Process for preparation of prostacyclin derivatives
Inventors
Gurjar, Mukund Keshav • Tripathy, Narendra Kumar • Pramanik, Chinmoy Mriganka
Assignees
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Publication Number
US-10556851-B2
Publication Date
2020-02-11
Expiration Date
Abstract
The invention relates to improved method of synthesis for Treprostinil comprising condensation reaction of the carbonyl compound having allyl, alkyl, crotyl or MEM-protected phenolic hydroxyl group, compound (4) with a hydroxyl-protected alkynol (5) to give the condensation product, compound (6). Subjecting compound (6) to oxidation, reduction, hydroxyl protection and carbonylation, cyclization reactions gave the tricyclic derivative (10). Further reactions comprising reduction, hydrogenation and deprotection of the phenolic and side-chain hydroxyl groups, wherein the sequence and choice of reagents was governed by protecting groups, gave the triol intermediate, compound (14). Cyanoalkylation at phenolic hydroxyl functionality and further hydrolysis yielded the prostacyclin compound, Treprostinil (1) and its pharmaceutically acceptable salts, having desired purity.
Core Innovation
The invention relates to an improved, industrially applicable process for the preparation of Treprostinil (1) and its pharmaceutically acceptable salts by using hydroxyl-protecting phenolic aldehyde substrates protected with easily removable groups. The protected phenolic aldehyde substrates include unsaturated alkyls such as allyl, crotyl, and propargyl, as well as alkyl, arylalkyl, and MEM/MOM protecting groups. A key aspect is that the process proceeds through defined intermediates, culminating in Treprostinil and its pharmaceutically acceptable salts.
The process comprises reacting compound (4) with compound (5) to provide compound (6), oxidizing compound (6) and asymmetrically reducing the resulting compound (7) to provide compound (8), and then treating compound (8) with a hydroxyl protecting reagent to give compound (9). The sequence further includes cyclizing compound (9) in the presence of dicobalt octacarbonyl (Co2(CO)8) to give compound (10), followed by hydrogenating to provide compound (11). Subsequent steps include treating compound (11) with a reducing agent to give compound (12), deprotecting the side-chain hydroxyl group in compound (12) to give compound (13), and treating compound (13) with a deprotecting agent to provide compound (14).
Finally, compound (14) is treated with halogenated acetonitrile to provide compound (15), and compound (15) is converted with alkaline hydrolysis followed by acidification to give Treprostinil (1) and its pharmaceutically acceptable salts. The disclosed embodiments emphasize impurity control and improved yield/purity, and they provide alternate embodiments and deprotection reagent systems, including noble-metal hydrogenation approaches, as well as specified deprotection reagent combinations. The description also includes formation of alkali metal salts such as treprostinil sodium as an example of pharmaceutically acceptable salts.
Claims Coverage
The provided claim set includes three independent claims covering a general Treprostinil preparation route, selected isolated intermediates, and a Treprostinil preparation route where R is an unsaturated alkyl selected from allyl, crotyl, or propargyl. Across the two process independent claims, the coverage is concentrated on a multi-step conversion through numbered intermediates with oxidation/asymmetric reduction, hydroxyl protection and Co2(CO)8 cyclization, hydrogenation/reduction, sequential deprotections, and final cyanoalkylation using halogenated acetonitrile followed by alkaline hydrolysis and acidification.
Treprostinil preparation via hydroxyl-protected phenolic aldehyde and sequential intermediate conversions
A process for the preparation of Treprostinil (1) and its pharmaceutically acceptable salts, comprising reacting compound (4) with compound (5) to provide compound (6), oxidizing compound (6) and asymmetrically reducing resulting compound (7) to provide compound (8), treating compound (8) with a hydroxyl protecting reagent to give compound (9), cyclizing compound (9) in presence of dicobalt octacarbonyl (Co2(CO)8) to give compound (10), and hydrogenating to provide compound (11), treating compound (11) with a reducing agent to give compound (12), deprotecting the side-chain hydroxyl group in compound (12) to give compound (13), treating compound (13) with a deprotecting agent to provide compound (14), and treating compound (14) with halogenated acetonitrile to provide compound (15), converting compound (15) with alkaline hydrolysis followed by acidification to give Treprostinil (1) and its pharmaceutically acceptable salts.
Isolated intermediates selected from specified compound numbers and stereoisomers
A compound selected from the group consisting of compounds (6α), (7α), (8α) and (10α) and stereoisomers thereof.
Treprostinil preparation with R as unsaturated alkyl through phenolic deprotection and side-chain deprotection
A process for the preparation of Treprostinil (1) and its pharmaceutically acceptable salts, comprising reacting compound (4) with compound (5) to give compound (6) wherein R is an unsaturated alkyl selected from allyl, crotyl, or propargyl, oxidizing compound (6) and asymmetrically reducing resulting compound (7) to provide compound (8), treating compound (8) with a hydroxyl protecting reagent to give compound (9), cyclizing compound (9) in presence of dicobalt octacarbonyl (Co2(CO)8) to yield compound (10), deprotecting the phenolic hydroxyl group in compound (10) to give compound (16), hydrogenating compound (16) to give compound (17), reducing compound (17) to give compound (18), and deprotecting the side-chain hydroxyl group of compound (18) to give compound (14), treating compound (14) with halogenated acetonitrile to give compound (15), converting compound (15) with alkaline hydrolysis followed by acidification to give Treprostinil (1) and its pharmaceutically acceptable salts.
Across the independent claims, the inventive core is the multi-step Treprostinil synthetic sequence defined by labeled intermediates and key transformations, including reacting compound (4) and compound (5) to form compound (6), oxidation and asymmetric reduction to compound (8), hydroxyl protection and Co2(CO)8 cyclization to compound (10), hydrogenation and reductions, sequential phenolic and side-chain deprotections to compound (14), and final halogenated acetonitrile treatment with alkaline hydrolysis and acidification to obtain Treprostinil and its pharmaceutically acceptable salts. A separate independent claim covers isolated intermediates selected from compounds (6α), (7α), (8α), and (10α) and their stereoisomers.
Stated Advantages
Improved yield/purity.
Impurity control and regulatory purity limits.
Documented Applications
Preparation of Treprostinil (1) and its pharmaceutically acceptable salts, including formation of alkali metal salts such as treprostinil sodium.
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