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Problems solved by technology
The method uses dangerous acetylene and heavy-smelling benzenesulfenyl chloride, especially benzenesulfenyl chloride is unstable and difficult to store, and the impurities produced by decomposition participate in the reaction, resulting in low yield, and benzenesulfenyl chloride is harmful to the environment. Large, in addition, long-term high-temperature heating during crystallization will produce new impurities. The total yield of this method is 13.8%-15.8%. The cost is high and it is not suitable for industrial production
Method used
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Embodiment 1、3
[0062] Example 1, Preparation of 3,3-ethylenedioxy-17β-cyano-17α-hydroxyl-19-norpregna-5(10), 9(11)-diene (compound III):
[0063] Add 3-ketal (2.0kg, 6.37mol), methanol (12L), sodium cyanide (343g, 7.0mol) and glacial acetic acid (440ml) into the reaction flask, stir the reaction overnight at room temperature, then pour into 24L ice Stir in water for 30 minutes to filter, wash the filter cake three times with water, and dry to obtain 2.06kg of white powder, mp: 176-178°C (decomposition), yield 95%, HPLC purity above 98%.
[0064] MS: 342(M+1)
[0065] Single crystal tests showed the absolute configuration as follows:
[0066]
Embodiment 2、17
[0067] Example 2, 17α-[(±)1-(1-ethoxy)ethyl]oxy-17β-cyano-3,3-ethylenedioxy-19-norpregna-5(10 ), the preparation of 9(11)-diene:
[0068] Compound III (2.0kg, 5.87mol) obtained in Example 1, THF (14L) and p-toluenesulfonic acid (12.0g, 70mmol) were added to the reaction flask, under ice-water cooling, vinyl ether (668ml, 7.04mol), kept stirring for 4h, added triethylamine (15ml), stirred for 10 minutes, the aqueous phase was extracted with dichloromethane, washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to obtain light yellow or colorless oil 2.43 kg, the yield is quantitative.
[0069] TLC (developer ethyl acetate:petroleum ether=1:5) of the above oil showed two compounds, solids were precipitated after cryogenic freezing, and most of them were obtained by crystallization with 10 times the amount of ethyl acetate petroleum ether (1:2). A highly reactive product, HPLC > 90%. A small amount of the mixture was separated by column...
Embodiment 3、17
[0072] Example 3, 17α-[(±)1-(1-ethoxy)ethyl]oxy-17β-cyano-3,3-ethylenedioxy-19-norpregna-5(10 ), the preparation of 9(11)-diene:
[0073]Add compound III (50.0g, 0.147mol), dichloromethane (500ml) and p-toluenesulfonic acid (0.3g, 1.74mmol) into the reaction flask, under ice water cooling, add vinyl ether (17ml, 0.18mol ), insulated and stirred for 4h, after the reaction was completed, the same treatment was performed to obtain light yellow oil 17α-[(±)1-(1-ethoxy)ethyl]-17β-cyano-3,3-ethylenedioxy- 19-norpregna-5(10), 9(11)-diene 60.7g, quantitative yield.
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Abstract
The invention provides a preparation method of ulipristal acetate (compound I), a key intermediate (compound of formula IV) for preparing the ulipristal acetate and the preparation of the key intermediate. The preparation method comprises the following steps: easy-to-get 3, 3-(ethylenedioxy group)-19-norpregn-5 (10), 9 (11)-diolefin-3, 17-diketone (compound II) and a cyanation reagent are additively reacted to obtain a compound III, then 17alpha-hydroxyl is protected to obtain the compound of formula IV, then the compound is reacted with a methyllithium or methyl Grignard reagent and hydrolyzed through acid to obtain the compound of formula V, the compound is reacted with ethylene glycol through the catalysis of p-toluene sulphonic acid and the like to obtain a compound VI, then the compound VI is epoxidized to obtain an epoxide VII which is then reacted with a Grignard reagent to obtain a compound VIII, a compound IX is obtained after hydrolysis under an acid condition, and finally the ulipristal acetate is obtained through acetylization, which is disclosed in the reaction formula, wherein R in the reaction formula is defined in the specification.
Description
technical field [0001] The invention relates to medicine, in particular to a preparation method of the medicine, in particular to a new preparation method of an antiprogestin and antiglucocorticoid drug ulipristal acetate, and to a new key intermediate and a preparation method thereof. Background technique [0002] Ulipristal acetate; compound I; chemical name: 17α-acetoxy-11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene -3,20-diketone) is a potent antiprogestogen and antiglucocorticoid drug. The structural formula is as follows: [0003] [0004] Ulipristal acetate has been approved for marketing in Europe and the United States. It is used within 5 days after unprotected sex or known or suspected contraceptive failure. It is an effective and safe emergency contraceptive. [0005] Related reports prepare the method for ulipristal acetate compound as follows: [0006] 1, U.S. Patent US4954490 method, (see reaction formula I), [0007] The method uses 3-methoxy-19...
Claims
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