Application of Pd catalyst in hydrogenation process for producing doxycycline

A doxycycline and production process technology, applied in the application field of chiral asymmetric hydrogenation production process, can solve the problems of inability to separate and recycle catalysts, low catalyst preparation yield, unfavorable industrial production, etc., and achieve high catalytic activity and three-dimensional Selective, beneficial to environmental protection, beneficial to the effect of industrialized production

Active Publication Date: 2011-06-08
KAIFENG PHARMA GRP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Currently used hydrogenation catalysts mainly include Pd/C and triphenylphosphorous rhodium chloride [Rh(Ph 3 P) 3 Cl ] , the former is a heterogeneous catalyst with poor stereoselectivity, the yield is only 60%, and the β-body content reaches 10%, but the catalyst can be recycled and regenerated; the latter is a homogeneous catalyst, the yield can reach 90%, the β - The volume content is lower than 2%, but the catalyst cannot be separated and recovered
Hu Hanfeng et al. (Hu Hanfeng. Research on the hydrogenation synthesis of doxycycline hydrochloride [J]. Jiangsu Chemical Industry, 2003, 31 (4): 36-37) proposed to use silica gel immobilized homogeneous rhodium catalyst for hydrogenation reaction, which can not only improve hydrogenation Yield and stereoselectivity, without affecting the separation and recovery of the catalyst, but the cost is high, which is not conducive to industrial production
In 2007, Gu Mi...

Method used

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  • Application of Pd catalyst in hydrogenation process for producing doxycycline
  • Application of Pd catalyst in hydrogenation process for producing doxycycline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Embodiment 1: preparation palladium supported catalyst

[0022] Synthesis of polyvinyl chloride polyvinyl polyamine-loaded palladium complex: In a three-necked flask equipped with an electric stirrer, a reflux condenser and a thermometer, add 5.0 grams of pvc and 20 mL polyvinyl polyamine, swell overnight, and then place it in a boiling water bath Heating and stirring in medium temperature for 2 hours, cooling, stirring with water (heat generation), cooling, suction filtration, washing with water until neutral and colorless, then washing with ethanol until the ethanol is colorless, vacuum drying to constant weight, to obtain brown polyvinyl chloride polyvinyl chloride Polyamines. IR: 3339.98, 1584.72, 1428.72, 1252.52, 1120.91 cm-1.

[0023] Preparation of palladium-supported catalyst: Weigh 2.0 g of the above-mentioned polyvinyl chloride polyethylene polyamine, dissolve 0.1 g of palladium dichloride in 50 ml of acetone (ultrasonic dissolution), put them together in a ...

Embodiment 2

[0024] Embodiment 2: Doxycycline is prepared by 11α-chloro-6-methylene oxytetracycline p-toluenesulfonate

[0025] Take 100 grams of 11α-chloro-6-methylene oxytetracycline p-toluenesulfonate, and dissolve 0.15 grams of the above-prepared catalyst pvc-pp-pd in 300 mL of ethanol, and place them in a reactor with hydrogen gas and stir for reaction. The reaction temperature is 50°C and the pressure is 0.4-0.5Mpa.

[0026] Analysis by high-pressure liquid chromatography showed the progress of the reaction. After the reaction, filter and recover the catalyst, add 50.85 g of solid sulfosalicylic acid to the filtrate to form a salt, stir the reaction and cool, filter, and use 1:1 (volume ratio) ethanol: Washed with aqueous solution and dried. 92.1 g (0.139 mol) of a-6-deoxyoxytetracycline sulfosalicylate was obtained, with a yield of 90.2%. The isomer content of β-6-deoxyoxytetracycline sulfosalicylate is 0.6%.

Embodiment 3

[0027] Embodiment 3: 11α-chloro-6-methylene oxytetracycline p-toluenesulfonate prepares doxycycline

[0028] Take 100 g of 11α-chloro-6-methylene oxytetracycline p-toluenesulfonate, add 0.08 g of the above-prepared catalyst pvc-pp-pd, dissolve in 250 ml of methanol, place in a reactor and pass through hydrogen to stir the reaction. The reaction temperature is 35°C, and the reaction pressure is 0.6-0.65Mpa.

[0029] Analysis by high pressure liquid chromatography showed the progress of the reaction. After the reaction, filter and recover the catalyst, add solid sulfosalicylic acid to the filtrate to form a salt of 63.56g, stir the reaction and cool, filter, wash with 50ml of 50% ethanol, and dry. 95.1 g of α-6-deoxyoxytetracycline sulfosalicylate was obtained, the yield was 92.8%, and the isomer content of β-6-deoxyoxytetracycline sulfosalicylate was 0.3%.

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Abstract

The invention discloses an application of a Pd catalyst in a hydrogenation process for producing doxycycline, belonging to the field of pharmaceutical chemistry synthesis. The method is as follows: based on polyvinyl chloride-polyethylene polyamine-loaded palladium complex (pvc-pp-Pd) used as a catalyst, and 11 alpha-chlorine-6-methylene oxytetracycline or 11 alpha-chlorine-6,12-hemiketal oxytetracycline or metacycline or salts thereof used as raw material, introducing hydrogen, stirring and reacting, filtering, adding sulfo-group salicylic acid to filtrate so as to form salt; and cooling, filtering, washing and drying so as to obtain alpha-6-deoxytetracycline sulfo-group salicylic acid salt, wherein the yield is higher than 90%, the content of the corresponding beta-6-deoxytetracycline sulfo-group salicylic acid salt isomer is less than 1%. The method has the advantages of mild reaction conditions, good reaction directionality and less side reactions; a toxic agent is not required inthe hydrogenation process, and pollutant emission is reduced, thereby being beneficial to protecting the environment; and the catalyst can be recycled, and production cost is reduced, thereby extremely being beneficial to industrial production.

Description

technical field [0001] The present invention relates to the application of Pd catalyst in the production process of hydrogenation of doxycycline, in particular to the application of loaded Pd catalyst in the production process of chiral asymmetric hydrogenation of antibiotic doxycycline intermediate α-6-deoxyoxytetracycline salt, belonging to The field of medicinal chemistry synthesis. Background technique [0002] Doxycycline, also known as doxycycline hydrochloride strong or deoxyoxytetracycline hydrochloride, is mainly used as an antibiotic drug for the treatment of fast purple stain-positive cocci and negative bacillus infections, and can also be used for typhus, scrub typhus, etc. Rickettsia infection is also effective for amoebic dysentery and atypical pneumonia. The current production process of doxycycline (1) uses oxytetracycline as a raw material, which is refined through chlorination, dehydration, hydrogenation, and transformation. Among them, the hydrogenation ...

Claims

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Application Information

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IPC IPC(8): C07C309/60C07C237/26C07C231/12C07C303/22B01J31/22
CPCY02P20/50Y02P20/584
Inventor 徐海伟吴亚姜平娟季明志崔浩朱松林周振陈水库朱成功朱文臣
Owner KAIFENG PHARMA GRP
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