydrofuran solution (18.7 mmol) of n-butyllithium was slowly added dropwise to the bottle, and after the addition was complete, stirring was continued at -78°C for 20 minutes. Start to add dropwise 4.7g of 4-tert-butyldimethylsiloxy hydroxybutyraldehyde in tetrahydrofuran (23.4mmol). After the dropwise addition, continue to stir at -78°C for 20 minutes, then add dropwise 10ml of saturated ammonium chloride solution to -40°C , stirred, raised to room temperature, added water, extracted 3 times with ethyl acetate, collected the organic phase, washed the organic phase with saturated brine once, dried the organic phase with anhydrous sodium sulfate, filtered the organic phase and concentrated under reduced pressure to obtain I-1 The crude product was puri...

Embodiment 3

[0075] Embodiment 3.I-1 (R 1 =TBS, X=Br) preparation

[0076] Add 3.2 g (8.2 mmol) of II (X=Br) into a 100 ml three-necked flask, add 32 ml of dry tetrahydrofuran, and cool to -78°C. Under nitrogen protection, 3.9 ml of a tetrahydrofuran solution (9.8 mmol) of n-butyllithium was slowly added dropwise to the bottle. After the addition was complete, stirring was continued at -78°C for 20 minutes. Start to add dropwise 2.5g of 4-tert-butyldimethylsiloxy hydroxybutyraldehyde in tetrahydrofuran (12.3mmol). After the dropwise addition, continue to stir at -78°C for 20 minutes, then rise to -40°C and add 10ml of saturated ammonium chloride solution dropwise , stirred, raised to room temperature, added water, extracted 3 times with ethyl acetate, collected the organic phase, washed the organic phase with saturated brine once, dried the organic phase with anhydrous sodium sulfate, filtered the organic phase, and concentrated under reduced pressure to obtain I- 1 The crude product was...

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Abstract

The invention relates to the technical field of medicine, in particular to a preparation method of Beraprost and its salt. The preparation method includes the steps of d), oxidizing a compound as shown in formula I-3 to prepare a compound as shown in formula IV, wherein the reaction equation is shown in the specification; e), and using IV compound as raw material to prepare the Beraprost or the salt of the Beraprost. The preparation method has the advantages that each reaction of the preparation process generates a single product, and the method is stable and controllable, environmentally friendly, good in yield, safe in process, and the like; the method is suitable for new drug research and development, capable of avoiding patent concentration, easy in refining and purification, easy in preparation and related impurity control, capable of optimizing a preparation process route and convenient to amplify.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of beraprost and its salt. Background technique [0002] Beraprost is a prostacyclin (PGI 2 ) derivatives, which are connected with a benzene ring in parallel on the secondary five-membered ring of prostacyclin, which increases the stability of the molecule. Beraprost sodium (Beraprost sodium) is the sodium salt form of the anticoagulant drug Beraprost, which is suitable for symptoms such as intermittent claudication, pain and cold sensation caused by pulmonary hypertension and chronic arterial occlusive disease. Beraprost sodium (English name: Beraprost sodium, trade name: Kaina or Dana, molecular formula: C 24 h 29 o 5 Na, molecular weight: 420.48) has the structure shown in formula V, and its chemical name is: (±)-2,3,3a,8b-tetrahydro-2-hydroxyl-1-(3-hydroxyl-4-methyl-1 Sodium -octene-6-ynyl)-1H-cyclopenta[b]benzofuran-5-butyrate. [0003] [000...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/93
CPCY02P20/55C07D307/93C07B2200/07
Inventor 杨世琼康立涛李倩
Owner BIOCOMPOUNDS PHARMACEUTICAL INC
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