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Intermediate compound for use in preparation of androst amino acid ester and synthesis method thereof

A technology of steroid amino acid ester and synthesis method, which is applied to the preparation of intermediate compounds of estrogen steroid amino acid ester and the field of synthesis thereof, can solve problems such as no reports, and achieve the effects of enhancing anti-tumor activity, simple method and convenient operation.

Inactive Publication Date: 2011-07-20
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

According to literature reports, when the 17th hydroxyl group is replaced by F, the antitumor activity of the compound disappears, and when it is replaced by methylene, the compound maintains the antitumor activity equivalent to that of 2-ME (Abby Ho et al., 2006), so by 2 Structural modification on the 17th position of -ME analogs is more promising to obtain new anti-tumor compounds that not only maintain or enhance anti-tumor activity but also increase its water solubility, thereby improving its bioavailability, but how to prepare this anti-tumor compound no reports

Method used

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  • Intermediate compound for use in preparation of androst amino acid ester and synthesis method thereof
  • Intermediate compound for use in preparation of androst amino acid ester and synthesis method thereof
  • Intermediate compound for use in preparation of androst amino acid ester and synthesis method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0028] Example 1: Preparation of 2-methoxy-3-benzyloxy-17β-hydroxyl-1,3,5(10)-estratriene-17-(N-benzyloxycarbonyl)β-alanine ester

[0029] (1), the preparation of N-benzyloxycarbonyl-beta-alanine

[0030] At -5°C, dissolve 10 mmol of β-alanine in 4.0 ml of 10% sodium hydroxide (NaOH) aqueous solution to obtain a solution, and add 14 mmol (ie 1.8 ml) of benzyl chloroformate while stirring The ester is added dropwise to the solution at a speed of 1 drop / 4 seconds for reaction, and a 10% sodium hydroxide (NaOH) aqueous solution is added dropwise to keep the pH at 8. After the drop is completed, place it at 10°C and stir the reaction After 15 hours, use ninhydrin as the color developing agent to develop color without purple color, then wash with 5ml / time of diethyl ether for 3 times, discard the diethyl ether to obtain the water phase, and adjust the pH of the water phase to 3 with concentrated hydrochloric acid with a mass concentration of 30%. , a milky white solid appeared, an...

Embodiment 2

[0033] Example 2: 16α-ethyl-2-methoxy-3-benzyloxy-17β-hydroxyl-1,3,5(10)-estratriene-17-(N-benzyloxycarbonyl)-L- Preparation of phenylalanine ester

[0034] (1), the preparation of N-benzyloxycarbonyl-L-phenylalanine

[0035] 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,...

Embodiment 3

[0038] Example 3: 16α-(N,N-dimethyl)aminomethyl-2-methoxy-3-benzyloxy-17β-hydroxyl-1,3,5(10)-estratriene-17- Preparation of (N-benzyloxycarbonyl)-L-leucine ester

[0039] (1), the preparation of N-benzyloxycarbonyl-L-leucine

[0040] 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 aci...

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Abstract

The invention relates to an intermediate compound for use in the preparation of androst amino acid ester and a synthesis method thereof, and solves the problem of the preparation of the intermediate compound that is used in the preparation of androst amino acid ester, which is a novel antitumor compound, for keeping or increasing the antitumor activity of androst amino acid ester and increasing the water solubility of androst amino acid ester. The method comprises: dissolving amino acid or small peptides in aqueous solution of sodium hydroxide or saturated solution of sodium bicarbonate; dripping benzyl chloroformate, adding ninhydrin for color developing till no purple color or performing lamina detection; washing with diethyl ether; removing diethyl ether; regulating the pH value of water phase with hydrochloric acid till milky solid appears, extracting with ethyl acetate, washing mixed extract with distilled water and saturated table salt solution, drying by anhydrous magnesium sulfate, performing suction filtration, concentrating and purifying; and dissolving a mixture of a compound A and the mother nucleus of a steride in a reaction solvent, adding a condensing agent and a catalyst, supplying extra condensing agent, performing lamina detection, filtering, concentrating and purifying. In the invention, the method is simple and the operation is convenient.

Description

1. Technical field [0001] The invention relates to the field of medicine, in particular to an intermediate compound for preparing estroamino acid ester 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 of anti-tumor activity. The National Cancer Institute (NCI) of the United States has studied the effect of 2-ME on 60 kinds of tumor cells, and the results show that 2-ME has a significant inhibitory effect on most tumor cells. Studies have also shown that 2-ME has low affinity with estrogen receptors, and it only acts on cells with active proliferation, but has no effect on resting cells, so it has no side effects on normal cells and tissues. The mechanism of action of 2-ME is different from that of traditional antitumor drugs. It can inhibit the growth of some new blood vessels, prevent...

Claims

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Application Information

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IPC IPC(8): C07J1/00
Inventor 施秀芳张振中张崇威张红岭张超锋郭丽芳
Owner ZHENGZHOU UNIV
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