Estrogen amino-acid ester compound with antitumor activity as well as synthetic method thereof

Abstract

The invention relates to an estrogen amino-acid ester compound with antitumor activity as well as a synthetic method thereof, effectively solving the preparation problems of the estrogen amino-acid ester compound with the antitumor activity. The synthetic method comprises the following steps of: dissolving amino acids or small molecule peptides to an aqueous solution of sodium hydroxide or a saturated solution of sodium bicarbonate, dripping carbobenzoxy chloride, making the solution react until the solution is not purple by developing with ninhydrin or carrying out film detection; washing with aether, removing aether, adjusting the pH value of the water phase with hydrochloric acid until milky white solid occurs and extracting with ethyl acetate; washing mixed solution with distilled water and saturated common salt solution, drying with anhydrous magnesium sulfate, carrying out suction filtration, concentrating and purifying; and then, mixing the mixed solution with sterides nucleus and dissolving the mixture to a reaction solvent, adding a condensing agent and a catalyst, supplementing an additional condensing agent, carrying out film detection, filtering, concentrating and purifying, dissolving in a dissolving solvent, adding palladium carbon for catalytic hydrogenation, detecting the film, filtering, concentrating and purifying. The estrogen amino-acid ester compound withantitumor activity, provided by the invention, has favorable water solubility and is superior to 2-methoxyestradiol in the tumor cell resistance action.

Description

1. Technical field

[0001] The invention relates to the field of medicine, in particular to an estroamino acid ester compound with antitumor activity and a synthesis method thereof. 2. Background technology

[0002] 2-Methoxyestradiol (2-ME), as a hormone compound, is the end product of estradiol metabolism in the body. In recent years, it has been found that it has a very broad-spectrum anti-tumor activity, which can be used to treat multiple myeloma, prostate cancer, breast cancer, thyroid cancer and other diseases. It has a broad-spectrum anti-tumor effect, and some cancer cells that have developed resistance to 2-ME is very sensitive. The mechanism of 2-ME is different from that of traditional antitumor drugs. Its antitumor mechanism is mainly: inhibiting cell proliferation; inducing apoptosis of tumor cells and endothelial cells; anti-angiogenesis; promoting cell cycle arrest; enhancing the radiation resistance of tumor cells. Sensitivity and more. However, 2-ME has d...

Examples

Embodiment 1

[0034] Example 1: Preparation of 2-methoxy-3,17β-dihydroxy-1,3,5(10)-estratriene-17-β-alanine ester

[0035] (1), the preparation of N-benzyloxycarbonyl-beta-alanine

[0036] At 5°C, 10 mmol of β-alanine was dissolved in 4.0 ml of 10% sodium hydroxide (NaOH) aqueous solution to obtain a solution, and 14 mmol (i.e. 1.8 ml) of benzyl chloroformate was added while stirring. Add dropwise to the solution solution at a speed of 1 drop / 4 seconds for reaction, and add dropwise a 10% sodium hydroxide (NaOH) aqueous solution to keep the pH at 8. After the drop is complete, place it at 10°C and stir for 15 minutes. After 1 hour, use ninhydrin as the color developing agent to develop the color without purple color, then wash with 5ml / time ether for 3 times, discard the ether to obtain the aqueous phase, and adjust the pH of the aqueous phase to 3 with concentrated hydrochloric acid with a mass concentration of 30%. A milky white solid appeared, and the liquid after the milky white solid ...

Embodiment 2

[0041] Example 2: Preparation of 16α-ethyl-2-methoxy-3,17β-dihydroxy-1,3,5(10)-estratriene-17-L-phenylalanine ester

[0042] (1), the preparation of N-benzyloxycarbonyl-L-phenylalanine

[0043] At -3°C, 10 mmol of L-phenylalanine was dissolved in 4.0 ml of 9% sodium hydroxide (NaOH) aqueous solution to obtain a solution, and 14 mmol (i.e. 1.8 ml) of chloroformic acid was added while stirring. The benzyl ester is added dropwise to the solution at a speed of 1 drop / 5 seconds for reaction, and a 9% sodium hydroxide (NaOH) aqueous solution is added dropwise to keep the pH at 8. After the drop is completed, place it at 15°C and stir React for 15 hours, do TLC detection, after the solution is completely reacted, wash 3 times with 5ml / time of diethyl ether, discard the diethyl ether to obtain the water phase, and adjust the pH of the water phase to 2 with concentrated hydrochloric acid with a mass concentration of 35%. , a milky white solid appeared, and the liquid after the milky w...

Embodiment 3

[0048] Example 3: 16α-(N,N-dimethyl)aminomethyl-2-methoxy-3,17β-dihydroxy-1,3,5(10)-estratriene-17-L-leu Preparation of Amino Acid Esters

[0049] (1), the preparation of N-benzyloxycarbonyl-L-leucine

[0050] At 2°C, 10 mmol of L-leucine was dissolved in 4.0 ml of 8% sodium hydroxide (NaOH) aqueous solution to obtain a solution, and 14 mmol (i.e. 1.8 ml) of benzyl chloroformate was added while stirring. Add dropwise to the solution solution at a speed of 1 drop / 6 seconds for reaction, and add dropwise an aqueous solution of sodium hydroxide (NaOH) with a mass concentration of 8% to keep the pH at 9. After the drop is complete, place it at 20°C and stir for 15 minutes. After 1 hour, use ninhydrin as the color developing agent to develop the color without purple color, then wash with 5ml / time of diethyl ether for 3 times, discard the diethyl ether to obtain the aqueous phase, and adjust the pH of the aqueous phase to 1 with concentrated hydrochloric acid with a mass concentrat...

1. Technical field

[0001] The invention relates to the field of medicine, in particular to an estroamino acid ester compound with antitumor activity and a synthesis method thereof. 2. Background technology

[0002] 2-Methoxyestradiol (2-ME), as a hormone compound, is the end product of estradiol metabolism in the body. In recent years, it has been found that it has a very broad-spectrum anti-tumor activity, which can be used to treat multiple myeloma, prostate cancer, breast cancer, thyroid cancer and other diseases. It has a broad-spectrum anti-tumor effect, and some cancer cells that have developed resistance to 2-ME is very sensitive. The mechanism of 2-ME is different from that of traditional antitumor drugs. Its antitumor mechanism is mainly: inhibiting cell proliferation; inducing apoptosis of tumor cells and endothelial cells; anti-angiogenesis; promoting cell cycle arrest; enhancing the radiation resistance of tumor cells. Sensitivity and more. However, 2-ME has d...

Examples

Embodiment 1

[0034] Example 1: Preparation of 2-methoxy-3,17β-dihydroxy-1,3,5(10)-estratriene-17-β-alanine ester

[0035] (1), the preparation of N-benzyloxycarbonyl-beta-alanine

[0036] At 5°C, 10 mmol of β-alanine was dissolved in 4.0 ml of 10% sodium hydroxide (NaOH) aqueous solution to obtain a solution, and 14 mmol (i.e. 1.8 ml) of benzyl chloroformate was added while stirring. Add dropwise to the solution solution at a speed of 1 drop / 4 seconds for reaction, and add dropwise a 10% sodium hydroxide (NaOH) aqueous solution to keep the pH at 8. After the drop is complete, place it at 10°C and stir for 15 minutes. After 1 hour, use ninhydrin as the color developing agent to develop the color without purple color, then wash with 5ml / time ether for 3 times, discard the ether to obtain the aqueous phase, and adjust the pH of the aqueous phase to 3 with concentrated hydrochloric acid with a mass concentration of 30%. A milky white solid appeared, and the liquid after the milky white solid ...

Embodiment 2

[0041] Example 2: Preparation of 16α-ethyl-2-methoxy-3,17β-dihydroxy-1,3,5(10)-estratriene-17-L-phenylalanine ester

[0042] (1), the preparation of N-benzyloxycarbonyl-L-phenylalanine

[0043] At -3°C, 10 mmol of L-phenylalanine was dissolved in 4.0 ml of 9% sodium hydroxide (NaOH) aqueous solution to obtain a solution, and 14 mmol (i.e. 1.8 ml) of chloroformic acid was added while stirring. The benzyl ester is added dropwise to the solution at a speed of 1 drop / 5 seconds for reaction, and a 9% sodium hydroxide (NaOH) aqueous solution is added dropwise to keep the pH at 8. After the drop is completed, place it at 15°C and stir React for 15 hours, do TLC detection, after the solution is completely reacted, wash 3 times with 5ml / time of diethyl ether, discard the diethyl ether to obtain the water phase, and adjust the pH of the water phase to 2 with concentrated hydrochloric acid with a mass concentration of 35%. , a milky white solid appeared, and the liquid after the milky w...

Embodiment 3

[0048] Example 3: 16α-(N,N-dimethyl)aminomethyl-2-methoxy-3,17β-dihydroxy-1,3,5(10)-estratriene-17-L-leu Preparation of Amino Acid Esters

[0049] (1), the preparation of N-benzyloxycarbonyl-L-leucine

[0050] At 2°C, 10 mmol of L-leucine was dissolved in 4.0 ml of 8% sodium hydroxide (NaOH) aqueous solution to obtain a solution, and 14 mmol (i.e. 1.8 ml) of benzyl chloroformate was added while stirring. Add dropwise to the solution solution at a speed of 1 drop / 6 seconds for reaction, and add dropwise an aqueous solution of sodium hydroxide (NaOH) with a mass concentration of 8% to keep the pH at 9. After the drop is complete, place it at 20°C and stir for 15 minutes. After 1 hour, use ninhydrin as the color developing agent to develop the color without purple color, then wash with 5ml / time of diethyl ether for 3 times, discard the diethyl ether to obtain the aqueous phase, and adjust the pH of the aqueous phase to 1 with concentrated hydrochloric acid with a mass concentrat...

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