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Preparation method of anastrozole derivatives

A technology of anastrozole and its derivatives, which is applied in the field of drug synthesis, can solve problems such as unreported synthesis methods of anastrozole derivatives, and achieve the effects of good environmental protection, simple operation methods, and important application value

Active Publication Date: 2018-10-02
TLC NANJING PHARMA RANDD CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The synthesis of anastrozole derivatives and related pharmacology and pharmacokinetic studies on anastrozole derivatives can provide test samples for the research and quality testing of anastrozole, and anastrozole derivatives also have good Pharmaceutical prospect, but there is no report on the synthetic method of anastrozole derivatives

Method used

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  • Preparation method of anastrozole derivatives
  • Preparation method of anastrozole derivatives
  • Preparation method of anastrozole derivatives

Examples

Experimental program
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preparation example Construction

[0030] Preparation of compound II: Dissolve 0.01mol 3,5-dimethylbenzeneacetonitrile in dry 20mL tetrahydrofuran, add alkali at -50°C, stir at -50°C for 0.5 hours, the reaction solution changes from a white solution Light yellow solution, add methyl iodide, and react at a certain temperature for 3 hours. Into the reaction solution, 30 mL of saturated ammonium chloride aqueous solution was added dropwise, and extracted twice with 30 mL of ethyl acetate. After the organic phases were combined, the organic phases were dried and evaporated to dryness to obtain a yellow oily compound II.

[0031] The type of base and the experimental data of reaction temperature are as follows:

[0032]

[0033] The results of the above screening experiments show that the best base for this step is lithium diisopropylamide, and the best reaction temperature is 10°C.

[0034] Preparation of compound III: Dissolve 0.009mol of compound II in 9mL of carbon tetrachloride, add 0.009mol of N-bromosuccinimide, ad...

Embodiment 2

[0061] Example 2 A preparation method of anastrozole derivative, which includes the following steps: figure 1 As shown,

[0062] Preparation of compound II: Dissolve 0.01mol 3,5-dimethylbenzeneacetonitrile in dry 20mL tetrahydrofuran, add alkali lithium diisopropylamide at -50°C, and stir at -50°C for 0.5 hours. The solution changed from a white solution to a light yellow solution, and then added methyl iodide, and reacted at 10°C for 3 hours. Into the reaction solution, 30 mL of saturated aqueous ammonium chloride was added dropwise, and extracted twice with 30 mL of ethyl acetate. After the organic phases were combined, the organic phases were dried and evaporated to dryness to obtain yellow oily compound II with a yield of 91.1%. The MS data of compound II is: 174.1[M+1], H 1 -NMR showed 3 hydrogen chemical shifts (6.94 to 7.07) on the benzene ring, and more than 1.7 to 2.4 methyl hydrogen chemical shifts.

[0063]

[0064] Preparation of compound III: Dissolve 0.009 mol of co...

Embodiment 3

[0074] Example 3 Functional Experiment of Anastrozole Derivatives

[0075] The pharmacological activity of the compound VIII anastrozole derivative prepared in Example 2 of the present invention was investigated, and the experimental results showed that the compound VIII anastrozole derivative can reduce the level of estrogen. Clinical observation of 120 postmenopausal breast cancer patients with progesterone receptor positive. Anastrozole derivatives have an effective rate of 42% in tumor shrinkage, and the effective rate of conversion to breast-conserving surgery for menopausal breast cancer patients who require mastectomy 36%, of which gynecological and vascular events in adverse reactions were reduced by 32%, and the recurrence rate was reduced by 35%, showing a good effect.

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Abstract

The invention discloses a preparation method of anastrozole derivatives, and belongs to the field of drug synthesis. The method has the advantages of reasonable process design, strong operability, mild reaction conditions and high yield and can realize industrialized production. With 3,5-dimethylphenylacetonitrile as a raw material, the anastrozole derivatives are synthesized through a six-step reaction. The prepared anastrozole derivatives provide important basis for scientific evaluation of quality, safety and efficacy of anastrozole, have good pharmacological activity, can be developed intodrugs for treatment of postmenopausal women with advanced breast cancer, and have important application value.

Description

Technical field [0001] The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of anastrozole derivatives. Background technique [0002] Breast cancer is a common malignant tumor in women, and its incidence in European and American countries is the first among female malignant tumors. With the changes in diet and living environment, the incidence is rising year by year and tends to be younger, which is a serious threat to women. Physical health and quality of life. Studies have shown that estrin is an important stimulating factor for the occurrence and development of breast cancer, and endocrine therapy is one of the important methods for breast cancer treatment. At present, the clinical endocrine drugs used to treat breast cancer are mainly divided into two categories, namely selective estrogen receptor modulators and aromatase inhibitors. [0003] Anastrozole (anastrozole) is a representative drug of aromatase inhibitors. It is a n...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/08A61P35/00A61P15/14
CPCA61P15/14A61P35/00C07D249/08
Inventor 吴文超曹锋张池崔希林
Owner TLC NANJING PHARMA RANDD CO LTD
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