Method for synthesizing doxycycline hydrochloride intermediate alpha-6-doxycycline through hydrogenation on basis of silica gel rhodium catalyst

A technology of doxycycline hydrochloride and deoxyoxytetracycline, applied in chemical instruments and methods, preparation of organic compounds, physical/chemical process catalysts, etc., can solve the problems of high process cost, high cost, large amount of catalyst, etc. Achieve high catalytic activity and selectivity, facilitate industrial production, and reduce production costs

Inactive Publication Date: 2014-01-01
HENAN NORMAL UNIV
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  • Summary
  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

At present, the hydrogenation catalyst widely used in factories is the heterogeneous Pd/C/poison method. In this method, the Pd/C is first poisoned by quinoline compounds, and part of its activity is lost, and then used for the hydrogenation reduction of oxytetracycline , so as to achieve stereoselective control, the ratio of α/β in the product is usually 60/30; there are also toxic agents such as methylthiourea added to the reaction system, although there is a certain stereoselectivity, but their carcinogenic toxicity and other belts There is a huge pressure on environmental protection; and the use of homogeneous catalysts such as rhodium complex catalysts can increase the yield to about 85%, and the β-body content is lower than 0.1%, but the catalyst consumption is large and cannot be recycled and reused, and the process cost is

Method used

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  • Method for synthesizing doxycycline hydrochloride intermediate alpha-6-doxycycline through hydrogenation on basis of silica gel rhodium catalyst
  • Method for synthesizing doxycycline hydrochloride intermediate alpha-6-doxycycline through hydrogenation on basis of silica gel rhodium catalyst
  • Method for synthesizing doxycycline hydrochloride intermediate alpha-6-doxycycline through hydrogenation on basis of silica gel rhodium catalyst

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Preparation of silica gel rhodium catalyst

[0027] (1) Silica gel activation

[0028] 3g of silica gel (10-100μm) was calcined and activated in a tube furnace at a heating rate of 2-10°C / min, raised to 120-150°C and kept for 1-5 hours to obtain 2.99g of activated silica gel. Infrared spectrum see figure 1 .

[0029] (2) De-ethanol

[0030] Add 2.99g of activated silica gel and 100ml of tetrahydrofuran into a three-necked flask, ventilate with nitrogen, stir at room temperature for 10-30min, add 6.0g of 3-aminopropyltriethoxysilane, stir at 40°C for 5-7 hours, filter with 10ml The filter cake was rinsed with tetrahydrofuran, and then vacuum-dried at 40° C. for 10 h to obtain 4.25 g of functionalized silica gel. The infrared spectrum of the resulting solid is shown in figure 2 . (3190cm -1 :NH 2 Symmetric stretching vibration, 2980cm -1 :CH 2 Antisymmetric stretching vibration, 2925cm -1 :CH 2 Symmetric stretching vibration, 1615cm -1 :NH 2 Scissor vibrati...

Embodiment 2

[0036] Preparation of silica gel rhodium catalyst

[0037] (1) Silica gel activation

[0038] 3g of silica gel (10-100μm) was calcined and activated in a tube furnace at a heating rate of 2-10°C / min, raised to 280-300°C and kept for 1-5 hours to obtain 2.99g of activated silica gel.

[0039] (2) De-ethanol

[0040] Add 2.99g of activated silica gel and 100ml of tetrahydrofuran into a three-necked flask, ventilate with nitrogen, stir at room temperature for 10-30min, add 1.5g of 3-aminopropyltriethoxysilane, stir for 4 hours at 20°C, filter with suction, and rinse with 10ml of tetrahydrofuran The filter cake was washed, and then vacuum-dried at 40° C. for 10 h to obtain 4.25 g of functionalized silica gel.

[0041] (3) Rhodium complex RhH(CO)[P(C 6 h 5 ) 3 ] 3 preparation of

[0042] Dissolve 0.257g rhodium trichloride trihydrate in 10ml ethanol, dissolve 2.53g triphenylphosphine in 100ml ethanol, mix and stir at room temperature for 15-20min, dissolve 0.75g potassium h...

Embodiment 3

[0046] Preparation of silica gel rhodium catalyst

[0047] (1) Silica gel activation

[0048] 3g of silica gel (10-100μm) was calcined and activated in a tube furnace at a heating rate of 2-10°C / min, raised to 200-250°C and kept for 4-5 hours to obtain 2.99g of activated silica gel.

[0049] (2) De-ethanol

[0050] Add 2.99g of activated silica gel and 100ml of tetrahydrofuran into a three-necked flask, blow nitrogen, stir at room temperature for 10-30min, add 9.0g of 3-aminopropyltriethoxysilane, stir at 70°C for 14 hours, filter with suction, and rinse with 10ml of tetrahydrofuran The filter cake was washed, and vacuum-dried at 40° C. for 10 h to obtain 4.25 g of functionalized silica gel.

[0051] (3) Rhodium complex RhCl(CO)[P(C 6 h 5 ) 3 ] 3 preparation of

[0052] Take 3.5g [Rh(CO) 2 Cl] 2 Dissolve in 10ml of chloroform, take 15g of triphenylphosphine and dissolve in 100ml of chloroform, stir at room temperature, drop the triphenylphosphine solution into the pre...

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Abstract

The invention discloses a method for synthesizing a doxycycline hydrochloride intermediate alpha-6-doxycycline through hydrogenation on the basis of a silica gel rhodium catalyst. The invention adopts the key technical scheme that the method comprises the following steps: (1), a rhodium complex is loaded on functionalization silica gel to prepare the silica gel rhodium catalyst; (2), the prepared silica gel rhodium catalyst is dispersed into an organic solvent, methacycline or the salt of the methacycline is used as a raw material, hydrogen is introduced, and the reaction lasts for 4 to 12 hours under the conditions that the pressure is 0.4 to 2.5 MPa and the reaction temperature is 40 to 120 DEG C, so that the doxycycline hydrochloride intermediate alpha-6-doxycycline is prepared. The silica gel rhodium catalyst in the invention has high catalytic activity and enantio selectivity and can be used for doxycycline hydrochloride production process, the yield can reach more than 60 percent, the content of beta-isomer is only 0.03 percent to 0.10 percent, the reaction condition is mild, the reaction directionality is excellent, side reactions are less, and the catalyst can be reduced, so that the production cost is lowered and the industrial production is facilitated.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a method for synthesizing doxycycline hydrochloride intermediate α-6-deoxyoxytetracycline based on the hydrogenation of a silica gel rhodium catalyst. Background technique [0002] Doxycycline hydrochloride is a good antibacterial drug. It is a long-acting broad-spectrum semi-synthetic tetracycline antibiotic processed by oxytetracycline. It has a broad antibacterial spectrum and strong antibacterial effect. In addition to the effect on Gram-positive bacteria and negative bacteria, it can also inhibit Rickettsia, Mycoplasma pneumoniae, Mycoplasma trachomatis and amoeba. In particular, common bacteria in the respiratory tract of patients with chronic bronchitis are more sensitive to doxycycline. And the medicine has certain antitussive, expectorant and antiasthmatic effects. In addition, the drug is also widely used in veterinary medicine to...

Claims

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Application Information

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IPC IPC(8): C07C237/26C07C231/12B01J31/22
CPCY02P20/584
Inventor 杨林韩会娟张水苗李鹏杨小丽李伟
Owner HENAN NORMAL UNIV
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