PROCESS FOR THE SYNTHESIS OF 4-((R)-2-{[6-((S)-3-METHOXY-PYRROLIDIN-1-YL)-2-PHENYL-PYRIMIDINE-4-CARBONYL]-AMINO}-3-PHOSPHONO-PROPIONYL)-PIPERAZINE-1-CARBOXYLIC ACID BUTYL ESTER

1 . A process for the manufacturing of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester (COMPOUND), or of a hydrochloride salt thereof

said process comprising the reaction of a compound of formula (I)

wherein R 1 and R 2 represent independently from each other (C 1-4 )alkyl,

with hydrochloride in a mixture comprising an organic solvent and water,

wherein the organic solvent is acetone, toluene, R 3 C(O)OR 4 or any mixture thereof, wherein R 3 represents hydrogen or (C 1-2 )alkyl and R 4 represents hydrogen or (C 1-3 )alkyl; and wherein the amount of water is less than 12 equivalents relative to the amount of compound of formula (I).

2 . A process according to claim 1 , wherein R 1 and R 2 are identical and represent methyl, ethyl, n-propyl, or iso-propyl.

3 . A process according to claim 1 , wherein R 1 and R 2 both represent ethyl.

4 . A process according to claim 1 , wherein the hydrochloride is added to the reaction mixture as hydrochloride gas or is generated in-situ by reaction of an electrophilic chloride source with a protic nucleophile.

5 . A process according to claim 1 , wherein the hydrochloride is generated in-situ by reaction of an electrophilic chloride source with a protic nucleophile.

6 . A process according to claim 1 , wherein the hydrochloride is generated in-situ by reaction of an electrophilic chloride source selected from (C 1-3 )alkyl-C(O)Cl with a protic nucleophile selected from water and (C 1-4 )alkanol.

7 . A process according to claim 1 , wherein the amount of hydrochloride that is added to the reaction mixture as hydrochloride gas; or that is generated in-situ by reaction of an electrophilic chloride source with a protic nucleophile, is between 0.9 and 5.0 equivalents relative to the amount of compound of formula (I).

8 . A process according to claim 1 , wherein the organic solvent is R 3 C(O)OR 4 or any mixture thereof, wherein R 3 represents hydrogen or (C 1-2 )alkyl and R 4 represents hydrogen or (C 1-3 )alkyl.

9 . A process according to claim 1 , wherein the organic solvent is acetic acid.

10 . A process according to claim 1 , wherein the amount of water is between 0.8 and 2.0 equivalents relative to the amount of compound of formula (I).

11 . A process according to claim 1 , wherein the reaction is performed at a temperature between 20° C. and 40° C.

12 . A process according to claim 1 , wherein an anti-solvent is added to the reaction mixture, wherein the anti-solvent is selected from acetone, ethyl acetate or any mixture thereof.

13 . A process according to claim 1 , wherein the process further comprises the step of recrystallizing 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride (COMPOUND-HCl) in crystalline form (I) from a mixture of acetone and water.

14 . A crystalline form of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride, characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 5.7°, 5.9°, and 12.9°.

15 . A crystalline form according to claim 14 , characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 5.1°, 5.7°, 5.9°, 11.0°, and 12.9°.

16 . A crystalline form according to claim 14 , characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 3.7°, 5.1°, 5.7°, 5.9°, 11.0°, 12.9°, 15.2°, 18.3°, 20.2°, and 21.0°.

17 . A process according to claim 1 , wherein R 1 and R 2 both represent ethyl; wherein the hydrochloride is generated in-situ by reaction of an electrophilic chloride source selected from (C 1-3 )alkyl-C(O)Cl with a protic nucleophile selected from water and (C 1-4 )alkanol; and wherein the organic solvent is R 3 C(O)OR 4 or any mixture thereof, wherein R 3 represents hydrogen or (C 1-2 )alkyl and R 4 represents hydrogen or (C 1-3 )alkyl.

18 . A process according to claim 17 , wherein the hydrochloride is generated in-situ by reaction of acetyl chloride with ethanol.

19 . A process according to claim 18 , wherein the amount of water is between 0.8 and 2.0 equivalents relative to the amount of compound of formula (I).

20 . A process according to claim 1 , wherein the process comprises isolating 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester (COMPOUND), or of a hydrochloride salt thereof.

21 . A process according to claim 1 , wherein the reaction mixture is treated after being stirred for a stirring time of at least 3 hours with seeding crystals of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride (COMPOUND-HCl).

22 . A process according to claim 1 , wherein the process comprises isolating 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride (COMPOUND-HCl) in crystalline form (I).

23 . A process according to claim 21 , wherein the process comprises isolating 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride (COMPOUND-HCl) in crystalline form (I).

24 . A process according to claim 17 , wherein the process further comprises the step of recrystallizing 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride (COMPOUND-HCl) in crystalline form (I) from a mixture of acetone and water.

25 . A process according to claim 24 , wherein the process comprises isolating 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride (COMPOUND-HCl) in crystalline form 2.