ITMI20120359A1 - PROCEDURE FOR THE PREPARATION OF USEFUL INTERMEDIATES IN THE PREPARATION OF A VIRAL PROTEASIS INHIBITOR - Google Patents
PROCEDURE FOR THE PREPARATION OF USEFUL INTERMEDIATES IN THE PREPARATION OF A VIRAL PROTEASIS INHIBITOR Download PDFInfo
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- ITMI20120359A1 ITMI20120359A1 IT000359A ITMI20120359A ITMI20120359A1 IT MI20120359 A1 ITMI20120359 A1 IT MI20120359A1 IT 000359 A IT000359 A IT 000359A IT MI20120359 A ITMI20120359 A IT MI20120359A IT MI20120359 A1 ITMI20120359 A1 IT MI20120359A1
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- 238000000034 method Methods 0.000 title claims description 49
- 238000002360 preparation method Methods 0.000 title claims description 23
- 239000000543 intermediate Substances 0.000 title description 9
- 230000003612 virological effect Effects 0.000 title description 4
- 239000003112 inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 83
- 150000003839 salts Chemical class 0.000 claims description 44
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 238000006482 condensation reaction Methods 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 17
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 15
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 15
- BBAWEDCPNXPBQM-GDEBMMAJSA-N telaprevir Chemical compound N([C@H](C(=O)N[C@H](C(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C(=O)N[C@@H](CCC)C(=O)C(=O)NC1CC1)C(C)(C)C)C1CCCCC1)C(=O)C1=CN=CC=N1 BBAWEDCPNXPBQM-GDEBMMAJSA-N 0.000 claims description 14
- 229960002935 telaprevir Drugs 0.000 claims description 14
- 108010017101 telaprevir Proteins 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 13
- -1 acyclic amine Chemical class 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- WAMWSIDTKSNDCU-ZETCQYMHSA-N (2s)-2-azaniumyl-2-cyclohexylacetate Chemical compound OC(=O)[C@@H](N)C1CCCCC1 WAMWSIDTKSNDCU-ZETCQYMHSA-N 0.000 claims description 9
- 230000003213 activating effect Effects 0.000 claims description 9
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- BMTZEAOGFDXDAD-UHFFFAOYSA-M 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium;chloride Chemical compound [Cl-].COC1=NC(OC)=NC([N+]2(C)CCOCC2)=N1 BMTZEAOGFDXDAD-UHFFFAOYSA-M 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- BZUKJNKTPCZNPM-LSDHHAIUSA-N (2s)-2-[[(2s)-2-cyclohexyl-2-(pyrazine-2-carbonylamino)acetyl]amino]-3,3-dimethylbutanoic acid Chemical compound N([C@H](C(=O)N[C@@H](C(C)(C)C)C(O)=O)C1CCCCC1)C(=O)C1=CN=CC=N1 BZUKJNKTPCZNPM-LSDHHAIUSA-N 0.000 claims description 6
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 6
- 239000011591 potassium Substances 0.000 claims description 6
- 229910052700 potassium Inorganic materials 0.000 claims description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- 125000002015 acyclic group Chemical group 0.000 claims description 2
- 150000004292 cyclic ethers Chemical class 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 150000004678 hydrides Chemical class 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- 230000004224 protection Effects 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims 2
- GEJCLNODLCIGDU-NSHDSACASA-N (2s)-2-cyclohexyl-2-(pyrazine-2-carbonylamino)acetic acid Chemical compound N([C@H](C(=O)O)C1CCCCC1)C(=O)C1=CN=CC=N1 GEJCLNODLCIGDU-NSHDSACASA-N 0.000 description 16
- 150000001413 amino acids Chemical class 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 238000000634 powder X-ray diffraction Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 238000010647 peptide synthesis reaction Methods 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- RFIOZSIHFNEKFF-UHFFFAOYSA-N piperazine-1-carboxylic acid Chemical compound OC(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-N 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- NIPZZXUFJPQHNH-UHFFFAOYSA-N pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN=CC=N1 NIPZZXUFJPQHNH-UHFFFAOYSA-N 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- PCTMTFRHKVHKIS-BMFZQQSSSA-N (1s,3r,4e,6e,8e,10e,12e,14e,16e,18s,19r,20r,21s,25r,27r,30r,31r,33s,35r,37s,38r)-3-[(2r,3s,4s,5s,6r)-4-amino-3,5-dihydroxy-6-methyloxan-2-yl]oxy-19,25,27,30,31,33,35,37-octahydroxy-18,20,21-trimethyl-23-oxo-22,39-dioxabicyclo[33.3.1]nonatriaconta-4,6,8,10 Chemical compound C1C=C2C[C@@H](OS(O)(=O)=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2.O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 PCTMTFRHKVHKIS-BMFZQQSSSA-N 0.000 description 1
- NPDBDJFLKKQMCM-SCSAIBSYSA-N (2s)-2-amino-3,3-dimethylbutanoic acid Chemical compound CC(C)(C)[C@H](N)C(O)=O NPDBDJFLKKQMCM-SCSAIBSYSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- SNDPXSYFESPGGJ-BYPYZUCNSA-N L-2-aminopentanoic acid Chemical compound CCC[C@H](N)C(O)=O SNDPXSYFESPGGJ-BYPYZUCNSA-N 0.000 description 1
- SNDPXSYFESPGGJ-UHFFFAOYSA-N L-norVal-OH Natural products CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 208000010710 hepatitis C virus infection Diseases 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000012792 lyophilization process Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- WCYLIGGIKNKWQX-RXMQYKEDSA-N methyl (2s)-2-amino-3,3-dimethylbutanoate Chemical compound COC(=O)[C@@H](N)C(C)(C)C WCYLIGGIKNKWQX-RXMQYKEDSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- BXGTVNLGPMZLAZ-UHFFFAOYSA-N n'-ethylmethanediimine;hydrochloride Chemical compound Cl.CCN=C=N BXGTVNLGPMZLAZ-UHFFFAOYSA-N 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000010963 scalable process Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- NPDBDJFLKKQMCM-UHFFFAOYSA-N tert-butylglycine Chemical compound CC(C)(C)C(N)C(O)=O NPDBDJFLKKQMCM-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
Description
Descrizione del brevetto per invenzione industriale avente per titolo: Description of the patent for industrial invention entitled:
“PROCEDIMENTO PER LA PREPARAZIONE DI INTERMEDI UTILI NELLA PREPARAZIONE DI UN INIBITORE DELLE PROTEASI VIRALI†⠀ œPROCESS FOR THE PREPARATION OF INTERMEDIATES USEFUL IN THE PREPARATION OF A VIRAL PROTEASE INHIBITORâ €
CAMPO DELL’INVENZIONE FIELD OF INVENTION
La presente invenzione riguarda un nuovo procedimento per la preparazione di intermedi sintetici peptidici utili nella preparazione di un inibitore delle proteasi virali. The present invention relates to a new process for the preparation of synthetic peptide intermediates useful in the preparation of a viral protease inhibitor.
STATO DELLA TECNICA STATE OF THE TECHNIQUE
(1S, 3aR, 6aS)-2-[(2S)-2-[[(2S)-2-cicloesil-2-[(2-pirazinilcarbonil) ammino]acetil]ammino]-3,3-dimetilbutanoil]-N-[(1S)-1-[(ciclopropilammino) (osso)acetil]butil]-3,3a,4,5,6,6a-esaidro-1H-ciclopenta[c]pirrolo-3-carbossiammide di formula (I), noto anche come Telaprevir, à ̈ un potente inibitore di proteasi virali ed à ̈ impiegato nel trattamento delle infezioni da epatite C. (1S, 3aR, 6aS) -2 - [(2S) -2 - [[(2S) -2-cyclohexyl-2 - [(2-pyrazinylcarbonyl) amino] acetyl] amino] -3,3-dimethylbutanoyl] -N - [(1S) -1 - [(cyclopropylamino) (oxo) acetyl] butyl] -3,3a, 4,5,6,6a-hexahydro-1H-cyclopenta [c] pyrrole-3-carboxyamide of formula (I) , also known as Telaprevir, is a potent viral protease inhibitor and is used in the treatment of hepatitis C infections.
(R) (R)
N O NO
H (S) O H (S) O
N(S)N H (S) H N (S) N H (S) H
N N (S) (S) N N N N (S) (S) N N
H H.
O O O O O O O O
(I) (THE)
La preparazione di Telaprevir à ̈ riportata in US 7,820,671 e prevede l’assemblaggio di 6 differenti unità strutturali, con la creazione di 5 legami di tipo ammidico come sotto riportato nello Schema The preparation of Telaprevir is reported in US 7,820,671 and involves the assembly of 6 different structural units, with the creation of 5 amide type bonds as shown below in the Scheme
N No.
H (S) (R) OH H (S) (R) OH
2N 2N
OH (S) H (S) OH (S) H (S)
2NOH<H>2NOH <H>
OH2<N>OH2 <N>
N OH N<H>2<N>(S) H(S)OOHO N OH N <H> 2 <N> (S) H (S) OOHO
O OR
O OR
A<B C D E>F A <B C D E> F
Schema Scheme
e la successiva ossidazione dell’ossidrile alcolico nell’unità strutturale di formula E. Le unità strutturali di formula A ed F sono rispettivamente l’acido pirazincarbossilico e la ciclopropilammina. and the subsequent oxidation of the alcoholic hydroxyl in the structural unit of formula E. The structural units of formula A and F are respectively pyrazincarboxylic acid and cyclopropylamine.
Le unità strutturali di formula B, C, D ed E sono invece amminoacidi tutti a configurazione (S). The structural units of formula B, C, D and E are all amino acids with configuration (S).
In particolare, i composti di formula B e C sono rispettivamente la (S)-cicloesilglicina e la (S)-tertleucina, amminoacidi reperibili in commercio. I composti di formula D ed E sono invece amminoacidi di sintesi con struttura più complessa. In particular, the compounds of formula B and C are respectively (S) -cyclohexylglycine and (S) -tertleucine, amino acids available on the market. The compounds of formula D and E are synthetic amino acids with a more complex structure.
La preparazione dei composti di formula D ed E Ã ̈ riportata in US 7,820,671. The preparation of the compounds of formula D and E is reported in US 7,820,671.
La preparazione dell’amminoacido derivato dalla nor-valina di formula E, riportata da tempo in letteratura, può essere effettuata con metodiche note. La preparazione dell’amminoacido chiave di formula D, piuttosto complessa, à ̈ stata descritta in US 7,820,671 ed in US7,776,887. The preparation of the amino acid derived from nor-valine of formula E, reported for some time in the literature, can be carried out with known methods. The rather complex preparation of the key amino acid of formula D has been described in US 7,820,671 and US 7,776,887.
Una volta preparate tutte le unità strutturali costituenti, queste possono essere assemblate ad ottenere Telaprevir, con metodiche note, ad esempio facendo reagire un residuo amminoacidico recante solo la funzione acida libera con un altro residuo recante la funzione amminica libera, in presenza di un agente condensante, secondo quanto previsto dalla classica sintesi peptidica. Once all the constituent structural units have been prepared, they can be assembled to obtain Telaprevir, with known methods, for example by reacting an amino acid residue bearing only the free acid function with another residue bearing the free amino function, in the presence of a condensing agent. , according to what is foreseen by the classic peptide synthesis.
L’assemblaggio delle unità strutturali A-F à ̈ però un punto chiave per l’effettiva industrializzazione del processo poiché la scelta erronea dell’agente condensante, della sequenza di assemblaggio degli amminoacidi o dell’eccessivo, ma purtroppo necessario, impiego dei gruppi protettivi potrebbero inficiare del tutto l’applicabilità su scala industriale della preparazione del peptide. However, the assembly of structural units A-F is a key point for the effective industrialization of the process since the wrong choice of the condensing agent, the amino acid assembly sequence or the excessive, but unfortunately necessary, use protective groups could completely invalidate the applicability of the peptide preparation on an industrial scale.
In US 7,820,671, ad esempio, l’assemblaggio degli amminoacidi à ̈ sequenziale per cui, considerando lo schema qui sotto riportato, il peptide ABC viene condensato prima con D a dare ABCD e successivamente con EF, mentre in US 7,776,887 prima si condensano C e D, selettivamente protetti, e poi nell’ordine B, A ed il residuo EF. In US 7,820,671, for example, the assembly of amino acids is sequential so that, considering the scheme below, the ABC peptide is condensed first with D to give ABCD and subsequently with EF, while in US 7,776,887 C is condensed first and D, selectively protected, and then in the order B, A and the residue EF.
O N O N
H (S) (R) OH H (S) (R) OH
2N 2N
OH H (S)<N>OH H (S) <N>
OH (S)2NOH<H>2OH (S) 2NOH <H> 2
N OH N<H>N OH N <H>
O2<N>(S) H(S) OHO O2 <N> (S) H (S) OHO
O OR
O OR
A<B C D E>F A <B C D E> F
Schema Scheme
In ogni caso, il procedimento sintetico ad ottenere Telaprevir prevede l’utilizzo continuo di gruppi protettivi e di tossici, costosi e complessi sistemi condensanti quali la coppia DCC (dicicloesilcarbodiimmide)/HOBt (1-idrossibenzotriazolo), oppure la coppia EDCI (N-(3-Dimetilaminopropil)-N′-etilcarbodiimmide cloridrato/HOAt (1-idrossi-7-azabenzotriazolo); o peggio ancora dei costosissimi Bop (Benzotriazolilossi)trisdimetilamminofosfonio esafluorofosfato e PyBop(Benzotriazolilossi)trispirrolidinofosfonio esafluorofosfato. In any case, the synthetic process to obtain Telaprevir involves the continuous use of protective groups and toxic, expensive and complex condensing systems such as the DCC (dicyclohexylcarbodiimide) / HOBt (1-hydroxybenzotriazole) pair, or the EDCI (N- (3-Dimethylaminopropyl) -Nâ € ²-ethylcarbodiimide hydrochloride / HOAt (1-hydroxy-7-azabenzotriazole); or even worse than the very expensive Bop (Benzotriazolyloxy) trisdimethylaminophospyrphonium hexafluorophosphate and PyBoxyfluorofoxyfoylofluorohydrophoxy triophoniophoniophonioxyfluoroxyphonioxyfluoroxyfluorohydrofoxy.
In particolare, la sintesi del peptide ABC descritta in US 7,820,671 prevede la reazione della cicloesilglicina (B) protetta come Boc (t-butilossicarbonil) o Cbz (benzilossicarbonil) con l’estere metilico della tertleucina (C) seguita, dopo rimozione del gruppo protettivo, da una seconda condensazione con l’acido piperazincarbossilico (A) sempre impiegando un sistema condensante impiegato per la sintesi peptidica. In particular, the synthesis of the ABC peptide described in US 7,820,671 involves the reaction of cyclohexylglycine (B) protected as Boc (t-butyloxycarbonyl) or Cbz (benzyloxycarbonyl) with the methyl ester of tertleucine (C) followed, after removal of the group protective, by a second condensation with piperazincarboxylic acid (A) always using a condensing system used for peptide synthesis.
Nel caso in cui il gruppo protettivo sia il Boc le due condensazioni sopra riportate avvengono con rese tra il 30 ed 36% (con una resa sull’intero procedimento sintetico solo dell’11%), mentre con l’impiego del gruppo protettivo Cbz risultano rese tra il 52 ed il 69%. Dette rese sono comunque inadeguate per un procedimento efficiente scalabile industrialmente. In the event that the protective group is Boc, the two condensations reported above occur with yields between 30 and 36% (with a yield on the entire synthetic process of only 11%), while with the use of the group protective Cbz are yields between 52 and 69%. These yields are however inadequate for an efficient industrially scalable process.
Chem. Commun.2010, 46, 7918-7920 descrive un procedimento per l’ottimizzazione della sintesi del peptide ABC che prevede la condensazione dell’acido (A) con la cicloesilglicina protetta come metilestere a ottenere il residuo AB che successivamente porta alla formazione del peptide ABC, per condensazione con la tertleucina metilestere senza l’impiego di gruppi protettivi della funzione amminica amminoacidica. Chem. Commun. 2010, 46, 7918-7920 describes a process for the optimization of the synthesis of the ABC peptide which involves the condensation of the acid (A) with the cyclohexylglycine protected as methyl ester to obtain the residue AB which subsequently leads to the formation of ABC peptide, by condensation with tertleucine methyl ester without the use of protective groups of the amino acid function.
La resa riportata di quest’ultimo procedimento à ̈ buona ma purtroppo la sintesi, tutta condotta in dimetilformammide a causa della insolubilità degli amminoacidi impiegati, fa ampiamente uso dei costosi agenti condensanti sopra riportati. The reported yield of this last process is good but unfortunately the synthesis, all carried out in dimethylformamide due to the insolubility of the amino acids used, makes extensive use of the expensive condensing agents listed above.
Esiste quindi la necessità di un metodo alternativo più vantaggioso per preparare Telaprevir su scala industriale, così come i suoi intermedi sintetici, in particolare l’intermedio peptidico ABC. Tale nuovo metodo dovrebbe in particolare essere più scalabile industrialmente, prevedere l’impiego di reagenti più economici, sicuri e di semplice manipolazione, prevedere condizioni blande di reazione ed allo stesso tempo fornire i composti desiderati in alte rese ed elevata purezza chimica. There is therefore a need for a more advantageous alternative method to prepare Telaprevir on an industrial scale, as well as its synthetic intermediates, in particular the peptide intermediate ABC. In particular, this new method should be more industrially scalable, provide for the use of cheaper, safer and easier to handle reagents, provide mild reaction conditions and at the same time provide the desired compounds in high yields and high chemical purity.
BREVE DESCRIZIONE DELLA FIGURA E METODI ANALITICI BRIEF DESCRIPTION OF THE FIGURE AND ANALYTICAL METHODS
L’acido (S)-2-((S)-2-cicloesil-2-(pirazin-2-carbossammido)acetammido)-3,3-dimetilbutanoico in forma cristallina, qui designata come Forma α, avente formula (II) dove i centri stereogenici indicati dall’asterisco * sono entrambi a configurazione assoluta (S), à ̈ stato caratterizzato tramite diffrazione da raggi X da polveri (XRPD) (X-ray powder diffraction). Gli spettri di diffrazione di raggi X (XRPD) sono stati raccolti con il diffrattometro X’Pert PRO Panalytical. Il detector usato à ̈ un detector lineare PSD (X’Celerator). La radiazione usata à ̈ Cu Kα filtrata con monocromatore di Nickel. The (S) -2 - ((S) -2-cyclohexyl-2- (pyrazine-2-carboxamido) acetamido) -3,3-dimethylbutanoic acid in crystalline form, herein designated as Form Î ±, having formula ( II) where the stereogenic centers indicated by the asterisk * are both in absolute configuration (S), it was characterized by X-ray powder diffraction (XRPD). X-ray diffraction spectra (XRPD) were collected with the Xâ € ™ Pert PRO Panalytical diffractometer. The detector used is a PSD (Xâ € ™ Celerator) linear detector. The radiation used is Cu KÎ ± filtered with a Nickel monochromator.
Figura: Spettro XRPD di acido (S)-2-((S)-2-cicloesil-2-(pirazin-2-carbossammido)acetammido)-3,3-dimetilbutanoico in forma cristallina, qui designata come Forma α; dove i picchi principali (espressi in ° in 2Î ̧) si riscontrano a: 5.37, 7.17, 10.38, 10.71, 14.43, 16.38, 17.10, 17.70, 18.09, 18.81, 20.04, 20.49, 20.88, 21.96 e 24.21 Figure: XRPD spectrum of (S) -2 - ((S) -2-cyclohexyl-2- (pyrazine-2-carboxamido) acetamido) -3,3-dimethylbutanoic acid in crystalline form, herein designated as Form Î ±; where the main peaks (expressed in ° in 2Î ̧) are found at: 5.37, 7.17, 10.38, 10.71, 14.43, 16.38, 17.10, 17.70, 18.09, 18.81, 20.04, 20.49, 20.88, 21.96 and 24.21
SOMMARIO DELL’INVENZIONE SUMMARY OF THE INVENTION
È stato qui sorprendentemente trovato che un composto di formula (II), o un suo sale, It has been surprisingly found here that a compound of formula (II), or a salt thereof,
N No.
O OR
H H.
N * OR N * OR
N N N N
H * H *
O O O O
(II) (II)
dove R à ̈ H, oppure un gruppo C1-C6alchile, lineare o ramificato, opzionalmente sostituito; e l’asterisco * indica la presenza di un centro stereogenico, può essere vantaggiosamente preparato mediante un processo comprendente la reazione di un composto di formula (III), o un suo sale, where R is H, or a C1-C6alkyl group, linear or branched, optionally substituted; and the asterisk * indicates the presence of a stereogenic center, it can be advantageously prepared by a process comprising the reaction of a compound of formula (III), or a salt thereof,
OR OR
H2N * H2N *
O OR
(III) (III)
dove R e l’asterisco * sono come sopra definiti, con un composto di formula (IV) where R and the asterisk * are as defined above, with a compound of formula (IV)
N No.
O OR
H H.
N No.
N OR*N OR *
O OR
(IV) (IV)
dove R e l’asterisco * sono come sopra definiti; in presenza di una base, un solvente e DMTMM (i.e. 4-(4,6-dimetossi(1,3,5)triazin-2-il)-4-metilmorfolinio cloruro). where R and the asterisk * are as defined above; in the presence of a base, a solvent and DMTMM (i.e. 4- (4,6-dimethoxy (1,3,5) triazin-2-yl) -4-methylmorpholinium chloride).
Un composto di formula (IV) può inoltre essere vantaggiosamente preparato per reazione di condensazione tra un composto di formula (V) o un suo sale, ed un composto di formula (VI), o un suo sale, A compound of formula (IV) can also be advantageously prepared by condensation reaction between a compound of formula (V) or a salt thereof, and a compound of formula (VI), or a salt thereof,
O N O N
H2N<*>H2N <*>
OH X N OH X N
O OR
(V) (VI) (V) (VI)
dove X Ã ̈ come qui di seguito definito. where X is as defined below.
I procedimenti dell’invenzione prevedono l’uso di reattivi economici e di blande condizioni di reazione e permettono, al contempo, di ottenere tutti i composti desiderati in elevata resa e purezza rispetto ai procedimenti noti. Questi vantaggi si riflettono quindi positivamente anche nel prodotto finale Telaprevir. The processes of the invention provide for the use of cheap reagents and mild reaction conditions and at the same time allow to obtain all the desired compounds in high yield and purity with respect to known processes. These advantages are therefore also positively reflected in the final Telaprevir product.
DESCRIZIONE DETTAGLIATA DELL’INVENZIONE DETAILED DESCRIPTION OF THE INVENTION
Oggetto della presente invenzione à ̈ un procedimento per la preparazione di un composto di formula (II), o un suo sale, The object of the present invention is a process for the preparation of a compound of formula (II), or a salt thereof,
N No.
O OR
H H.
N * OR N * OR
N N N N
H * H *
O O O O
(II) (II)
dove R à ̈ H, oppure un gruppo C1-C6alchile, lineare o ramificato, opzionalmente sostituito; e l’asterisco * indica la presenza di un centro stereogenico a configurazione (R) oppure (S) o una loro miscela racemica; comprendente la reazione di condensazione di un composto di formula (III), o un suo sale, where R is H, or a C1-C6alkyl group, linear or branched, optionally substituted; and the asterisk * indicates the presence of a stereogenic center with (R) or (S) configuration or a racemic mixture thereof; comprising the condensation reaction of a compound of formula (III), or a salt thereof,
OR OR
H2N * H2N *
O OR
(III) (III)
dove R e l’asterisco * sono come sopra definiti, con un composto di formula (IV), o un suo sale, where R and the asterisk * are as defined above, with a compound of formula (IV), or a salt thereof,
N No.
O OR
H H.
N No.
N OR N OR
* *
O OR
(IV) (IV)
dove R e l’asterisco * sono come sopra definiti; e, se il caso, la conversione di un composto di formula (II) in un altro composto di formula (II), e/o, se il caso, la conversione di un acido di formula (II) in un suo sale, e/o, se il caso, la conversione di un sale di un acido di formula (II) nell’acido libero; dove detta reazione di condensazione à ̈ effettuata in presenza di una base, DMTMM (i.e. 4-(4,6-dimetossi(1,3,5)triazin-2-il)-4-metilmorfolinio cloruro),ed in un solvente. where R and the asterisk * are as defined above; and, if applicable, the conversion of a compound of formula (II) to another compound of formula (II), and / or, if applicable, the conversion of an acid of formula (II) into a salt thereof, and / or, if necessary, the conversion of a salt of an acid of formula (II) into the free acid; where said condensation reaction is carried out in the presence of a base, DMTMM (i.e. 4- (4,6-dimethoxy (1,3,5) triazin-2-yl) -4-methylmorpholinium chloride), and in a solvent.
Un sale di un composto di formula (II), (III) o (IV) Ã ̈ tipicamente un suo sale farmaceuticamente accettabile, ad esempio di sodio, potassio o calcio. A salt of a compound of formula (II), (III) or (IV) is typically a pharmaceutically acceptable salt thereof, for example of sodium, potassium or calcium.
Un gruppo C1-C6alchile à ̈ preferibilmente un gruppo C1-C4alchile, preferibilmente metile, etile, isopropile o tert-butile, opzionalmente sostituito da uno o più sostituenti, tipicamente da 1 a 3, scelti indipendentemente tra fenile e alogeno, ad esempio fluoro, cloro e iodio, preferibilmente fluoro. A C1-C6alkyl group is preferably a C1-C4alkyl group, preferably methyl, ethyl, isopropyl or tert-butyl, optionally substituted by one or more substituents, typically from 1 to 3, independently selected from phenyl and halogen, for example fluorine, chlorine and iodine, preferably fluorine.
La reazione di condensazione procede con completa ritenzione della configurazione assoluta. Le configurazioni assolute dei centri stereogenici di un composto finale di formula (II) saranno pertanto le stesse presenti sugli intermedi di formula (III) e (IV) impiegati nella reazione. The condensation reaction proceeds with complete retention of the absolute configuration. The absolute configurations of the stereogenic centers of a final compound of formula (II) will therefore be the same as those present on the intermediates of formula (III) and (IV) used in the reaction.
Una base può essere organica o inorganica. Una base organica può essere scelta ad esempio tra un’ammina terziaria, ciclica o aciclica, ad esempio N-metil-morfolina, DBU (diazabicicloundecene), oppure imidazolo. Una base inorganica può essere scelta ad esempio tra un carbonato di un metallo alcalino o alcalino terroso; un idrossido di un metallo alcalino o alcalino terroso; un idruro di un metallo alcalino o alcalino terroso, ad esempio sodio, potassio oppure calcio, preferibilmente sodio o potassio. A base can be organic or inorganic. An organic base can be chosen, for example, from a tertiary, cyclic or acyclic amine, for example N-methyl-morpholine, DBU (diazabicicloundecene), or imidazole. An inorganic base can be chosen, for example, from a carbonate of an alkaline or alkaline earth metal; a hydroxide of an alkali or alkaline earth metal; a hydride of an alkaline or alkaline earth metal, for example sodium, potassium or calcium, preferably sodium or potassium.
Una base in accordo alla presente invenzione à ̈ preferibilmente N-metil-morfolina. A base according to the present invention is preferably N-methyl-morpholine.
Un solvente in accordo alla presente invenzione può essere ad esempio un solvente polare aprotico, tipicamente un’ammide, ad esempio dimetilformammide, dimetilacetammide o N-metilpirrolidone, preferibilmente dimetilacetammide; acetonitrile o dimetilsolfossido; un etere aciclico o ciclico, ad esempio metil tertbutiletere, tetraidrofurano o diossano; un solvente clorurato, ad esempio, diclorometano, dicloroetano, cloroformio o clorobenzene; un estere, ad esempio acetato di etile o di metile; un solvente apolare aprotico tipicamente toluene; un solvente polare protico, tipicamente un C1-C8alcanolo lineare o ramificato, ad esempio un C1-C5alcanolo; l’acqua od una miscela di due o più, preferibilmente di due o tre, di detti solventi. A solvent according to the present invention can be for example an aprotic polar solvent, typically an amide, for example dimethylformamide, dimethylacetamide or N-methylpyrrolidone, preferably dimethylacetamide; acetonitrile or dimethyl sulfoxide; an acyclic or cyclic ether, for example methyl tertbutyl ether, tetrahydrofuran or dioxane; a chlorinated solvent, for example, dichloromethane, dichloroethane, chloroform or chlorobenzene; an ester, for example ethyl or methyl acetate; a non-polar aprotic solvent typically toluene; a polar protic solvent, typically a linear or branched C1-C8alkanol, for example a C1-C5alkanol; water or a mixture of two or more, preferably two or three, of said solvents.
Un solvente preferito à ̈ etile acetato. A preferred solvent is ethyl acetate.
DMTMM Ã ̈ utilizzato in rapporto almeno stechiometrico rispetto al composto di formula (IV), o un suo sale. DMTMM is used in at least stoichiometric ratio with respect to the compound of formula (IV), or a salt thereof.
La reazione di condensazione può essere condotta ad una temperatura compresa tra circa 0°C e la temperatura di riflusso del solvente, preferibilmente tra circa 10°C e 70°C, più preferibilmente tra circa 15°C e circa 50°C. The condensation reaction can be carried out at a temperature comprised between about 0 ° C and the reflux temperature of the solvent, preferably between about 10 ° C and 70 ° C, more preferably between about 15 ° C and about 50 ° C.
In accordo ad un aspetto particolarmente preferito, la reazione di condensazione può essere effettuata in presenza di N-metilmorfolina ed in acetato di etile. According to a particularly preferred aspect, the condensation reaction can be carried out in the presence of N-methylmorpholine and in ethyl acetate.
Un composto di formula (II) può essere convertito in un altro composto di formula (II) in accordo a metodi noti. Ad esempio un composto di formula (II), dove R à ̈ C1-C6alchile può essere convertito in un composto di formula (II) dove R à ̈ H, per idrolisi della funzione esterea secondo metodiche note. Similmente l’acido carbossilico di formula (II) dove R à ̈ H può essere esterificato in accordo a metodi noti. A compound of formula (II) can be converted into another compound of formula (II) according to known methods. For example, a compound of formula (II), where R is C1-C6alkyl, can be converted into a compound of formula (II) where R is H, by hydrolysis of the ester function according to known methods. Similarly, the carboxylic acid of formula (II) where R à ̈ H can be esterified according to known methods.
Un composto di formula (II) può essere convertito in suo sale, oppure un suo sale convertito nell’acido libero, in accordo a metodi noti. A compound of formula (II) can be converted into its salt, or its salt converted into free acid, according to known methods.
La presente invenzione fornisce inoltre un procedimento per la preparazione di Telaprevir di formula (I), comprendente l’uso come intermedio di un composto di formula (II), o un suo sale, ottenuto in accordo alla presente invenzione. Detto procedimento può essere effettuato secondo quanto riportato in US 7,820,671. The present invention also provides a process for the preparation of Telaprevir of formula (I), comprising the use as intermediate of a compound of formula (II), or a salt thereof, obtained in accordance with the present invention. Said procedure can be carried out according to what is reported in US 7,820,671.
In alternativa, la preparazione di un composto di formula (I) può essere effettuata mediante un procedimento comprende il “coupling†tra un composto di formula (II), o un suo sale,e il tripeptide DEF, in presenza di DMTMM (i.e. 4-(4,6-dimetossi (1,3,5) triazin-2-il)-4-metilmorfolin cloruro). Alternatively, the preparation of a compound of formula (I) can be carried out by means of a process comprising â € œcouplingâ € between a compound of formula (II), or a salt thereof, and the tripeptide DEF, in the presence of DMTMM (i.e. 4- (4,6-dimethoxy (1,3,5) triazin-2-yl) -4-methylmorfolin chloride).
N No.
O (R) O (R)
H H.
N (S) OH N (S) OH
N N (S) (S) O N N (S) (S) O
H N H (S) H H N H (S) H
O ONN O ONN
H (S) H (S)
O O O O
(II) DEF (II) DEF
Il composto di formula (II), in cui R à ̈ H, dove i centri stereogenici indicati dall’asterisco * sono entrambi a configurazione assoluta (S), secondo quanto riportato in US 7,820,671 à ̈ ottenuto mediante liofilizzazione di una soluzione del composto di formula (II) in acetonitrile e acqua. The compound of formula (II), in which R is H, where the stereogenic centers indicated by the asterisk * are both in absolute configuration (S), as reported in US 7,820,671, is obtained by lyophilization of a solution of the compound of formula (II) in acetonitrile and water.
In accordo al procedimento dell’invenzione, l’acido (S)-2-((S)-2-cicloesil-2-(pirazin-2-carbossammido)acetammido)-3,3-dimetilbutanoico, à ̈ invece ottenuto allo stato solido cristallino, in una forma qui designata come Forma α, che presenta uno spettro XRPD dove i picchi principali (espressi in ° in 2Î ̧) si riscontrano a: 5.37, 7.17, 10.38, 10.71, 14.43, 16.38, 17.10, 17.70, 18.09, 18.81, 20.04, 20.49, 20.88, 21.96 e 24.21; come riportato in Figura. According to the process of the invention, the (S) -2 - ((S) -2-cyclohexyl-2- (pyrazin-2-carboxy amido) acetamido) -3,3-dimethylbutanoic acid, is instead obtained in the crystalline solid state, in a form here designated as Form Î ±, which presents an XRPD spectrum where the main peaks (expressed in ° in 2Î ̧) are found at: 5.37, 7.17, 10.38, 10.71, 14.43, 16.38, 17.10, 17.70, 18.09, 18.81, 20.04, 20.49, 20.88, 21.96 and 24.21; as shown in the Figure.
Pertanto un ulteriore oggetto della presente invenzione à ̈ l’acido (S)-2-((S)-2-cicloesil-2-(pirazin-2-carbossammido)acetammido)-3,3-dimetilbutanoico in forma cristallina, in particolare nella forma cristallina qui designata come Forma α. Therefore, a further object of the present invention is (S) -2 - ((S) -2-cyclohexyl-2- (pyrazin-2-carboxamido) acetamido) -3,3-dimethylbutanoic acid in crystalline form, in particular in the crystalline form here designated as Form Î ±.
Come noto, la tecnica di liofilizzazione richiede l’utilizzo di apparecchiature specifiche, che sono costose e non disponibili in tutti gli impianti di produzione dei principi attivi farmaceutici. Inoltre, la tecnica di liofilizzazione à ̈ caratterizzata da una scarsa efficienza energetica, in quanto il solvente (acqua) viene rimosso sotto vuoto a bassa temperatura. Tale metodo viene generalmente utilizzato quando le normali tecniche di isolamento degli intermedi chimici non sono applicabili, soprattutto a causa della scarsa stabilità termica dei prodotti stessi. Inoltre, i composti ottenuti mediante un processo di liofilizzazione sono generalmente in forma amorfa e molto spesso risultano fortemente igroscopici (si veda ad esempio “Polymorphism in Pharmaceuticals Solids†, pag. 538 editore Informa Healthcare USA, Inc, Harry G. Brittain- second edition, (New York, 2009)). È noto che l’assorbimento di acqua durante le reazioni di condensazione ha un effetto negativo sia sulla resa che sulla qualità del prodotto ottenuto. Pertanto l’utilizzo di detto acido di formula (II), in cui R à ̈ H, dove i centri stereogenici indicati dall’asterisco * sono entrambi a configurazione assoluta (S), nella reazione di condensazione col tripeptide DEF sopra descritta, in forma solida cristallina, ed in particolare nella sua Forma α, ne influenza As is known, the freeze-drying technique requires the use of specific equipment, which is expensive and not available in all plants for the production of active pharmaceutical ingredients. Furthermore, the freeze-drying technique is characterized by poor energy efficiency, as the solvent (water) is removed under vacuum at a low temperature. This method is generally used when the normal techniques of isolation of chemical intermediates are not applicable, above all due to the poor thermal stability of the products themselves. Furthermore, the compounds obtained through a lyophilization process are generally in amorphous form and very often are strongly hygroscopic (see for example â € œPolymorphism in Pharmaceuticals Solidsâ €, page 538 publisher Informa Healthcare USA, Inc, Harry G. Brittain- second edition, (New York, 2009)). It is known that the absorption of water during condensation reactions has a negative effect on both the yield and the quality of the product obtained. Therefore the use of said acid of formula (II), in which R is H, where the stereogenic centers indicated by the asterisk * are both with absolute configuration (S), in the condensation reaction with the DEF tripeptide described above, in crystalline solid form, and in particular in its Î ± Form, it influences it
positivamente la sua cinetica superando così i problemi connessi all’uso della positively its kinetics thus overcoming the problems connected with the use of
forma amorfa. amorphous form.
Un composto di formula (II) dove i centri stereogenici indicati A compound of formula (II) where the stereogenic centers indicated
dall’asterisco * sono entrambi a configurazione assoluta (S), in particolare in from the asterisk * are both in absolute configuration (S), in particular in
forma cristallina, preferibilmente nella nuova forma cristallina α, ottenuto in crystalline form, preferably in the new crystalline form Î ±, obtained in
accordo al procedimento dell’invenzione, può essere vantaggiosamente according to the process of the invention, it can be advantageously
utilizzato in un procedimento per la preparazione di Telaprevir di formula (I). used in a process for the preparation of Telaprevir of formula (I).
E’ stato sorprendentemente trovato che un composto di formula (IV), o It has been surprisingly found that a compound of formula (IV), o
un suo sale, come sopra definito, può essere vantaggiosamente preparato in un a salt thereof, as defined above, can be advantageously prepared in a
modo relativamente semplice ed in elevata resa e purezza, mediante un relatively simple way and in high yield and purity, by means of a
procedimento comprendente la condensazione tra l’acido process comprising condensation between acid
piperazincarbossilico, o un suo sale, e la cicloesilglicina o un suo sale. piperazincarboxylic, or a salt thereof, and cyclohexylglycine or a salt thereof.
In accordo ad suo un ulteriore aspetto, l’invenzione quindi fornisce un According to a further aspect, the invention therefore provides a
procedimento per la preparazione di un composto di formula (IV), o un suo sale, process for the preparation of a compound of formula (IV), or a salt thereof,
N No.
O OR
H H.
N No.
N OR*N OR *
O OR
(IV) (IV)
dove R à ̈ H, e l’asterisco * à ̈ come sopra definito; comprendente la where R is H, and the asterisk * is as defined above; comprising the
reazione di condensazione tra un composto di formula (V) o un suo sale, condensation reaction between a compound of formula (V) or a salt thereof,
N No.
X X
N No.
O OR
(V) (V)
dove X Ã ̈ OH, oppure preferibilmente il residuo reattivo di un acido carbossilico; con un composto di formula (VI), o un suo sale where X is OH, or preferably the reactive residue of a carboxylic acid; with a compound of formula (VI), or a salt thereof
O OR
H2N<*>H2N <*>
OH OH
(VI) (YOU)
e, se il caso, la conversione di un composto di formula (IV) dove X à ̈ H, così ottenuto, in un altro composto di formula (IV), dove X à ̈ un gruppo C1-C6alchile, lineare o ramificato, opzionalmente sostituito, oppure in un suo sale. and, if applicable, the conversion of a compound of formula (IV) where X is H, thus obtained, into another compound of formula (IV), where X is a C1-C6alkyl group, linear or branched, optionally replaced, or in one of its salt.
Un sale di un composto di formula (IV), (V) oppure (VI) Ã ̈ tipicamente un sale farmaceuticamente accettabile. A salt of a compound of formula (IV), (V) or (VI) is typically a pharmaceutically acceptable salt.
Il centro stereogenico in un composto di formula (IV) o di un composto di formula (VI) può essere (R) o (S) o una loro miscela racemica. La reazione di condensazione procede con completa ritenzione della configurazione assoluta, quindi la configurazione assoluta del centro stereogenico di un composto di formula (IV) sarà la stessa del composto di formula (VI) impiegato nella reazione. The stereogenic center in a compound of formula (IV) or of a compound of formula (VI) can be (R) or (S) or a racemic mixture thereof. The condensation reaction proceeds with complete retention of the absolute configuration, therefore the absolute configuration of the stereogenic center of a compound of formula (IV) will be the same as the compound of formula (VI) used in the reaction.
Il residuo reattivo di un acido carbossilico di formula (V) à ̈ un buon gruppo uscente, come noto. Esempi di residui reattivi X sono in particolare alogeno, preferibilmente cloro; imidazolo; oppure un gruppo -OCORa, oppure -OCOORa, dove Ra à ̈ un C1-C6alchile, lineare o ramificato, opzionalmente sostituito ad esempio da fenile o da alogeno, ad esempio cloro o fluoro. The reactive residue of a carboxylic acid of formula (V) is a good leaving group, as is known. Examples of reactive residues X are in particular halogen, preferably chlorine; imidazole; or a group -OCORa, or -OCOORa, where Ra is a C1-C6alkyl, linear or branched, optionally substituted for example by phenyl or halogen, for example chlorine or fluorine.
In accordo ad un aspetto preferito, la reazione di condensazione tra un composto di formula (V) ed un composto di formula (VI) può essere effettuata attivando l’acido carbossilico di formula (V) mediante reazione con un agente attivante in un solvente, ed eventualmente in presenza di una base, ad ottenere un suo derivato reattivo,e facendolo successivamente reagire, ad esempio nella stessa miscela di reazione, con la cicloesilglicina (VI), o un suo sale, senza l’impiego di protezioni né sulla funzione acida né su quella amminica della cicloesilglicina. According to a preferred aspect, the condensation reaction between a compound of formula (V) and a compound of formula (VI) can be carried out by activating the carboxylic acid of formula (V) by reaction with an activating agent in a solvent , and possibly in the presence of a base, to obtain a reactive derivative thereof, and subsequently making it react, for example in the same reaction mixture, with cyclohexylglycine (VI), or one of its salt, without the use of protections or on the acid or amino function of cyclohexylglycine.
L’attivazione di un acido carbossilico di formula (V) ad ottenere un suo derivato reattivo può essere ottenuta per reazione con un opportuno agente attivante, in accordo a metodi noti. The activation of a carboxylic acid of formula (V) to obtain a reactive derivative thereof can be obtained by reaction with a suitable activating agent, according to known methods.
Ad esempio, un agente attivante in grado di convertire un composto di formula (V), dove X à ̈ OH, in un altro composto di formula (V), dove X à ̈ cloro à ̈ ad esempio il cloruro di tionile. For example, an activating agent capable of converting a compound of formula (V), where X is OH, into another compound of formula (V), where X is chlorine is for example thionyl chloride.
Un agente attivante in grado di convertire un composto di formula (V),dove X à ̈ OH, in un composto di formula (V), dove X à ̈ -OCORa à ̈ ad esempio un cloruro acilico, ad esempio acetil cloruro o pivaloil cloruro. An activating agent capable of converting a compound of formula (V), where X is OH, into a compound of formula (V), where X is for example an acyl chloride, for example acetyl chloride or pivaloyl chloride.
Un agente attivante in grado di convertire un composto di formula (V), dove X à ̈ OH, in un composto di formula (V), dove X à ̈ -OCOORa à ̈ ad esempio un alchil cloroformiato, ad esempio etil o isopropil cloroformiato An activating agent capable of converting a compound of formula (V), where X is OH, into a compound of formula (V), where X is -OCOORa is for example an alkyl chloroformate, for example ethyl or isopropyl chloroformate
Un agente attivante comune in grado di convertire un composto di formula (V), dove X à ̈ OH, in un composto di formula (V), dove X à ̈ imidazolo à ̈ ad esempio il carbonil diimidazolo (CDI). A common activating agent capable of converting a compound of formula (V), where X is OH, into a compound of formula (V), where X is imidazole is for example carbonyl diimidazole (CDI).
La reazione tra un composto di formula (V), un suo sale, oppure un suo derivato reattivo, ed un composto di formula (VI), o un suo sale, può essere condotta in presenza di una base ed in un solvente scelto ad esempio tra quelli menzionati sopra in relazione alla reazione tra un composto di formula (III) ed un composto di formula (IV). The reaction between a compound of formula (V), a salt thereof, or a reactive derivative thereof, and a compound of formula (VI), or a salt thereof, can be carried out in the presence of a base and in a solvent selected for example among those mentioned above in relation to the reaction between a compound of formula (III) and a compound of formula (IV).
Preferibilmente la reazione di condensazione à ̈ effettuata in tetraidrofurano utilizzando un composto di formula (V) dove X à ̈ imidazolo. Preferably the condensation reaction is carried out in tetrahydrofuran using a compound of formula (V) where X is imidazole.
La reazione di condensazione può essere condotta ad una temperatura compresa tra circa 0°C e la temperatura di riflusso del solvente, preferibilmente tra circa 40°C e circa 70°C. The condensation reaction can be carried out at a temperature between about 0 ° C and the reflux temperature of the solvent, preferably between about 40 ° C and about 70 ° C.
Un composto di formula (IV) dove R à ̈ H può essere convertito in un altro composto di formula (IV) dove R à ̈ come sopra definito in accordo a metodi noti. A compound of formula (IV) where R is H can be converted into another compound of formula (IV) where R is as defined above according to known methods.
Un composto di formula (IV), (V) o (VI) può essere convertito in un suo sale ed analogamente la conversione di un suo sale nel composto libero, possono essere effettuate in accordo a metodi noti. A compound having formula (IV), (V) or (VI) can be converted into one of its salt and similarly the conversion of one of its salt into the free compound can be carried out according to known methods.
Un composto di formula (IV) dove il centro stereogenico indicato dall’asterisco * à ̈ a configurazione assoluta (S), ottenuto in accordo al procedimento di cui alla presente invenzione, può essere vantaggiosamente utilizzato in un procedimento per la preparazione di Telaprevir di formula (I). A compound of formula (IV) where the stereogenic center indicated by the asterisk * is of absolute configuration (S), obtained according to the process of the present invention, can be advantageously used in a process for the preparation of Telaprevir of formula (I).
Pertanto la presente invenzione fornisce inoltre un procedimento per la preparazione di Telaprevir di formula (I), comprendente l’uso come intermedio di un composto di formula (IV), o un suo sale, ottenuto in accordo alla presente invenzione. Therefore, the present invention also provides a process for the preparation of Telaprevir of formula (I), comprising the use as intermediate of a compound of formula (IV), or a salt thereof, obtained in accordance with the present invention.
Un composto di formula (IV), come sopra definito, dove il centro stereogenico indicato dall’asterisco * à ̈ a configurazione assoluta (R) oppure à ̈ una miscela (R,S), ottenuto in accordo al procedimento di cui alla presente invenzione, così analogamente un composto di formula (II), come sopra definito, in cui almeno uno dei centri stereogenici indicati dall’asterisco * à ̈ a configurazione assoluta (R) oppure à ̈ una miscela (R,S), possono essere vantaggiosamente utilizzati in un procedimento per la preparazione di diastereoisomeri di Telaprevir di formula (I). Tali composti trovano utile applicazione in chimica analitica nella determinazione della purezza chimica e stereochimica di Telaprevir. A compound of formula (IV), as defined above, where the stereogenic center indicated by the asterisk * has an absolute configuration (R) or is a mixture (R, S), obtained according to the procedure described in the present invention, thus similarly a compound of formula (II), as defined above, in which at least one of the stereogenic centers indicated by the asterisk * has an absolute configuration (R) or is a mixture (R, S), can be advantageously used in a process for the preparation of Telaprevir diastereomers of formula (I). These compounds find useful application in analytical chemistry in the determination of the chemical and stereochemical purity of Telaprevir.
I seguenti esempi illustrano l’invenzione. The following examples illustrate the invention.
Esempio 1 - Sintesi di acido (S)-2-cicloesil-2-(pirazin-2-carbossammido)-acetico (IV) Example 1 - Synthesis of (S) -2-cyclohexyl-2- (pyrazin-2-carboxamido) -acetic acid (IV)
Ad una sospensione di acido pirazincarbossilico (7,90 g, 63,6 mmol) in tetraidrofurano (40 ml) mantenuto sotto atmosfera inerte a temperatura ambiente, si aggiunge carbonildiimidazolo (10,8 g, 66,8 mmol) e si scalda alla temperatura di 55-60°C per 1,5-2 ore. Si raffredda la soluzione ottenuta a temperatura ambiente e si aggiunge lentamente, gocciolando in circa 2 ore, ad una soluzione di L-cicloesil-glicina sale di potassio (12,4 g, 63,6 mmol) in alcool tert-butilico (120 ml) mantenuta sotto atmosfera inerte e con vigorosa agitazione. Terminata l’aggiunta si lascia reagire a temperatura ambiente per 16-18 ore. La miscela di reazione viene diluita con acqua (100 ml) e concentrata a 45-50°C sotto pressione ridotta per allontanare il solvente organico, alla soluzione acquosa si aggiunge acido cloridrico 5-10% fino pH 1-2 circa. Il solido in sospensione viene filtrato ed essiccato in stufa a 50°C sotto pressione ridotta per 24 ore, si ottengono 15,2 g di prodotto grezzo, che viene impiegato come tale per le reazioni successive, con una resa del 91%. To a suspension of pyrazincarboxylic acid (7.90 g, 63.6 mmol) in tetrahydrofuran (40 ml) maintained under an inert atmosphere at room temperature, carbonyldiimidazole (10.8 g, 66.8 mmol) is added and heated to temperature of 55-60 ° C for 1.5-2 hours. The solution obtained is cooled to room temperature and added slowly, dropping in about 2 hours, to a solution of L-cyclohexyl-glycine potassium salt (12.4 g, 63.6 mmol) in tert-butyl alcohol (120 ml ) maintained under an inert atmosphere and with vigorous stirring. Once the addition is complete, it is left to react at room temperature for 16-18 hours. The reaction mixture is diluted with water (100 ml) and concentrated at 45-50 ° C under reduced pressure to remove the organic solvent, 5-10% hydrochloric acid up to pH 1-2 is added to the aqueous solution. The solid in suspension is filtered and dried in an oven at 50 ° C under reduced pressure for 24 hours, 15.2 g of crude product are obtained, which is used as such for the subsequent reactions, with a yield of 91%.
<1>H-NMR 300 MHz, Î ́ (DMSO-d6): 9,18 (d, 1H); 8,88 (d, 1H); 8,76 (dd, 1H); 8,46 (bd, 1H); 4,38 (dd, 1H); 1,90 (m, 1H); 1,74-1,50 (m, 5H); 1,30-0,98 (m, 5H). <1> H-NMR 300 MHz, Î ́ (DMSO-d6): 9.18 (d, 1H); 8.88 (d, 1H); 8.76 (dd, 1H); 8.46 (bd, 1H); 4.38 (dd, 1H); 1.90 (m, 1H); 1.74-1.50 (m, 5H); 1.30-0.98 (m, 5H).
Esempio 2 - Sintesi di (S)-2-((S)-2-cicloesil-2-(pirazin-2-carbossammido)-3,3-dimetilbutanoato di metile (II) Example 2 - Synthesis of (S) -2 - ((S) -2-cyclohexyl-2- (pyrazine-2-carboxamido) -3,3-dimethylbutanoate of methyl (II)
Alla soluzione ottenuta miscelando acido (S)-2-cicloesil-2-(pirazin-2-carbossammido)-acetico (20,0 g, 76,0 mmol), L-tert-leucina metilestere (11,0 g, 76,0 mmol) e N-metil-morfolina (23,1 g, 228 mmol) in etile acetato (400 ml) e mantenuta sotto atmosfera inerte, si aggiunge 4-(4,6-dimetossi-1,3,5-triazin-2-il)-4-metilmorfolina cloridrato (23,1 g, 83,6 mmol) a temperatura ambiente e si lascia reagire per 2-3 ore. Si spegne la miscela di reazione aggiungendo una soluzione acquosa di acido cloridrico 1M (300 ml), si separano le fasi e si lava la fase organica con una soluzione di acido cloridrico 1 M (200 ml), successivamente con una soluzione satura di sodio bicarbonato (2x200 ml) e infine con una soluzione satura di sodio cloruro (100 ml). La fase organica anidrificata con sodio solfato viene concentrata a residuo, si ottiene un prodotto grezzo con una purezza HPLC del 98%, solido bianco di 28,7g, con una resa del 96%. To the solution obtained by mixing (S) -2-cyclohexyl-2- (pyrazine-2-carboxamido) -acetic acid (20.0 g, 76.0 mmol), L-tert-leucine methyl ester (11.0 g, 76, 0 mmol) and N-methyl-morpholine (23.1 g, 228 mmol) in ethyl acetate (400 ml) and maintained under an inert atmosphere, 4- (4,6-dimethoxy-1,3,5-triazin- 2-yl) -4-methylmorpholine hydrochloride (23.1 g, 83.6 mmol) at room temperature and left to react for 2-3 hours. The reaction mixture is quenched by adding an aqueous solution of 1M hydrochloric acid (300 ml), the phases are separated and the organic phase is washed with a 1 M hydrochloric acid solution (200 ml), subsequently with a saturated solution of sodium bicarbonate (2x200 ml) and finally with a saturated sodium chloride solution (100 ml). The organic phase anhydrified with sodium sulphate is concentrated to a residue, a crude product with an HPLC purity of 98% is obtained, a white solid of 28.7g, with a yield of 96%.
<1>H-NMR 300 MHz, Î ́ (CDCl3): 9,40 (d, 1H); 8,69 (d, 1H); 8,49 (dd, 1H); 8,30 (bd, J=9Hz, 1H); 6,96 (bd, J=9Hz, 1H); 4,63 (dd, 1H); 4,41 (d, J=9Hz, 1H); 3,68 (s, 3H); 1,85-1,55 (m, 6H); 1,18-1,02 (m, 5H); 0,87 (s, 9H). <1> H-NMR 300 MHz, Î ́ (CDCl3): 9.40 (d, 1H); 8.69 (d, 1H); 8.49 (dd, 1H); 8.30 (bd, J = 9Hz, 1H); 6.96 (bd, J = 9Hz, 1H); 4.63 (dd, 1H); 4.41 (d, J = 9Hz, 1H); 3.68 (s, 3H); 1.85-1.55 (m, 6H); 1.18-1.02 (m, 5H); 0.87 (s, 9H).
<13>C-NMR 100 MHz, Î ́ (CDCl3): 171,22; 170,23; 162,55; 146,98; 144,10; 143,70; 142,29; 54,74; 57,58; 54,85; 51,35; 40,26; 34,17; 29,11; 28,33; 26,09; 25,60; 25,41. <13> C-NMR 100 MHz, Î ́ (CDCl3): 171.22; 170.23; 162.55; 146.98; 144.10; 143.70; 142.29; 54.74; 57.58; 54.85; 51.35; 40.26; 34.17; 29.11; 28.33; 26.09; 25.60; 25.41.
MS(ES<+>): m/z 413 [M+Na]<+>. MS (ES <+>): m / z 413 [M + Na] <+>.
Esempio 3 - Sintesi di acido (S)-2-((S)-2-cicloesil-2-(pirazin-2carbossammido)acetammido)-3,3-dimetilbutanoico (II) Example 3 - Synthesis of (S) -2 - ((S) -2-cyclohexyl-2- (pyrazine-2carboxamido) acetamido) -3,3-dimethylbutanoic acid (II)
Ad una soluzione di (S)-2 -((S)-2-cicloesil-2-(pirazin-2-carbossammido)-3,3-dimetilbutanoato di metile (28,7 g, 73,5 mmol) in metanolo (150 ml) mantenuta sotto atmosfera inerte, si aggiunge una soluzione acquosa di sodio idrossido 1M (440 ml, 440 mmol), la miscela viene riscaldata a 40-45°C e mantenuta in agitazione per 24 ore. Si acidifica con acido cloridrico 37% fino pH 1-2 e si estrae con etile acetato (3x200 ml), le fasi organiche riunite sono lavate con una soluzione satura di sodio cloruro (200 ml) anidrificate con sodio solfato e concentrate a residuo. Il grezzo ottenuto viene ripreso con etile acetato e scaldato alla temperatura di riflusso per circa un’ora, si raffredda in 4-5 ore fino a 0-5°C e si filtra il solido lavando con etile acetato (3x50 ml). Si essicca il solido a 45-50°C a pressione ridotta e si ottengono 26,5 g di prodotto cristallino con una purezza HPLC del 99,7% e una resa del 95%. To a solution of methyl (S) -2 - ((S) -2-cyclohexyl-2- (pyrazine-2-carboxamido) -3,3-dimethylbutanoate (28.7 g, 73.5 mmol) in methanol ( 150 ml) maintained under an inert atmosphere, an aqueous solution of sodium hydroxide 1M (440 ml, 440 mmol) is added, the mixture is heated to 40-45 ° C and stirred for 24 hours. It is acidified with 37% hydrochloric acid up to pH 1-2 and extracted with ethyl acetate (3x200 ml), the combined organic phases are washed with a saturated sodium chloride solution (200 ml), anhydrified with sodium sulphate and concentrated to a residue. The crude obtained is taken up with ethyl acetate and heated at reflux temperature for about an hour, it is cooled in 4-5 hours to 0-5 ° C and the solid is filtered by washing with ethyl acetate (3x50 ml). The solid is dried at 45-50 ° C at reduced pressure and 26.5 g of crystalline product are obtained with an HPLC purity of 99.7% and a yield of 95%.
<1>H-NMR 300 MHz, Î ́ (CD3OD): 9,23 (s, 1H); 8,77 (s, 1H); 8,66 (s, 1H); 8,30 (bd, J=9Hz, 1H); 4,65 (d, J=7Hz, 1H); 4,32-4,30 (m, 1H); 1,88-1,59 (m, 6H); 1,24-1,07 (m, 5H); 0,99 (s, 9H). <1> H-NMR 300 MHz, Î ́ (CD3OD): 9.23 (s, 1H); 8.77 (s, 1H); 8.66 (s, 1H); 8.30 (bd, J = 9Hz, 1H); 4.65 (d, J = 7Hz, 1H); 4.32-4.30 (m, 1H); 1.88-1.59 (m, 6H); 1.24-1.07 (m, 5H); 0.99 (s, 9H).
<13>C-NMR 100 MHz, Î ́ (CD3OD): 172,05; 171,45; 162,95; 147,06; 143,95; 143,08; 142,93; 60,38; 57,77; 39,91; 33,09; 28,07; 26,26; 25,91; 25,56; 25,21; 24,84. <13> C-NMR 100 MHz, Î ́ (CD3OD): 172.05; 171.45; 162.95; 147.06; 143.95; 143.08; 142.93; 60.38; 57.77; 39.91; 33.09; 28.07; 26.26; 25.91; 25.56; 25.21; 24.84.
MS(ES<+>): m/z 399 [M+Na]<+>. MS (ES <+>): m / z 399 [M + Na] <+>.
L’analisi XRPD di acido (S)-2-((S)-2-cicloesil-2-(pirazin-2-carbossammido)acetammido)-3,3-dimetilbutanoico, come visibile dalla Figura, rileva picchi principali (espressi in ° in 2Î ̧) che si riscontrano a: 5.37, 7.17, 10.38, 10.71, 14.43, 16.38, 17.10, 17.70, 18.09, 18.81, 20.04, 20.49, 20.88, 21.96 e 24.21. The XRPD analysis of (S) -2 - ((S) -2-cyclohexyl-2- (pyrazine-2-carboxamido) acetamido) -3,3-dimethylbutanoic acid, as shown in the Figure, reveals main peaks (expressed in ° in 2Î ̧) which are found at: 5.37, 7.17, 10.38, 10.71, 14.43, 16.38, 17.10, 17.70, 18.09, 18.81, 20.04, 20.49, 20.88, 21.96 and 24.21.
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DISCLOSED ANONYMOUSLY: "Intermediates of (1S,3aR,6aS)-N-(1(S)-(2-(Cyclopropylamino)oxalyl)but yl)-2-(N-(pyrazin-2-ylcarbonyl)-L-cyclohexylglycyl-3-methyl-L-valyl)p erhydrocyclopenta[c]pyrrole-1-carboxamide", IP.COM JOURNAL, IP.COM INC., WEST HENRIETTA, NY, US, 16 October 2011 (2011-10-16), XP013146490, ISSN: 1533-0001 * |
FARKAS ET AL: "Efficient activation of carboxyl polysaccharides for the preparation of conjugates", CARBOHYDRATE POLYMERS, APPLIED SCIENCE PUBLISHERS, LTD. BARKING, GB, vol. 68, no. 1, 7 February 2007 (2007-02-07), pages 187 - 190, XP005878277, ISSN: 0144-8617, DOI: 10.1016/J.CARBPOL.2006.07.013 * |
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