Preparation method for beraprost intermediate

Abstract

The invention discloses a preparation method for a beraprost intermediate. The preparation method comprises the following steps: (1) preparation of cyclopentadiene: a step of weighing dicyclopentadiene, adding BHT, carrying out heating to 180-200 DEG C for distilling, collecting fractions at 40-50 DEG C, and after collection is finished, carrying out secondary distillation so as to obtain the cyclopentadiene; and (2) preparation of the beraprost intermediate: a step of adding the cyclopentadiene into a solvent A, carrying out cooling in a cold trap to minus 72 DEG C, diluting a bromine reagentwith the solvent A, slowly dropwise adding a solvent A solution of the bromine reagent, controlling a temperature at minus 70 DEG C, and carrying out a reaction so as to obtain 3,5-dibromocyclopentene, then dissolving 2,4,6-tribromophenol into an anhydrous solvent B, carrying out a reaction, and carrying out post-treatment operation B so as to prepare the beraprost intermediate. By adoption of the preparation method disclosed by the invention, impurities generated in the process production process are effectively reduced; the yield is improved; meanwhile, the process is green and environmentally-friendly; and the cost of environmentally-friendly treatment is reduced.

Description

technical field

[0001] The invention relates to the field of preparation of prostacyclin intermediates, in particular to a preparation method of beraprost intermediates. Background technique

[0002] Beraprost (Beraprost) is a derivative of prostacyclin (PgI2), in order to stabilize the secondary five-membered ring structure of prostacyclin, a benzene ring is connected in parallel. Prostacyclin derivatives are oral anticoagulant drugs, which have drug activities such as inhibiting platelet aggregation, reducing gastric juice secretion, inhibiting injury, and bronchodilation, among which beraprost sodium is the first one that can be taken orally. Beraprost is a synthetic benzoprostacyclin analogue of natural prostacyclin, which has six chiral centers and is a racemic compound composed of four isomers. Beraprost sodium is developed by Chinoin of Hungary and Toray of Japan respectively, and the trade names of Kaina and Dana are listed in China respectively.

[0003] People's ...

Examples

Embodiment 1

[0038] Embodiment 1 prepares cyclopentadiene:

[0039] Depolymerization of cyclopentadiene:

[0040] Because of its conjugated diene and a methylene ring structure, cyclopentadiene is very active and prone to reactions such as polymerization, addition, and oxidation. It can be polymerized into dicyclopentadiene at room temperature, and it needs to be stored at -20°C, which limits its application. Usually, high-temperature depolymerization of dicyclopentadiene is used to produce cyclopentadiene.

[0041] Take 500g of dicyclopentadiene and put it into 200mg of 2,6-di-tert-butyl-4-methylphenol (BHT), heat it to 180-200°C for distillation with a thorn-type distillation head, and collect the fraction at 40-50°C. The second distillation was carried out, and BHT (5 mg) was added to the collected fractions after the distillation was completed, and 300 g of cyclopentadiene was collected, with a yield of 60%.

Embodiment 2

[0042] Example 2 Preparation of 3,5-dibromocyclopentene

[0043] The synthesis method of 3,5-dibromocyclopentene is as follows:

[0044] .

[0045] The preparation steps of 3,5-dibromocyclopentene are as follows:

[0046] Add 300g of cyclopentadiene to 120mL of chloroform in a cold well and cool down to -72°C. After the temperature drops to -72°C, dilute 726g of Br2 with 300mL of chloroform, and use a constant pressure dropping funnel to dilute the Br 2 The liquid is slowly added dropwise into the reaction system, and the temperature is controlled at -70°C during the dropwise addition, and the dropwise addition is completed;

[0047] The reaction system was naturally heated to 0°C, and saturated aqueous sodium bisulfite solution was added until the color of the solution faded, separated, the aqueous phase was extracted once with chloroform, the organic phase was combined, and the organic phase was washed once with saturated sodium bisulfite, and then washed with Wash once...

Embodiment 3

[0050] The difference between this example and Example 1 is that NBS (1620g) was diluted with 300mL chloroform and added dropwise to the reaction system as a bromine reagent, and finally 670g fraction was collected (the fraction was 3,5-dibromocyclopentene), producing rate of 66%.

technical field

[0001] The invention relates to the field of preparation of prostacyclin intermediates, in particular to a preparation method of beraprost intermediates. Background technique

[0002] Beraprost (Beraprost) is a derivative of prostacyclin (PgI2), in order to stabilize the secondary five-membered ring structure of prostacyclin, a benzene ring is connected in parallel. Prostacyclin derivatives are oral anticoagulant drugs, which have drug activities such as inhibiting platelet aggregation, reducing gastric juice secretion, inhibiting injury, and bronchodilation, among which beraprost sodium is the first one that can be taken orally. Beraprost is a synthetic benzoprostacyclin analogue of natural prostacyclin, which has six chiral centers and is a racemic compound composed of four isomers. Beraprost sodium is developed by Chinoin of Hungary and Toray of Japan respectively, and the trade names of Kaina and Dana are listed in China respectively.

[0003] People's ...

Examples

Embodiment 1

[0038] Embodiment 1 prepares cyclopentadiene:

[0039] Depolymerization of cyclopentadiene:

[0040] Because of its conjugated diene and a methylene ring structure, cyclopentadiene is very active and prone to reactions such as polymerization, addition, and oxidation. It can be polymerized into dicyclopentadiene at room temperature, and it needs to be stored at -20°C, which limits its application. Usually, high-temperature depolymerization of dicyclopentadiene is used to produce cyclopentadiene.

[0041] Take 500g of dicyclopentadiene and put it into 200mg of 2,6-di-tert-butyl-4-methylphenol (BHT), heat it to 180-200°C for distillation with a thorn-type distillation head, and collect the fraction at 40-50°C. The second distillation was carried out, and BHT (5 mg) was added to the collected fractions after the distillation was completed, and 300 g of cyclopentadiene was collected, with a yield of 60%.

Embodiment 2

[0042] Example 2 Preparation of 3,5-dibromocyclopentene

[0043] The synthesis method of 3,5-dibromocyclopentene is as follows:

[0044] .

[0045] The preparation steps of 3,5-dibromocyclopentene are as follows:

[0046] Add 300g of cyclopentadiene to 120mL of chloroform in a cold well and cool down to -72°C. After the temperature drops to -72°C, dilute 726g of Br2 with 300mL of chloroform, and use a constant pressure dropping funnel to dilute the Br 2 The liquid is slowly added dropwise into the reaction system, and the temperature is controlled at -70°C during the dropwise addition, and the dropwise addition is completed;

[0047] The reaction system was naturally heated to 0°C, and saturated aqueous sodium bisulfite solution was added until the color of the solution faded, separated, the aqueous phase was extracted once with chloroform, the organic phase was combined, and the organic phase was washed once with saturated sodium bisulfite, and then washed with Wash once...

Embodiment 3

[0050] The difference between this example and Example 1 is that NBS (1620g) was diluted with 300mL chloroform and added dropwise to the reaction system as a bromine reagent, and finally 670g fraction was collected (the fraction was 3,5-dibromocyclopentene), producing rate of 66%.

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