Preparation method of norethindrone acetate

A technology of norethisterone acetate and a synthesis method is applied in the field of drug preparation, can solve the problems of large 3-position acetylenic impurities, is unsuitable for industrial production, difficult to purify and the like, achieves mild reaction, is suitable for industrial production and operation low cost effect

Inactive Publication Date: 2020-11-03
ZHEJIANG SHENZHOU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The method needs to be dehydrated with toluene to produce potassium acetylide, the energy consumption is high, and the 3-position ketone group also undergoes acetylenic reaction, and a large 3-position acetylenated impurity will be obtained, which is difficult to be purified and removed, and the purification is difficult, and This method is not suitable for industrial production

Method used

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  • Preparation method of norethindrone acetate
  • Preparation method of norethindrone acetate
  • Preparation method of norethindrone acetate

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Effect test

Embodiment 1

[0029] A kind of preparation method of norethindrone acetate of embodiment 1 comprises the steps:

[0030] 1) Protection reaction: Add 50g of 19-nor-4-androstenedione (1) into 50ml of methanol, add 250ml of trimethyl orthoformate, 5g of pyridine hydrochloride, control the temperature at 30°C and stir the reaction. After the reaction, add 5ml of triethylamine, cooled to 5°C, filtered and dried to obtain 51.5g of intermediate 2;

[0031] 2) Alkynylation reaction: 51.5g of intermediate (2) obtained in step 1) was added to 750ml of acetone, 100g of potassium tert-butoxide was added, acetylene was introduced, and the reaction was stirred at 0°C. Sulfuric acid aqueous solution neutralized, concentrated, added water for water analysis, and filtered to obtain 53g of intermediate 3.

[0032] 3) Hydrolysis reaction: 53g of intermediate (3) obtained in step 2) was added to 750ml of tetrahydrofuran, and 250ml of 5% hydrochloric acid aqueous solution was added, and the reaction was stirre...

Embodiment 2

[0034] A kind of preparation method of norethindrone acetate of embodiment 2 comprises the steps:

[0035] 1) Protection reaction: Add 50g of 19-nor-4-androstenedione (1) into 500ml of ethanol, add 50ml of triethyl orthoformate, 0.5g of pyridinium hydrobromide, control the temperature at 20°C and stir the reaction. , add 0.5ml triethylamine, cool down to -5°C, filter and dry to obtain 53.0g intermediate 2;

[0036] 2) Alkynylation reaction: 53.0g of intermediate (2) obtained in step 1) is added to 300ml of tetrahydrofuran, 27g of potassium isobutoxide is added, acetylene is passed through, and the reaction is stirred at 20°C under control. After the reaction is completed, use 30% Neutralize with acetic acid aqueous solution, concentrate, add water for water analysis, and filter to obtain 54 g of intermediate 3.

[0037] 3) Hydrolysis reaction: 54g of intermediate (3) obtained in step 2) was added to 1500ml of acetone, 110ml of 10% hydrochloric acid aqueous solution was added,...

Embodiment 3

[0039] A kind of preparation method of norethindrone acetate of embodiment 3 comprises the steps:

[0040] 1) Protection reaction: Add 50g of 19-nor-4-androstenedione (1) into 1000ml of pyrrolidine, add 150ml of triethyl orthoformate, 10g of p-toluenesulfonic acid, and control the temperature at 60°C to stir the reaction. After the reaction, Add 10ml of pyridine, cool down to -10°C, filter and dry to obtain 55.0g of intermediate 2;

[0041]2) Alkynylation reaction: 55.0g of intermediate (2) obtained in step 1) is added in 1650ml of toluene, 275g of potassium ethylate is added, acetylene is passed through, and the reaction is stirred at 50° C. Neutralize, concentrate, add water for water analysis, and filter to obtain 57g of intermediate 3.

[0042] 3) Hydrolysis reaction: 57g of intermediate (3) obtained in step 2) was added to 300ml of methyl tetrahydrofuran, and 29ml of 30% sulfuric acid aqueous solution was added to control the stirring reaction at 0°C. After the reaction ...

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Abstract

The invention discloses a preparation method of norethindrone acetate, and belongs to the technical field of preparation and processing of medicines. According to the method, 19-nor-4-rostenedione isused as an initial raw material, and the norethindrone acetate is prepared through four steps of protection, ethynylation, hydrolysis and esterification. According to the preparation method of norethindrone acetate, the defects of a traditional process are overcome, reaction conditions are mild, and formation of impurities is reduced; the method is high in overall conversion rate, simple and convenient to operate, suitable for industrial production and wide in market prospect.

Description

technical field [0001] The invention relates to the technical field of preparation of medicines, in particular to a preparation method of norethindrone acetate. Background technique [0002] Norethindrone acetate, the English name is Norethisterone Acetate, the chemical name is 17α-ethynyl-17β-hydroxyestr-4-en-3-one 17-acetate, it is a derivative of 19-desmethyltestosterone, and it is a An orally effective progesterone that can inhibit the secretion of luteinizing releasing hormone in the hypothalamus and act on the pituitary gland to reduce its sensitivity to luteinizing releasing hormone, thereby blocking the release of gonadotropin and producing ovulation inhibition, therefore It is mainly used in combination with ethinyl estradiol as a short-acting oral contraceptive. [0003] The synthesis method of norethindrone included in the "National Compilation of Raw Materials Processes" uses 19-nor-4-androstenedione as a starting material to obtain norethindrone by direct acety...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J1/00A61P15/18A61P5/34
CPCA61P5/34A61P15/18C07J1/0096
Inventor 邵振平王荣王炳乾王洪福黄橙橙雷灵芝王友富
Owner ZHEJIANG SHENZHOU PHARMA
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