Ulipristal Acetate Synthesis via Protected Intermediates
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Solution Overview
Problem
Existing methods for preparing Ulipristal acetate are not adaptable to industrialized production due to high costs, low yields, complex reaction conditions, and environmental concerns, making them inefficient and unsustainable.
Innovation Solution
A method utilizing 3-Ethylene Ketal as the starting material, with a series of eight mild reaction steps involving cyanation, hydroxy protection, hydrolysis, ketal formation, oxidation, Grignard reaction, and acetylation, to produce Ulipristal acetate with high purity and yield, suitable for industrial production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If conventional methods (US4954490, US5929262, WO2004078709, CN200780021915.9) are used to prepare Ulipristal acetate, then the product can be obtained, but the total yield is low (0.62%-15.8%), costs are very high, and the production process is complex with many steps
Solution Approach 1:
The invention introduces a preliminary protection step where the 17α-hydroxyl group is protected as a silyl ether derivative before subsequent reactions. This preliminary action prevents unwanted side reactions at the hydroxyl group during cyanation and other transformations, thereby improving overall yield and simplifying the process by avoiding complex purification steps later.
Solution Approach 2:
The invention extracts or removes unnecessary intermediate steps from the conventional synthesis routes. By using the protected intermediate (compound IV) directly in subsequent reactions and eliminating the need for chromatic purification steps, the process is streamlined to achieve higher yields with fewer operations.
2Reliability
If conventional methods are used, then Ulipristal acetate can be produced, but the reaction conditions are complex and strict (requiring ultra low temperature, anhydrous anaerobic conditions, or dangerous reagents)
Solution Approach 1:
The invention changes the reaction parameters from extreme conditions to mild conditions. The cyanation reaction proceeds at room temperature without requiring ultra-low temperatures (-70°C) or anhydrous anaerobic conditions. The use of protected intermediates allows reactions to be conducted in simpler, more operationally convenient conditions while maintaining high reliability.
Solution Approach 2:
The invention replaces expensive and dangerous reagents (such as DBB, phenylsulfenyl chloride, and acetylene) with cheaper, safer, and easier-to-handle alternatives. The protected intermediate approach allows use of standard reagents under conventional conditions, eliminating the need for specialized equipment and expertise.
3Manufacturing precision
If conventional methods are used, then product can be obtained, but environmental pollution is severe (phenylsulfenyl chloride deeply pollutes environments) and safety issues arise (acetylene with great danger)
Solution Approach 1:
The invention converts potentially harmful reagents into benign alternatives. Instead of using phenylsulfenyl chloride which deeply pollutes the environment, the process uses protected intermediates that can be handled under conventional conditions with standard reagents. The protected hydroxyl group prevents formation of harmful byproducts and eliminates the need for dangerous reagents, thereby eliminating environmental pollution while maintaining product quality.
4Reliability
If conventional methods are used, then Ulipristal acetate can be synthesized, but the number of steps is too many (up to ten reactions) and some intermediates need chromatography purification
Solution Approach 1:
The invention merges multiple separate reaction steps into a more streamlined sequence. The protected intermediate (compound IV) serves as a versatile platform that can undergo cyanation, hydrolysis, and other transformations in sequence without requiring isolation and purification of each intermediate. This merging of steps reduces the total number of operations from ten to six while maintaining product stability and quality.
Solution Approach 2:
The invention enables continuous transformation of the protected intermediate through multiple reactions without interrupting the synthetic sequence for chromatography purification. The silyl protecting group remains intact throughout the reaction sequence, allowing continuous useful action to proceed without time-consuming purification steps, thereby reducing the overall number of steps while ensuring product stability.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The method achieves a high yield of Ulipristal acetate with over 99% purity, reducing costs and environmental impact, and simplifying the production process, making it adaptable to industrialized production.
Implementation Method 1
3-β-cyano group (a compound III) is obtained by an addition reaction in an solvent of the 3-Ethylene ketal with a cyanation reagent
Implementation Method 2
17α-hydroxy is protected by dimethyl chloromethyl silicane
Implementation Method 3
the hydroxy protective group reagents are selected from organosilyl matter such as trimethylsilyl lithium, trimethyl chlorosilane and chlorochloromethyl dimethylsilane, or vinyl ether CH2=CHOR1
Implementation Method 4
a compound V is obtained by acid hydrolyzing the compound IV after the compound IV reacts with methyl lithium or a methyl Grignard reagent
Implementation Method 5
a compound V is obtained by acid hydrolyzing the compound IV
Implementation Method 6
3,3,20,20-bis(ethylendioxyl)-17α-hydroxyl-19-norpregna-5(10),9(11)-diene (a compound VI) is obtained after the compound V reacting with ethylene glycol in the presence of p-toluenesulfonic acid
Implementation Method 7
3,3,20,20-bis(ethylendioxyl)-17α-hydroxyl-5α,10α-epoxy-19-norpregna-9(11)-ene (a compound VII) is obtained by oxidizing the compound VI with hydrogen peroxide
Implementation Method 8
3,3,20,20-bis(ethylendioxyl)-5α-17α-dihydroxyl-11β-[4-(N,N-dimethylamino)-phenyl-]-19-norpregna-9(11)-ene (a compound VIII) is obtained by Grignard reaction of the compound VII and 4-(N,N-dimethylamino) phenylmagnesium bromide Grignard reagent
Implementation Method 9
17α-hydroxy-11β-[4-(N,N-dimethylamino)-phenyl-]-19-norpregna-9(11)-diene-3,20-dione (compound IX) is obtained by hydrolyzing the compound VIII under an acid condition
Implementation Method 10
Ulipristal acetate (a compound I) is obtained after the compound IX reacts with an acetylation reagent comprising anhydrous acetic acid, perchloric acid and acetic anhydride
Data Source
AI summary
A method as well as new intermediates for preparing Ulipristal acetate (a compound I) and a method for preparing the new intermediates are provided. The intermediate in a constitutional formula IV is conductive to reacting with methyl lithium or methyl Grignard reagent, a protective group is easy to be removed after a reaction, side reactions are few, a mid-term treatment is simple, the reagents used are cheap, costs are low and the yield is high, if a compound in a constitutional formula V is obtained by the reaction of a compound in a constitutional formula III and the intermediate in the constitutional formula IV, the yield of a two-step reaction is 75%, a purity is above 98%. wherein R is defined in the specification.