A kind of synthetic method of fondaparinux sodium intermediate
A technology of fondaparinux sodium and a synthesis method, which is applied in the field of synthesis of fondaparinux sodium intermediates, can solve problems such as unfavorable large production, long operation time, many by-products, etc., and achieves simplified operation, reduced time cost, Yield improvement effect
Active Publication Date: 2018-08-31
江苏美迪克化学品有限公司
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Problems solved by technology
[0010] However, in this synthetic route, formula III (the intermediate shown in the above-mentioned formula c) must be obtained from formula I through two-step reactions, which not only has many by-products and low conversion rate, but also a plurality of reaction steps means that it needs to increase More reaction equipment and more operating time are not conducive to large-scale industrial production
Method used
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Embodiment 1
[0066] Embodiment 1 is by the compound shown in D-glucose synthetic formula 2
[0067] The preparation of the compound shown in formula 6
[0068] Add 45g of D-glucose, 1800ml of water, and 303.6g of triethylamine into the reaction bottle, start stirring, cool to 0-5°C, add 170.1g of 2-chloro-1,3-dimethylimidazole hydrochloride in batches, After the addition, keep the reaction at 0-5°C for 30 minutes, concentrate the reaction solution to dryness under reduced pressure, add 400ml of acetonitrile, stir for 1 hour, filter, wash the filter cake with 100ml of acetonitrile, combine the filtrates, and concentrate under reduced pressure to obtain the compound shown in formula 6 , which can be directly used for feeding in the next step;
[0069] The preparation of the compound shown in formula 5
[0070] Dissolve the compound shown in formula 6 in 1500ml of pyridine, add 20g of Novozym435 (immobilized Candida antarctica lipase) and 47.2g of succinimide acetate, place in a shaker and ...
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Abstract
The invention discloses a method for synthesizing an intermediate of fondaparinux sodium represented by a formula 1. The method comprises the step of subjecting a compound represented by a formula 2 and benzaldehyde, which serve as reaction raw materials, to acetal protective reaction and diacetyl removing reaction in an organic solvent in the presence of mixed acid, thereby obtaining the intermediate of fondaparinux sodium represented by the formula 1 in one step, wherein the mixed acid is prepared from concentrated sulfuric acid and para-toluenesulfonic acid which are in the mass ratio of 1to (0.1 to 5), the concentrated sulfuric acid is a sulfuric acid aqueous solution with the mass fraction of 70% to 98%, the organic solvent contains toluene, of which the volume accounts for 5% to 15%that of the organic solvent; a volume ratio of water to the organic solvent in an initial reaction system is controlled to (0.005 to 0.04) to 1. The method has the advantages of being high in conversion ratio, high in reaction rate, simple in operation and applicable to large-scale production. The formula 1 and formula 2 are shown in the description.
Description
technical field [0001] The invention belongs to the field of sugar chemistry, is applied in fine chemical industry and pharmaceutical chemical industry, and specifically relates to a synthetic method of fondaparinux sodium intermediate. Background technique [0002] Fondaparinux sodium is a synthetic heparin pentasaccharide drug (English name fondaparinuxsodium), which is the first indirect inhibitor of antithrombin-dependent factor Xa developed and produced by Sanofi Winthrop Industrie in France. The chemical structural formula is the following formula a (with D, E, F, G, H respectively representing 5 monosaccharides from left to right). [0003] [0004] The total synthetic route of fondaparinux sodium is relatively long, and the number of reaction steps varies from 50 steps to more than 70 steps. At present, the main construction strategies are (D+EF)+GH and D+(EF+GH). Among them, the following structure (Formula b) is an important intermediate for introducing EF disa...
Claims
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IPC IPC(8): C07H9/04C07H1/00
CPCC07H1/00C07H9/04
Inventor 杨盟徐肖洁景亚婷
Owner 江苏美迪克化学品有限公司