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Beraprost sodium intermediates and preparation method thereof

A beraprost sodium and compound technology, applied in the field of beraprost sodium intermediates and their preparation, can solve the problems of high equipment requirements, short steps, high toxicity, etc., and achieve the avoidance of toxic reagents, mild reaction conditions, and high yield. Effect

Inactive Publication Date: 2014-01-15
SHANGHAI TECHWELL BIOPHARMACEUTICALS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] This synthetic route has the following disadvantages: the toxicity of DCC (dicyclohexylcarbodiimide) used in the oxidation reaction is relatively high, and the by-product urea derivatives generated by the reaction are difficult to remove from the system, thereby affecting the quality of the product
[0010] The steps of this reaction route are relatively short, and the protective group on the secondary hydroxyl group is removed before the reduction, but the two-step reaction of Swern oxidation and reduction requires a low temperature of -70 ~ -80 ° C, and anhydrous and oxygen-free operation is required, and the equipment is The requirements are high, and it is difficult to further industrialize production

Method used

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  • Beraprost sodium intermediates and preparation method thereof
  • Beraprost sodium intermediates and preparation method thereof
  • Beraprost sodium intermediates and preparation method thereof

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preparation example Construction

[0076] The preparation method of formula I compound

[0077] The preparation method of the compound of formula I provided by the invention comprises the following steps:

[0078]

[0079] (a) using the compound of formula II as a raw material, protecting the hydroxyl group of the compound of formula II to generate a compound of formula I of the structure shown in formula Ia; and optionally

[0080] (b) the compound of formula Ia removes the protecting group R' to obtain the compound of formula I of the structure shown in formula Ib; and optionally

[0081] (c) the compound of formula Ib is oxidized to obtain the compound of formula I of the structure shown in formula Ic; and optionally

[0082] (d) the compound of formula Ic reacts with the phosphoric acid ester shown in formula X, obtains the compound of formula I of structure shown in formula Id,

[0083]

[0084] In the formula, Ri and Rii are independently selected from C 1-4 alkyl;

[0085] In the various formul...

Embodiment 1

[0122] The preparation of formula II compound

[0123] (where R 1is methyl, R' is tert-butyldiphenylsilyloxy)

[0124] In a 500ml four-neck bottle, 15g of the compound of formula Z (R 1 (methyl) was dissolved in 100ml of dichloromethane, 5ml of triethylamine and 0.34g of DMAP were added, under nitrogen protection, cooled to 0°C, and 50ml of dichloromethane solution containing 12.8g of tert-butyldiphenylchlorosilane was added dropwise , stirred for 2 hours, and the reaction was complete. Add 75ml of dilute citric acid aqueous solution to wash several times, wash with 300ml saturated NaCl solution, dry over anhydrous sodium sulfate, filter, and concentrate to obtain a slightly yellow liquid. After purification by column chromatography, 26.1 g was obtained, yield: 97.9%. The reaction product of this step can be put into the next step reaction without purification.

[0125] MS:567.5[M+Na] +

[0126] 1 H-NMR (400MHz, CDCl 3 ), δH: 0.75(9H,s), 1.75-2.84(11H,m), 3.52(3H,s), ...

Embodiment 2

[0128] The preparation of formula II compound

[0129] (where R 1 is ethyl, R' is tert-butyldimethylsilyloxy)

[0130] In a 500ml four-neck bottle, 15g of the compound of formula Z (R 1 is ethyl) dissolved in 100ml of dichloromethane, add 5ml of triethylamine, 0.33g of DMAP, under the protection of nitrogen, cool to 0°C, drop into 50ml of dichloromethane solution containing 11.6g of tert-butyldimethylsilyl chloride , stirred for 2 hours, and the reaction was complete. Add 75ml of dilute citric acid aqueous solution to wash several times, wash with 300ml saturated NaCl solution, dry over anhydrous sodium sulfate, filter, and concentrate to obtain a slightly yellow liquid. After purification by column chromatography, 20.2 g was obtained, yield: 99.3%. The reaction product of this step can be put into the next step reaction without purification.

[0131] MS:457.5[M+Na] +

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Abstract

The invention discloses beraprost sodium intermediates and a preparation method thereof. Specifically, provided is the beraprost sodium intermediate compounds represented by the formula I and the preparation method thereof. The preparation method comprises the steps: (a) protecting hydroxyl of a compound represented by the formula II, and thus generating a compound represented by the formula Ia; optionally (b) carrying out a deprotection reaction of the compound represented by the formula Ia to obtain a compound represented by the formula Ib; optionally (c) oxidizing the compound represented by the formula Ib to obtain a compound represented by the formula Ic; and optionally (d) carrying out a reaction of the compound represented by the formula Ic and phosphate ester to obtain a compound represented by the formula Id. Structures and definitions of substituent groups are defined as described in the specification. The method disclosed by the invention is mild in reaction conditions and high in yield, can avoid the use of toxic reagents, and is suitable for industrialized production.

Description

technical field [0001] The invention relates to a beraprost sodium intermediate and a preparation method thereof. Background technique [0002] Beraprost Sodium was developed by Japan Toray Co., Ltd. (Toray) and listed in China under the trade name Dana. The structure of the marketed beraprost sodium is shown in formula V, which is a racemic compound composed of 4 isomers. [0003] [0004] Beraprost sodium belongs to the prostacyclin class of drugs (prostacyclin, PGI 2 ). Prostacyclin is a vasoactive substance synthesized by vascular endothelial cells, which has anti-platelet and vasodilation effects. Simple PGI 2 Short half-life, pharmacological effects are very limited. In 1992, activated PGI 2 The analog oral drug, beraprost sodium, was successfully developed. Because of its stable structure and long half-life, it is widely used clinically to treat chronic arterial occlusive disease (ASO) of lower extremities. [0005] Patents EP084856, EP463162A1 and Tetrahedro...

Claims

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Application Information

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IPC IPC(8): C07F7/18C07D407/12C07D307/93
CPCY02P20/55
Inventor 唐志军何兵明季晓铭
Owner SHANGHAI TECHWELL BIOPHARMACEUTICALS CO LTD
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