Process for preparing vildagliptin
AssigneeMedichem, S.A.
InventorsStephen Winter, Jordi Bosch, Jordi Puig Serrano, Jose Javier Soto
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Abstract
The present invention relates to a process for preparing vildagliptin of formula (I) with high chemical and enantiomeric purity and compositions comprising vildagliptin. In addition, the present invention relates to (2S,2′S)-1,1′-[[(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)imino]bis(1-oxo-2,1-ethanediyl)]di(2-pyrrolidinecarbonitrile) of formula (II), processes for preparing, and compositions comprising a compound for formula (II). Furthermore, the invention relates to processes for determining the purity of vildagliptin using a compound of formula (II).
Claims23
The compound (2S)-1-[N-(3-hydroxytricyclo[3.3.1.137]dec-1-yl)glycyl]-2-pyrrolidinecarbonitrile of formula (I):
- comprising (2S,2′S)-1,1′-[[(3 -hydroxytricyclo[3.3.1.13,7]dec-1-yl)imino]bis(1-oxo-2,1-ethanediyl)]di(2-pyrrolidinecarbonitrile) of formula (II):
- in an amount up to about 5%.
The compound (2S,2′S)-1,1′-[[(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)imino]bis(1-oxo-2,1-ethanediyl)]di(2-pyrrolidinecarbonitrile) of formula (II) and salts thereof:
The compound (2S)-1-[N-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)glycyl]-2-pyrrolidinecarbonitrile of formula (I):
- comprising less than 0.01% of (2R)-1-[N-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)glycyl]-2-pyrrolidinecarbonitrile.
A process for preparing (2S)-1-[N-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)glycyl]-2-pyrrolidinecarbonitrile of formula (I):
- comprising reacting a compound of formula (III):
- wherein R is hydrogen or an oxygen protecting group, in a solvent comprising at least one ether, with a compound of formula (IV):
- wherein X is halogen and Y is —C(O)NH2 or —CN;
- removing the oxygen protecting group, R, when R is an oxygen protecting group;
- and converting —C(O)NH2 to —CN when Y is —C(O)NH2;
- and optionally crystallizing the compound of formula (I) from a solvent comprising at least one ketone;
- with the proviso that when R of compound (III) is hydrogen, Y of compound (IV) is —C(O)NH2.
A process for preparing (2S)-1-[N-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)glycyl]-2-pyrrolidinecarbonitrile of formula (I):
- comprising reacting a compound of formula (III):
- wherein R is hydrogen or an oxygen protecting group, with a compound of formula (IV):
- wherein X is halogen and Y is —C(O)NH2 or —CN, in the presence of an inorganic base comprising an alkali metal carbonate, in a solvent comprising at least one ester, in the absence of potassium iodide, and at a temperature of less than or about 50° C.;
- removing the oxygen protecting group, R, when R is an oxygen protecting group;
- converting —C(O)NH2 to —CN when Y is —C(O)NH2;
- and optionally crystallizing the compound of formula (I) from a solvent comprising at least one ketone or a mixture of at least one ether and at least one alcohol;
- with the proviso that when R of compound (III) is hydrogen, Y of compound (IV) is —C(O)NH2.
A process for preparing (2S,2′S)-1,1′-[[(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)imino]bis(1-oxo-2,1-ethanediyl)]di(2-pyrrolidinecarbonitrile) of formula (II):
- comprising reacting a compound of formula (III):
- wherein R is hydrogen or an oxygen protecting group, with a compound of formula (IV):
- wherein X is halogen and Y is —C(O)NH2 or —CN;
- removing the oxygen protecting group, R, when R is an oxygen protecting group;
- and converting —C(O)NH2 to —CN when Y is —C(O)NH2.
A method for determining the purity of the compound of formula (I) comprising:
- a) identifying the retention times of compounds of formulae (I) and (II) using high performance liquid chromatography (HPLC);
- b) analyzing a sample comprising a compound of formula (I) using HPLC;
- and c) comparing the areas of the peaks associated with the retention times of compounds of formulae (I) and (II) in the sample, thereby determining the purity of the compound of formula (I).
A method for determining the enantiomeric purity of the compound of formula (I) comprising:
- a) identifying the retention times of the compound of formula (I) and the compound (2R)-1-[N-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)glycyl]-2-pyrrolidinecarbonitrile using high performance liquid chromatography (HPLC);
- b) analyzing a sample comprising the compound of formula (I) using HPLC;
- and c) comparing the areas of the peaks associated with the retention times of the compound of formula (I) and the compound (2R)-1-[N-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)glycyl]-2-pyrrolidinecarbonitrile in the sample, thereby determining the enantiomeric purity of the compound of formula (I).
A method for determining the enantiomeric purity of the compound of formula (I) comprising:
- a) identifying the retention times of the compound of formula (I) and the compound (2R)-1-[N-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)glycyl]-2-pyrrolidinecarbonitrile using high performance liquid chromatography (HPLC) coupled with a Ultra-Violet Spectrometer (UV);
- b) analyzing a sample comprising the compound of formula (I) using HPLC;
- and c) comparing the areas of the peaks associated with the retention times of the compound of formula (I) and the compound (2R)-1-[N-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)glycyl]-2-pyrrolidinecarbonitrile in the sample, thereby determining the enantiomeric purity of the compound of formula (I).
A method for determining the enantiomeric purity of the compound of formula (I) comprising:
- a) identifying the retention times of the compound of formula (I) and the compound (2R)-1-[N-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)glycyl]-2-pyrrolidinecarbonitrile using high performance liquid chromatography (HPLC) coupled with a Mass Spectrometer (MS);
- b) analyzing a sample comprising the compound of formula (I) using HPLC;
- and c) comparing the areas of the peaks associated with the retention times of the compound of formula (I) and the compound (2R)-1-[N-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)glycyl]-2-pyrrolidinecarbonitrile in the sample, thereby determining the enantiomeric purity of the compound of formula (I).
Dependencies are inferred from the claim text.