Ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate], processes for its preparation and its use
View Patent ↗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.
1. A salt which is Ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate].
2. The salt as claimed in claim 1 having a chemical purity of greater than or equal to 98%.
3. The salt as claimed in claim 1 having an enantiomeric purity of greater than 83.4% ee.
4. The salt as claimed in claim 3 having an enantiomeric purity of greater than or equal to 95% ee.
5. The salt as claimed in claim 3 having an enantiomeric purity of greater than or equal to 98% ee.
6. 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].
7. The process as claimed in claim 6 , wherein the crystalline form of the salt, ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate], has a higher chemical purity than the starting material (2R)-2-bromo-3-phenylpropionic acid.
8. The process as claimed in claim 7 , the chemical purity of the crystalline form of the salt, ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate], is greater than 92.5 %.
9. The process as claimed in claim 7 , wherein the chemical purity of the crystalline form of the salt, ethane-1,2-di-aminium bis[(2R)-2-bromo-3-phenylpropanoate]is at least 98 %.
10. The process as claimed in claim 6 , wherein the crystalline form of the salt, ethane-1,2-di-aminium bis[(2R)-2-bromo-3-phenylpropanoate], is isolated in process step b) by filtering off, or filtering off with suction, the crystalline salt, washing the crystalline salt with 2-propanol and drying the crystalline salt.
11. A process for the preparation of a compound of the formula (I)
wherein
R 1 is H, C 1 –C 4 -alkyl or an aryl-Y— group, where Y is a single bond or C 1 –C 4 -alkyl,
R 3 is H, acetyl, or benzoyl, and
Z is (CH 2 ) n , —O—, S, NR 6 or N—C(O)R 7 , where n is an integer 0 or 1, R 6 is H, C 1 –C 4 -alkyl or an aryl-Y— group, and R 7 is CF 3 , C 1 –C 10 -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 R 3 of formula (I) is acetyl or benzoyl, then optionally converting a compound of formula (I) to a compound of formula (I), wherein R 3 is H;
or
e) reacting (2R)-2-bromo-3-phenylpropionic acid with a thio reactant to give (S)-2-(R 3 -thio)-3-phenylpropionic acid, wherein R 3 is acetyl or benzoyl; then
f) reacting (S)-2-(R 3 -thio)-3-phenylpropionic acid with a compound of the formula (II) to give a compound of the formula (I); and
g) when R 3 of formula (I) is acetyl or benzoyl, then optionally converting a compound of formula (I) to a compound of formula (I) wherein R 3 is H.
12. The process as claimed in claim 11 wherein the compound of the formula (I) is described by a compound of the formula (Ia)
13. The process as claimed in claim 11 , further comprising isolating (2R)-2-bromo-3-phenylpropionic acid in step (a).
14. The process as claimed in claim 11 wherein the thio reactant is thioacetate.
15. The process as claimed in claim 11 wherein R 3 is acetyl.
16. 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).
17. The process as claimed in claim 16 , further comprising isolating (2R)-2-bromo-3-phenylpropionic acid in step (a).