Epirubicin hydrochloride intermediate compound V

A technology of epirubicin hydrochloride and compounds, applied in sugar derivatives, sugar derivatives, organic chemistry, etc., can solve problems such as physical and mental health hazards, high production costs, and high material loss rate

Active Publication Date: 2017-05-31
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The organic solvents used in this method, such as propylene oxide, are extremely harmful to the physical and mental health of producers, and the waste liquid produced is difficult to handle, which puts a huge pressure on the environment; at the same time, the final hydrolysis stage adopts multi-step hydrolysis with different pH conditions, it is difficult to precisely control, and thus puts forward extremely high requirements on the operator's technology, so the production cost of this process is huge, the environment is polluted seriously, and it is not conducive to large-scale industrial production
And this process is relatively harsh to the water content of raw material 4'-epidaunorubicin and the humidity during reaction, in the actual application process, it is found that a slight change in water content will cause excessive 4'-epidaunorubicin residues defects, the final product quality is difficult to guarantee, and the material loss rate is extremely high
[0008] The patent US20070142309 provides a variety of synthetic rou...

Method used

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  • Epirubicin hydrochloride intermediate compound V
  • Epirubicin hydrochloride intermediate compound V
  • Epirubicin hydrochloride intermediate compound V

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0109] Preparation of intermediate compound III:

[0110] Add dichloromethane and daunorubicin hydrochloride (daunorubicin hydrochloride:dichloromethane=1:60 (W / V, g / mL)) into a 1000 mL three-necked glass reaction flask. Start stirring, control the temperature at 5°C, and check the dissolution of the material after 10 to 15 minutes. If it is not completely dissolved, continue to stir; Daunorubicin hydrochloride: methyl alcohol: camphorsulfonic acid=1:177:1 (W / V / W, g / mL / g)), after stirring for 1 hour, add trimethyl orthoformate (daunorubicin hydrochloride: Trimethyl orthoformate=1:2 (W / V, g / mL)); after adding, stir for 2 hours; Element: trifluoroacetic anhydride = 1:2 (W / V, g / mL), after the addition is complete, stir for 1 hour.

[0111] After completion of the reaction, methanol (daunorubicin hydrochloride: methanol=1:30 (W / V, g / mL)) was added to the reaction solution, and after stirring for 10 minutes, 8% sodium bicarbonate solution was added to adjust the pH value to 7.0~ ...

Embodiment 2

[0113] Preparation of intermediate compound III:

[0114]Add 1,4-dioxane and daunorubicin hydrochloride (daunorubicin hydrochloride: 1,4-dioxane=1:70 (W / V, g / mL) in the 1000mL three-neck glass reaction flask )). Start stirring, control the temperature at 10°C, and after 10 to 15 minutes, check the dissolution of the material, if it is not completely dissolved, continue stirring; if it is completely dissolved, cool the material liquid to 5°C, and add a methanol solution of camphorsulfonic acid ( Daunorubicin hydrochloride: methyl alcohol: camphorsulfonic acid=1:177:1 (W / V / W, g / mL / g)), after stirring for 1 hour, add trimethyl orthoformate (daunorubicin hydrochloride: Trimethyl orthoformate=1:1 (W / V, g / mL)); after adding, stir for 3 hours; Vegetation: trifluoroacetic anhydride = 1:4 (W / V, g / mL)), after the addition was complete, stir for 1.5 hours.

[0115] After completion of the reaction, add methanol (daunorubicin hydrochloride: methanol=1:40 (W / V, g / mL)) in the reaction so...

Embodiment 3

[0117] Preparation of intermediate compound III:

[0118] Add tetrahydrofuran and daunorubicin hydrochloride (daunorubicin hydrochloride: tetrahydrofuran = 1:50 (W / V, g / mL)) into a 1000 mL three-necked glass reaction flask. Start stirring, control the temperature at 8°C, and check the dissolution of the material after 10 to 15 minutes. If it is not completely dissolved, continue to stir; Daunorubicin hydrochloride: methyl alcohol: camphorsulfonic acid=1:177:1 (W / V / W, g / mL / g)), after stirring for 1 hour, add trimethyl orthoformate (daunorubicin hydrochloride: Trimethyl orthoformate=1:5 (W / V, g / mL)); after adding, stir for 3 hours; Element: trifluoroacetic anhydride = 1:5 (W / V, g / mL)), after the addition was complete, stir for 1.5 hours.

[0119] After completion of the reaction, add methanol (daunorubicin hydrochloride: methanol=1:20 (W / V, g / mL)) in the reaction solution, after stirring for 15 minutes, add 8% sodium bicarbonate solution to adjust the pH value to 7.0~ 8.0. T...

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PUM

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Abstract

The invention provides a novel intermediate and a novel route for synthesizing epirubicin hydrochloride by utilizing the intermediate. The route is simple, cheap and efficient, achieves better energy conservation and emission reduction, and avoids the problems that an intermediate generated by the existing epirubicin hydrochloride synthesis route is water-instable and easy to decompose and a yield of the whole route is low. The route uses a low-cost and easy-to-obtain reagent and adopts a removable selective protection means; generated impurities are few; the purity is high; a yield is high.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to an intermediate compound V of epirubicin hydrochloride. Background technique [0002] Epirubicin hydrochloride, also known as epirubicin hydrochloride, belongs to anthraquinone antibiotics, chemical name: (8S,10S)-10-[(3′-amino-2′,3′,6′-trideoxy-α -L-arabinosyl)-O-]-6,8,11-trihydroxy-8-glycolyl-1-methoxy-7,8,9,10-tetrahydrotetracene-5 ,12-diketone hydrochloride, its structure is shown below: [0003] [0004] It is an isomer of doxorubicin, and its mechanism of action is to intercalate directly between DNA nucleobase pairs, interfere with the transcription process, and prevent the formation of tumor cell mRNA, thereby inhibiting the synthesis of DNA and RNA. In addition, epirubicin hydrochloride also inhibits topoisomerase II. As a cell cycle non-specific drug, it is effective for a variety of transplanted tumors. The clinical efficacy is equal to or slightly ...

Claims

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Application Information

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IPC IPC(8): C07H15/252C07H1/00C07H1/06
CPCC07H1/00C07H1/06C07H15/252
Inventor 刁玉林张贵民
Owner LUNAN PHARMA GROUP CORPORATION
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