Ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate], processes for its preparation and its use
AssigneeSanofi-Aventis Deutschland GmbH
InventorsJavier Manero, Tobias Metzenthin, Rainer Gauler
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Abstract
The present invention relates to ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenyl-propanoate], the preparation of ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenyl-propanoate] from (2R)-2-bromo-3-phenylpropionic acid and ethylenediamine in 2-propanol, and the use of ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenyl-propanoate] for the preparation of ACE/NEP inhibitors.
Claims17
A salt which is Ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate].
A process for the preparation of a crystalline salt form of the salt, ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate], which comprises
- a) mixing (2R)-2-bromo-3-phenylpropionic acid, ethylenediamine and 2-propanol, whereupon the salt, ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate], crystallizes out from the solution, and
- b) isolating the crystallized salt, ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate].
A process for the preparation of a compound of the formula (I)
- wherein
- R1 is H, C1–C4-alkyl or an aryl-Y— group, where Y is a single bond or C1–C4-alkyl,
- R3 is H, acetyl, or benzoyl, and
- Z is (CH2)n, —O—, S, NR6 or N—C(O)R7, where n is an integer 0 or 1, R6 is H, C1–C4-alkyl or an aryl-Y— group, and R7 is CF3, C1–C10-alkyl or an aryl-Y— group,
- which comprises
- a) synthesizing (2R)-2-bromo-3-phenylpropionic acid from ethane-1,2-di-aminium bis[(2R)-2-bromo-3-phenylpropanoate] by addition of an acid;
- then
- either
- b) reacting (2R)-2-bromo-3-phenylpropionic acid with a compound of the formula (II)
- to form a 2-bromo-3-phenylpropionamide compound;
- then
- c) reacting the 2-bromo-3-phenylpropionamide compound with a thio reactant to give a compound of the formula (I);
- and
- d) when R3 of formula (I) is acetyl or benzoyl, then optionally converting a compound of formula (I) to a compound of formula (I), wherein R3 is H;
- or
- e) reacting (2R)-2-bromo-3-phenylpropionic acid with a thio reactant to give (S)-2-(R3-thio)-3-phenylpropionic acid, wherein R3 is acetyl or benzoyl;
- then
- f) reacting (S)-2-(R3-thio)-3-phenylpropionic acid with a compound of the formula (II) to give a compound of the formula (I);
- and
- g) when R3 of formula (I) is acetyl or benzoyl, then optionally converting a compound of formula (I) to a compound of formula (I) wherein R3 is H.
A process for the preparation of the compound of the formula (III)
- which comprises
- a) synthesizing (2R)-2-bromo-3-phenylpropionic acid from ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate] by addition of an acid;
- then
- b) reacting (2R)-2-bromo-3-phenylpropionic acid with thioacetate to give (S)-2-(acetylthio)-3-phenylpropionic acid;
- and
- c) reacting (acetylthio)-3-phenylpropionic acid with a compound of the formula (IV)
- to form a compound of formula (V)
- d) converting a compound of formula (V) to a compound of formula (Ill).
Dependencies are inferred from the claim text.