DE NOVO Synthesis of Cyclocreatine and Subsequent Conversion to Cyclocreatine Phosphate Via a Continuous Flow Reactor (CFR) System
AssigneeNour Heart, Inc.
InventorsSalwa Elgebaly, Robert Todd
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Abstract
A highly efficient and safe N-cyanation and N-phosphorylation reagent for the de novo synthesis of pharmaceutically acceptable cyclocreatine and salts was achieved using trichloroacetonitrile in lieu of highly toxic cyanogen bromide (CNBr) for generating the required cyclocreatine (CCr) intermediates, followed by highly effective N-phosphorylation through pH control using phosphoryl chloride with high conversion to the corresponding cyclocreatine phosphate (CCrP) targets. A continuous flow reactor system was engineered to improve the efficiency of the process and deliver a product with improved yield, safety, and cost efficiency.
Claims11
A process for synthesizing a compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein R5 is a mono-valent cation and R6 is H or a cation, using a continuous flow reactor (CFR) system including at least two flow cells, the method comprising:
- providing an aqueous solution of cyclocreatine intermediate of formula (III), wherein R1 is H and R2 is CH2CO2H or CH2CO2Na or CH2CO2Y, the Y being a carboxyl protecting group;
- providing a first aqueous solution of a base;
- providing phosphoryl chloride;
- mixing the aqueous solution of cyclocreatine intermediate of formula (III), the first aqueous solution of the base, and the phosphoryl chloride in a first flow cell to generate an aqueous solution of cyclocreatine phosphate as a Zwitterion complex in a first stage;
- collecting the aqueous solution of cyclocreatine phosphate in a second flow cell;
- and
- injecting a second aqueous solution of the base to the second flow cell in a second stage so as to control pH value and to generate an aqueous solution of cyclocreatine phosphate disodium dihydrate (CCrP—Na2).
A method for synthesizing a compound of formula (IV) or a pharmaceutically acceptable salt thereof,
- the method comprising:
- reacting a compound of formula (I):
- with a compound of formula (II)
- R4—C≡N (II)
- to generate an intermediate of formula (III):
- or an acceptable salt thereof, and
- reacting the intermediate of formula (III) with phosphoryl chloride by N-phosphorylation to yield final product of formula (IV):
- wherein:
- R1 is H,
- R2 is CH2CO2H or CH2CO2Y, wherein Y is Na, K, or a carboxyl protecting group,
- R3 is CH2CO2H or CH2CO2Y, wherein Y is Na, K, or a carboxyl protecting group,
- R4 is CCl3,
- R5 is a mono-valent cation, and
- R6 is H or a cation.
A method for synthesizing cyclocreatine of formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:
- reacting a compound of formula (I):
- with a compound of formula (II)
- R4—C≡N (II)
- to generate cyclocreatine of formula (III) or an acceptable salt thereof,
- wherein:
- R1 is H,
- R2 is CH2CO2H or CH2CO2Y, wherein Y is Na, K, or a carboxyl protecting group,
- R3 is CH2CO2H or CH2CO2Y, wherein Y is Na, K, or a carboxyl protecting group, and
- R4 is CCl3.
Dependencies are inferred from the claim text.