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Exemestane intermediate and preparation method therefor and application thereof

A technology for exemestane and an intermediate, which is applied in the field of 6-aminomethyl-4-ene-3,17-androstanedione and its preparation, can solve the problem of low total yield, unsuitability for industrial production, Jones reagent is expensive and other problems, to achieve the effect of improving purity and yield

Inactive Publication Date: 2015-11-04
ZHEJIANG MEDICINE CO LTD XINCHANG PHAMACEUTICAL FACTORY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The raw material dehydrotestosterone (6) of this method is more expensive, and the Jones reagent is expensive, pollutes a lot, and the total yield is low, so it is not suitable for industrialized production

Method used

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  • Exemestane intermediate and preparation method therefor and application thereof
  • Exemestane intermediate and preparation method therefor and application thereof
  • Exemestane intermediate and preparation method therefor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Example 1: Preparation of 6-(N-methyl-N-phenyl)-aminomethyl-4-ene-3,17-androstadione (1).

[0043] 20g of raw material androstenedione (2), 130ml of anhydrous tetrahydrofuran, 20ml of absolute ethanol, 20ml of triethyl orthoformate, 0.26g of p-toluenesulfonic acid in a four-necked bottle with a thermometer and mechanical stirring, at 40 The reaction was stirred at °C for 2 hours. 8 g of N-methylaniline and 2.2 g of paraformaldehyde were added, and the stirring reaction was continued for 7 hours. The solvent tetrahydrofuran was evaporated under reduced pressure below 40°C, 60 ml of methanol was added, stirred and dissolved at 40°C, cooled to 0°C, and stirred for 1 hour. After filtering and drying, a light yellow solid (1) was obtained. The crude product was 27.1 g, the liquid phase content was 95.5%, and the yield was 91%.

[0044] Product structure verification (see attached Figure 3-6 ):

[0045] 1 HNMR (δ, ppm, 400MHz, CDCl 3 ):7.239-7.278 (m, 2H, benzene ring); ...

Embodiment 2

[0049] Example 2: Preparation of 6-methylene-4-ene-3,17-androstadione (4) from (1).

[0050] Mix 27 grams of the crude product 6-(N-methyl-N-phenyl)-aminomethyl-4-ene-3,17-androstadione (1) from the previous step, 36.5% hydrochloric acid and 90 milliliters of dichloromethane , stirred at 15-20°C to carry out the elimination reaction, the liquid phase followed the reaction process, and the reaction was completed in about 3 hours. The crude product of androstanedione (4) is 18.0 grams of light yellow powder, the liquid phase content is 92%, and the yield is 87%. Calculated from the raw material (2), the two-step total yield of the new process is 79.5%, and the product content is 92%. Product structure verification (see attached figure 1 ,2):

[0051] 1 HNMR (δ, ppm, 400MHz, CDCl 3 ):5.917(s,1H,CH=C); 5.103,4.999(s,2H,C=CH 2 );2.578-2.610(m,1H);2.462-2.482(m,1H);2.366-2.531(m,2H);1.727-2.172(m,8H);1.572-1.678(m,1H);1.130(s ,3H,CH 3 ); 1.172-1.520(m,4H); 0.920(s,3H,CH 3 )...

Embodiment 3-8

[0053] Example 3-8: Experiment on the preparation conditions of 6-(N-methyl-N-phenyl)-aminomethyl-4-ene-3,17-androstanedione (1).

[0054] The amount of feed, the order of addition, and the reaction conditions are all the same as in Example 1, the difference being that the amount of methanol and the crystallization temperature were changed during the aftertreatment. The results are shown in Table 1.

[0055] Table 1: Using different methanol consumption and crystallization temperature, the results are as follows:

[0056]

[0057]

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Abstract

The invention relates to an exemestane intermediate, particularly 6-(N-methyl-N-phenyl)-amine methyl-4-ene-3,17-androstanedione and a preparation method therefor and application thereof. The structural formula of the exemestane intermediate is a formula shown in the description. The 6-(N-methyl-N-phenyl)-amine methyl-4-ene-3,17-androstanedione prepared by the method provided by the invention can be used for preparing 6-methylene-4-ene-3,17-androstanedione through elimination reaction and the 6-methylene-4-ene-3,17-androstanedione is further oxidized to prepare exemestane. By using the intermediate provided by the invention to prepare exemestane, the purity and yield of exemestane are remarkably improved, the long-term troubled problem on the yield and purity of synthesized exemestane in the field is solved, and industrial practices verify that the exemestane intermediate has extreme value.

Description

Technical field: [0001] The present invention relates to an intermediate of exemestane, specifically 6-(N-methyl-N-phenyl)-aminomethyl-4-ene-3,17-androstadione and its preparation method and application . Background technique: [0002] Exemestane, whose chemical name is 6-methylene-androst-1,4-diene-3,17-dione, is a second-generation aromatase inhibitor, clinically used in the treatment of metastatic breast cancer Cancer and as an adjuvant therapy for early breast cancer, it has definite curative effect, good tolerance and relatively few side effects. There are two main methods of synthesis: [0003] 1. Using androst-4-ene-3,17-dione (2) as a raw material, the Mannich reaction occurs with dimethylamine hydrochloride and paraformaldehyde to prepare the 6-methylene compound (4), and then Exemestane (5) can be prepared by oxidative dehydrogenation with oxidants such as DDQ or chlorobenzoquinone. Its synthetic route is as follows: [0004] [0005] The yield of the first...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J41/00C07J1/00
CPCC07J41/0038C07J1/0011
Inventor 曹瑞伟吴国锋沈润溥宋小华谢斌李炜徐慧婷杨建锋钱诗筠
Owner ZHEJIANG MEDICINE CO LTD XINCHANG PHAMACEUTICAL FACTORY
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