Process for the preparation of Cetrorelix acetate

1. A process for the preparation of Cetrorelix acetate

comprising:

a) loading first protected amino acid Fmoc-D-Alanine

on a suitable acid sensitive resin to obtain intermediate

using solid phase synthesizer;

b) deprotecting the Fmoc group of intermediate and coupling intermediate with the required amino acids using a suitable coupling agent in the said order, wherein the order of amino acids are Fmoc-D-alanine, Fmoc-L-proline, Fmoc-D-Arginine(Pbf), Fmoc-L-leucine, Fmoc-D-citruline, Fmoc-O-tert-butyl-L-tyrosine, Fmoc-O-tert-butyl-L-serine, D-3-(3′-pyridyl)-D-alanine, Fmoc-D-4-chlorophenyl alanine, N-acetyl-D-3-(2-naphthyl)alanine to form protected peptide intermediate;

c) cleaving protected peptide intermediate from the resin and deprotecting the side chain protecting groups to yield Cetrorelix trifluoro acetate;

d) purifying Cetrorelix trifluoro acetate by Flash chromatography;

e) converting Cetrorelix trifluoro acetate to Cetrorelix acetate by salt exchange method to obtain pure Cetrorelix acetate.

2. The process as claimed in claim 1 , wherein the amino protecting group is selected from group comprising of Fmoc (9-fluorenyl methoxy carbonyl), Boc (tert-butyloxycarbonyl), Cbz (Benzyloxycarbonyl), Bpoc (2-(4-biphenyl)-2-propyloxycarbonyl), 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf).

3. The process as claimed in claim 1 , wherein the hydroxyl protecting group is selected from the group comprising of DMT (dimethoxy trityl), MMT (Methoxytrityl), TRT (Trityl), tert-butyl, t-butoxy carbonyl.

4. The process as claimed in claim 1 , wherein the coupling agent (s) is selected from the group comprising of phosgene, carbonyldiimidazole (CDI), HOBt (Hydroxy benzotriazole), TBTU (0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate), DCC (1,3-dicyclohexylcarbodiimide), DIC (Diisopropylcarbodiimide), HBTU (O-Benzotriazole-N,N,N′ N-tetramethyluronium hexafluoro phosphate), BOP (Benzotriazol-I-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate), PyBOP (Benzotriazol-1-yloxy tri(pyrrolidino)phosphonium hexafluorophosphate), PyBrOP (Bromotri(pyrrolidino)phosphonium hexafluorophosphate), Chlorotri(pyrrolidino)phosphonium hexafluorophosphate (PyCIOP), Ethyl-2-cyano-2-(hydroxyimino) acetate (Oxyma Pure), 0-(6-Chlorobenzotriazold-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TCTU), Ethyl 1,2-dihydro-2-ethoxyquinoline-1-carboxylate(EEDQ),1-Cyano-2-ethoxy-2oxoethyHdenaminooxy)dimethylamino morpholino carbenium hexafluorophosphate (COMU), 3-(Diethoxy-phosphoryloxy)-3H-benzo[d][1,2,3] triazin-4-one (DEPBT), 1-hydroxy 7-azabenzotriazole (HoAt), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidhexafluoro phosphate (HATU), dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium tetra fluoroborate (TATU) or mixtures thereof.

5. The process as claimed in claim 1 , wherein the deprotecting agent used is selected from a group comprising of 4 MP (4-methylpiperidine), PP (piperidine), and PZ (piperazine), pyridine, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), TFA (trifluro acetic acid), TES (Triethyl silane), TIS (Triisopropyl silane), thioanisole, anisole, EDT(Ethanedithiol), phenol, DMS (Dimethyl sulfide), p-cresol, m-cresol or mixtures thereof.

6. A process for the purification of Cetrorelix trifluoroacetate with purity greater than 99.0% by Flash chromatography, which comprises of:

I. mixing Cetrorelix trifluoroacetate salt in a suitable diluent;

II. eluting the sample through cartridge; and

III. isolating pure Cetrorelix trifluoroacetate salt.

7. The process as claimed in claim 6 , wherein the buffer used is selected from trifluoroacetic acid (TFA), o-phosphoric acid (OPA), ammonium acetate buffer or mixtures thereof.

8. A process for the preparation of Cetrorelix acetate with purity greater than 99.0% by converting Cetrorelix trifluoroacetate salt to Cetrorelix acetate salt by desalting and exchanging with suitable salt by passing through resin and acid.

9. The process as claimed in claim 8 , wherein Cetrorelix trifluoroacetate salt is desalted by passing over suitable basic resin selected from macroporous strongly basic anion exchange resin in chloride form with Sty-DVB matrix and Benzyl trimethyl amine as functional group, PolyAPTAC, or poly (acrylamido-N-propyltrimethylammonium chloride) and PolyMAPTAC, or poly[(3-(methacryloylamino)-propyl] trimethylammonium chloride) and suitable acid used is glacial acetic acid.

10. A Cetrorelix acetate having purity greater than 99% by HPLC and wherein one or more of the following

a. less than 1.0% (w/w) of impurity A;

b. less than 1.0% (w/w) of impurity B;

c. less than 1.0% (w/w) of impurity C;

d. less than 1.0% (w/w) of impurity D; and

e. heavy metals less than 10 ppm.