Betulinic acid-amino acid derivative, and preparation method and application thereof

A technology of betulinic acid and amino acids, which is applied in the field of medicine and its preparation and application, can solve the problems of seriousness, side effects, and increased risk of osteosarcoma, and achieve the effect of enhanced activity and simple synthesis method

Inactive Publication Date: 2015-10-14
EAST CHINA NORMAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, long-term use of parathyroid hormone will increase the risk of osteosarcoma (Curr.Osteoporos.Rep.2008, 6, 12-16), and only short-term use is recommended clinically (2 years in the United States, 18 months in Europe)
[0004] At present, the commonly used drugs for the treatment of osteoporosis have serious side effects, which are far from meeting the needs. Therefore, it is an urgent need to develop novel, more effective and safer anti-osteoporosis drugs.

Method used

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  • Betulinic acid-amino acid derivative, and preparation method and application thereof
  • Betulinic acid-amino acid derivative, and preparation method and application thereof
  • Betulinic acid-amino acid derivative, and preparation method and application thereof

Examples

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preparation example Construction

[0029] The preparation method of betulinic acid-amino acid derivative shown in formula (I) of the present invention comprises the following steps:

[0030] Step 1, using compound a (XJ-479) as a raw material to acylate with 1.5 times the molar amount of acetic anhydride and 1 times the molar amount of pyridine under nitrogen protection for 0.5 hours to obtain compound b, the solvent is anhydrous tetrahydrofuran, and the reaction temperature is 30 °C, the obtained product was purified by silica gel column chromatography to obtain betulinic acid derivative b with a yield of 87%.

[0031] In step 2, compound b was reacted with 5 times molar amount of oxalyl chloride in dichloromethane under the protection of nitrogen for 18 hours to obtain compound c, which was directly used in the next step without purification.

[0032] Step 3, compound c is mixed with 1.2 times the molar amount of glycine methyl ester hydrochloride, L-alanine methyl ester hydrochloride, L-valine methyl ester h...

Embodiment 1

[0035] Embodiment 1: Preparation of betulinic acid derivative CL-1

[0036]

[0037] Under the protection of nitrogen, 480 mg of compound a was dissolved in a mixed solvent of 10 mL THF, 1.5 times the molar amount of acetic anhydride and 1 times the molar amount of pyridine were added dropwise, the reaction temperature was 30°C, and the reaction was stirred for 0.5 hours. After the reaction was completed, 50 mL of ethyl acetate and 10 mL of saturated aqueous sodium bicarbonate were added, the aqueous layer was extracted twice with 100 mL of ethyl acetate, the organic layers were combined, washed with saturated brine, anhydrous Na 2 SO 4 The crude product obtained by drying and concentrating under reduced pressure was subjected to silica gel column chromatography (PE:EA=2:1) ​​to obtain 302 mg of compound b with a yield of 87%. 1 HNMR (CDCl 3 , 400MHz) δ: 7.94(s, 1H), 4.70(s, 1H), 4.57(s, 1H), 3.00-2.94(m, 1H), 2.53-2.50(m, 1H), 2.31-2.26(m, 1H), 2.14-2.12(m, 1H), 2.01(s,...

Embodiment 2

[0041] Embodiment 2: the preparation of betulinic acid derivative CL-2

[0042] In this example, steps 1, 2, and 3 are the same as in Example 1, that is, compound d(R'=CH 3 ) The synthetic method is similar to embodiment 1, just changes raw material glycine methyl ester hydrochloride into L-alanine methyl ester hydrochloride. Yield 65%. 1 H NMR (400MHz, DMSO) δ7.99(s, 1H), 7.41(d, J=7.4Hz, 1H), 7.19(s, 1H), 6.92(s, 1H), 4.67(s, 1H), 4.55 (s, 1H), 4.19(m, 3H), 2.99(td, J=10.9, 4.2Hz, 2H), 2.60(m, 2H), 2.51(s, 3H), 2.17(d, J=13.0Hz, 1H), 2.07-1.83(m, 3H), 1.77(m, 1H), 1.65(s, 3H), 1.60-1.33(m, 11H), 1.31(s, 3H), 1.30(s, 3H), 1.28 (s, 3H), 1.26(s, 3H), 1.22(s, 2H), 1.20(s, 3H), 1.17-0.98(m, 3H), 0.96(s, 3H), 0.90(s, 3H), 0.71(s, 3H).

[0043] Dissolve 300 mg of compound d in 10 mL of THF, add 0.2 mL of distilled water, add 3 times the molar amount of LiOH, stir at room temperature for two hours, wash twice with 1M HCl after the reaction, wash with 10 mL of saturated saline, ...

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Abstract

The invention discloses a betulinic acid-amino acid derivative represented by a formula (I) and a preparation method thereof. The preparation method comprises the following steps of carrying out acylation reaction on a compound represented by a formula (a), acetic anhydride and pyridine under the protection of nitrogen so as to obtain a compound represented by a formula (b), reacting the compound of the formula (b) with oxalyl chloride so as to obtain a compound represented by a formula (c), then, respectively reacting the compound of the formula (c) with glycino methyl ester, L-alanine methyl ester, L-valine methyl ester, L-isoleucine methyl ester and L-glutamic acid methyl ester so as to obtain a compound represented by a formula (d), and washing, drying and purifying after reacting the compound of the formula (d) with LiOH so as to obtain the betulinic acid-amino acid derivative represented by the formula (I). The preparation method is high in synthetic efficiency and simple and convenient in process. The invention further discloses application of the betulinic acid-amino acid derivative represented by the formula (I) in preparation of a drug for treating osteoporosis; and the betulinic acid-amino acid derivative can be used as an osteoclast precursor differentiation inhibitor and has the obviously increased osteoclast precursor differentiation activity inhibition effect.

Description

technical field [0001] The invention belongs to the technical field of medicine and its preparation and application, and in particular relates to a betulinic acid-sugar derivative, a preparation method thereof and an application in preparation of an anti-osteoporosis medicine. Background technique [0002] Osteoporosis (osteoporosis, OP) is a common and frequently occurring disease worldwide, and it is a "stealth epidemic" that engulfs the health of the elderly. The World Health Organization defines osteoporosis as: a systemic skeletal disease characterized by decreased bone mass and degeneration of bone microstructure, resulting in increased bone fragility and susceptibility to fractures. Because there are no obvious early symptoms, osteoporosis can be called an "invisible killer" and is easily overlooked by people. Once the disease is not treated in time, it may lead to hip fractures, vertebral fractures, etc., which will not only cause a heavy burden on life, but even en...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J71/00A61P19/10
CPCC07J71/0047
Inventor 汤杰刘明耀常亮仇文卫罗剑杨帆石英
Owner EAST CHINA NORMAL UNIV
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