WO2024033278A1 - Process for manufacturing an antibiotic macrocyclic peptide - Google Patents
Process for manufacturing an antibiotic macrocyclic peptide Download PDFInfo
- Publication number
- WO2024033278A1 WO2024033278A1 PCT/EP2023/071759 EP2023071759W WO2024033278A1 WO 2024033278 A1 WO2024033278 A1 WO 2024033278A1 EP 2023071759 W EP2023071759 W EP 2023071759W WO 2024033278 A1 WO2024033278 A1 WO 2024033278A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- palladium
- equivalents
- process according
- tert
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 136
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 36
- 230000003115 biocidal effect Effects 0.000 title description 5
- 239000003242 anti bacterial agent Substances 0.000 title description 2
- 108090000765 processed proteins & peptides Proteins 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 59
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 198
- 229910052763 palladium Inorganic materials 0.000 claims description 65
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 48
- 150000001499 aryl bromides Chemical class 0.000 claims description 46
- 239000003054 catalyst Substances 0.000 claims description 44
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 30
- 229940126214 compound 3 Drugs 0.000 claims description 25
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 23
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 20
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 claims description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- 235000010290 biphenyl Nutrition 0.000 claims description 15
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 15
- 239000011541 reaction mixture Substances 0.000 claims description 14
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 13
- 239000003446 ligand Substances 0.000 claims description 13
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 12
- DRNAQRXLOSUHBQ-UHFFFAOYSA-N cphos Chemical compound CN(C)C1=CC=CC(N(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 DRNAQRXLOSUHBQ-UHFFFAOYSA-N 0.000 claims description 12
- -1 2-(2- aminoethyl)phenyl Chemical group 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
- MXFYYFVVIIWKFE-UHFFFAOYSA-N dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phosphane Chemical compound CC(C)OC1=CC=CC(OC(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 MXFYYFVVIIWKFE-UHFFFAOYSA-N 0.000 claims description 11
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 claims description 11
- PQCXFUXRTRESBD-UHFFFAOYSA-N (4-methoxycarbonylphenyl)boronic acid Chemical compound COC(=O)C1=CC=C(B(O)O)C=C1 PQCXFUXRTRESBD-UHFFFAOYSA-N 0.000 claims description 10
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 10
- RBYGDVHOECIAFC-UHFFFAOYSA-L acetonitrile;palladium(2+);dichloride Chemical compound [Cl-].[Cl-].[Pd+2].CC#N.CC#N RBYGDVHOECIAFC-UHFFFAOYSA-L 0.000 claims description 10
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 claims description 10
- 125000005394 methallyl group Chemical group 0.000 claims description 10
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 10
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 9
- 238000011065 in-situ storage Methods 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 8
- 239000003849 aromatic solvent Substances 0.000 claims description 7
- 239000000243 solution Substances 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 230000001476 alcoholic effect Effects 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 235000015320 potassium carbonate Nutrition 0.000 claims description 6
- ZMPSAJZWHPLTKH-HYTOEPEZSA-L (e)-but-2-ene;chloropalladium(1+) Chemical compound [Pd+]Cl.[Pd+]Cl.C\C=C\[CH2-].C\C=C\[CH2-] ZMPSAJZWHPLTKH-HYTOEPEZSA-L 0.000 claims description 5
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 claims description 5
- UKSZBOKPHAQOMP-UHFFFAOYSA-N 1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].C=1C=CC=CC=1C=CC(=O)C=CC1=CC=CC=C1.C=1C=CC=CC=1C=CC(=O)C=CC1=CC=CC=C1 UKSZBOKPHAQOMP-UHFFFAOYSA-N 0.000 claims description 5
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 claims description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 5
- VSWDORGPIHIGNW-UHFFFAOYSA-N Pyrrolidine dithiocarbamic acid Chemical compound SC(=S)N1CCCC1 VSWDORGPIHIGNW-UHFFFAOYSA-N 0.000 claims description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 5
- 229960004308 acetylcysteine Drugs 0.000 claims description 5
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 5
- 150000007529 inorganic bases Chemical group 0.000 claims description 5
- RYOPVFUGUFDYKP-UHFFFAOYSA-L n,n-dimethyl-1-phenylmethanamine;palladium(2+);dichloride Chemical compound [Pd+]Cl.[Pd+]Cl.CN(C)CC1=CC=CC=[C-]1.CN(C)CC1=CC=CC=[C-]1 RYOPVFUGUFDYKP-UHFFFAOYSA-L 0.000 claims description 5
- PENAXHPKEVTBLF-UHFFFAOYSA-L palladium(2+);prop-1-ene;dichloride Chemical compound [Pd+]Cl.[Pd+]Cl.[CH2-]C=C.[CH2-]C=C PENAXHPKEVTBLF-UHFFFAOYSA-L 0.000 claims description 5
- JKDRQYIYVJVOPF-FDGPNNRMSA-L palladium(ii) acetylacetonate Chemical compound [Pd+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O JKDRQYIYVJVOPF-FDGPNNRMSA-L 0.000 claims description 5
- INIOZDBICVTGEO-UHFFFAOYSA-L palladium(ii) bromide Chemical compound Br[Pd]Br INIOZDBICVTGEO-UHFFFAOYSA-L 0.000 claims description 5
- ABKFMURDLHTMLE-UHFFFAOYSA-N palladium;3-prop-2-enylidenecyclopentene Chemical compound [Pd].C=C[CH-]C1=CC=CC1 ABKFMURDLHTMLE-UHFFFAOYSA-N 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 5
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims description 5
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 5
- 235000019798 tripotassium phosphate Nutrition 0.000 claims description 5
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 4
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 claims description 4
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 125000003944 tolyl group Chemical group 0.000 claims description 4
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims description 3
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 229910021516 thallium(I) hydroxide Inorganic materials 0.000 claims description 3
- 150000001805 chlorine compounds Chemical class 0.000 claims description 2
- 229930007927 cymene Natural products 0.000 claims description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 2
- 229940078552 o-xylene Drugs 0.000 claims description 2
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 claims description 2
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 claims description 2
- 239000011877 solvent mixture Substances 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 150000003738 xylenes Chemical class 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract description 8
- NJFUXFYUHIHHOJ-FSEITFBQSA-N 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid Chemical compound CN1[C@@H](CC2=CNC3=C2C=CC=C3)C(=O)NCC2=C(C=CC=C2SC2=C(CN[C@@H](CCCN)C(=O)N[C@@H](CCCCN)C1=O)C=CC=N2)C1=CC=C(C=C1)C(O)=O NJFUXFYUHIHHOJ-FSEITFBQSA-N 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
- 238000006069 Suzuki reaction reaction Methods 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 235000015165 citric acid Nutrition 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- 150000002940 palladium Chemical class 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000126 substance Chemical group 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 241000588626 Acinetobacter baumannii Species 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- UTWGRMYWDUMKNY-UHFFFAOYSA-N indole-1-carboxylic acid Chemical compound C1=CC=C2N(C(=O)O)C=CC2=C1 UTWGRMYWDUMKNY-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- IQTHEAQKKVAXGV-UHFFFAOYSA-N 4-ditert-butylphosphanyl-n,n-dimethylaniline Chemical compound CN(C)C1=CC=C(P(C(C)(C)C)C(C)(C)C)C=C1 IQTHEAQKKVAXGV-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 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 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- QMVMDYSTJSUDKC-UHFFFAOYSA-N [4-[(2-methylpropan-2-yl)oxycarbonyl]phenyl]boronic acid Chemical compound CC(C)(C)OC(=O)C1=CC=C(B(O)O)C=C1 QMVMDYSTJSUDKC-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- HTJWUNNIRKDDIV-UHFFFAOYSA-N bis(1-adamantyl)-butylphosphane Chemical compound C1C(C2)CC(C3)CC2CC13P(CCCC)C1(C2)CC(C3)CC2CC3C1 HTJWUNNIRKDDIV-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- JFKBSRFAWDZHEK-UHFFFAOYSA-N butyl(ditert-butyl)phosphane Chemical group CCCCP(C(C)(C)C)C(C)(C)C JFKBSRFAWDZHEK-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- WDIIYWASEVHBBT-UHFFFAOYSA-N di(propan-2-yl)phosphane Chemical compound CC(C)PC(C)C WDIIYWASEVHBBT-UHFFFAOYSA-N 0.000 description 1
- JUZAKZRALSJLOV-UHFFFAOYSA-N dicyclohexyl-[1-(2-methoxyphenyl)pyrrol-2-yl]phosphane Chemical group COC1=CC=CC=C1N1C(P(C2CCCCC2)C2CCCCC2)=CC=C1 JUZAKZRALSJLOV-UHFFFAOYSA-N 0.000 description 1
- HDULBKVLSJEMGN-UHFFFAOYSA-N dicyclohexylphosphane Chemical compound C1CCCCC1PC1CCCCC1 HDULBKVLSJEMGN-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- LZWLLMFYVGUUAL-UHFFFAOYSA-L ditert-butyl(cyclopenta-1,3-dien-1-yl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.CC(C)(C)P(C(C)(C)C)C1=CC=C[CH-]1.CC(C)(C)P(C(C)(C)C)C1=CC=C[CH-]1 LZWLLMFYVGUUAL-UHFFFAOYSA-L 0.000 description 1
- WDUDHEOUGWAKFD-UHFFFAOYSA-N ditert-butyl(cyclopenta-2,4-dien-1-yl)phosphane;iron(2+) Chemical compound [Fe+2].CC(C)(C)P(C(C)(C)C)C1=CC=C[CH-]1.CC(C)(C)P(C(C)(C)C)C1=CC=C[CH-]1 WDUDHEOUGWAKFD-UHFFFAOYSA-N 0.000 description 1
- XOJNEFQLMRCOMS-UHFFFAOYSA-N ditert-butyl(phenyl)phosphane Chemical compound CC(C)(C)P(C(C)(C)C)C1=CC=CC=C1 XOJNEFQLMRCOMS-UHFFFAOYSA-N 0.000 description 1
- ILWCCADVRXVLTN-UHFFFAOYSA-N ditert-butyl-[4-(trifluoromethyl)phenyl]phosphane Chemical compound CC(C)(C)P(C(C)(C)C)C1=CC=C(C(F)(F)F)C=C1 ILWCCADVRXVLTN-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000004702 methyl esters Chemical group 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- BQQJSZUDBXOSAG-UHFFFAOYSA-N tris(1-adamantyl)phosphane Chemical compound C1C(C2)CC(C3)CC2CC13P(C12CC3CC(CC(C3)C1)C2)C(C1)(C2)CC3CC2CC1C3 BQQJSZUDBXOSAG-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 229940126977 zosurabalpin Drugs 0.000 description 1
Classifications
-
- 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
- C07K5/0815—Tripeptides with the first amino acid being basic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- the invention relates to a novel process for manufacturing 4-[(11S,14S,17S)-14-(4- Aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2- thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid (I), or a pharmaceutically acceptable salt thereof.
- the invention further relates to certain synthetic intermediates that are useful for the novel process according to the invention.
- the process according to the invention is particularly suitable for large-scale manufacturing of the compound of formula (I) under GMP conditions.
- the compound of formula (I) is a potent antibiotic with selective action against Acinetobacter baumannii, as discussed in WO2019206853.
- the compound of formula (I) is also known under the INN zosurabalpin (WHO Drug Information, Vol.36, No.2, 2022).
- WO2019206853 discloses a laboratory scale synthesis of the compound of formula (I), which relies on a Suzuki coupling reaction that is characterized by a high catalyst loading (about 20 mol%) and a relatively high amount of a boronic acid building block (about 1.5 equivalents).
- the high catalyst loading in addition to generating high costs, also leads to CNE/13.07.2023 palladium impurities in the final product that are difficult to remove.
- the use of high amounts of boronic acid results in the formation of organic impurities.
- the process disclosed in WO2019206853 involves the use of the toxic solvent dioxane, and relies on chromatography to purify certain intermediates, as well as the final product.
- the process for making the compound of formula (I) as described in WO2019206853 is not well suited for an industrial scale synthesis of said compound of formula (I). Accordingly, there is a high unmet need for a new process for manufacturing the compound of formula (I), in order to provide patients with this new treatment option for infections with Acinetobacter baumannii and resulting diseases. Summary of the Invention The present invention provides an improved process for manufacturing the compound of formula (I), which overcomes the problems outlined above. The present invention also provides certain synthetic intermediates that are useful in the new process.
- palladium catalyst refers to any palladium catalyst that enables the reaction of aryl bromide 1 as described herein with (4-carbomethoxyphenyl)boronic acid (2) to afford compound 3 as defined herein on an industrial scale.
- the palladium catalyzed reaction according to the invention requires a zero valent palladium species (Pd(0)).
- Pd(0) zero valent palladium species
- Exemplary catalytically active Pd(0) species may be applied directly or may be formed in situ from a palladium source in combination with a phosphine ligand.
- the palladium catalyst is a preformed palladium catalyst.
- preformed catalytically active Pd(0) reagents include: Pd(PPh3)4 and Pd(L)2, wherein L is selected from PBu 3 , AmPhos, CPhos, RuPhos, and SPhos.
- [PdI(L)]2 (L PtBu3, AmPhos).
- Examples of palladium sources that form a palladium catalyst in situ in combination with a suitable ligand include: palladium bis(dibenzylideneacetone) (Pd(dba) 2 ), (Pd 2 (dba) 3 ), bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh 3 ) 2 Cl 2 ), palladium acetate (Pd(OAc) 2 , palladium trifluoracetate (Pd(TFA)2), palladium chloride (PdCl2), palladium bromide (PdBr2),palladium iodide (PdI2), palladium bis acetylacetonate (Pd(acac)2), (Pd(PPh3)4), bis(acetonitrile)- palladium(II) dichloride (PdCl 2 (CH 3 CN
- ligands that form palladium catalysts in situ in combination with a palladium source described above include: mono or diphosphines such as PtBu3, PAd3, AmPhos, cataCXiumA, PtBu2Bu, PtBu2Ph, PtBu2-p-C6H4CF3, cataCXium POMeCy, CPhos, RuPhos, SPhos, dppf, dcypf, dippf, and dtbpf.
- mono or diphosphines such as PtBu3, PAd3, AmPhos, cataCXiumA, PtBu2Bu, PtBu2Ph, PtBu2-p-C6H4CF3, cataCXium POMeCy, CPhos, RuPhos, SPhos, dppf, dcypf, dippf, and dtbpf.
- salt refers to any kind of salts formed by reacting the compounds disclosed herein with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, N-acetylcystein and the like.
- inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid
- organic acids such as acetic acid, propionic acid, glycolic acid,
- salts may also be prepared by addition of an inorganic base or an organic base to the free acid.
- Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like.
- Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins and the like.
- the present invention provides a process for manufacturing compound 3, or a salt thereof, 3 comprising: (a) reacting aryl bromide 1 + with (4-carbomethoxyphenyl)boronic acid (2) in the presence of a palladium catalyst and a base, to afford said compound 3.
- the present invention provides a process for manufacturing compound 3, or a salt thereof, 3 comprising: (a) reacting aryl bromide 1 + with (4-carbomethoxyphenyl)boronic acid (2) in the presence of a palladium catalyst and a base in an aromatic solvent, to afford said compound 3; wherein said palladium catalyst is selected from: i) a preformed catalyst selected from Pd(PPh 3 ) 4 , Pd(L 1 ) 2 , [Pd(L 1 )XCl], [Pd(L 1 )X]trifluoromethanesulfonate, [Pd(L 1 )(2-(2′-amino-1,1′-biphenyl)Cl]; [Pd(L 1 )(2-(2′-amino-1,1′-biphenyl)]methanesulfonate, [Pd(L 1 )(2-(2′- methylamino-1,1′-bipheny
- said palladium catalyst is selected from: i) a preformed catalyst selected from Pd(PPh3)4, Pd(L 1 )2, [Pd(L 1 )XCl], [Pd(L 1 )X]trifluoromethanesulfonate, [Pd(L 1 )(2-(2′-amino-1,1′-biphenyl)Cl]; [Pd(L 1 )(2-(2′-amino-1,1′-biphenyl)]methanesulfonate, [Pd(L 1 )(2-(2′-methylamino- 1,1′-biphenyl)]methanesulfonate, [Pd(L 1 )(2-(2-aminoethyl)phenyl)Cl], Pd(L 2 )Cl2, Pd(L 2 )2Cl2, and [PdI(L 3 )]2; where
- said palladium catalyst is selected from Pd(PPh3)4, Pd(L 1 )2, [Pd(L 1 )XCl], [Pd(L 1 )X]trifluoromethanesulfonate, [Pd(L 1 )(2-(2′-amino-1,1′-biphenyl)Cl]; [Pd(L 1 )(2-(2′- amino-1,1′-biphenyl)]methanesulfonate, [Pd(L 1 )(2-(2′-methylamino-1,1′- biphenyl)]methanesulfonate, [Pd(L 1 )(2-(2-aminoethyl)phenyl)Cl], Pd(L 2 )Cl2, Pd(L 2 )2Cl2, and [PdI(L 3 )]2; wherein X is selected from allyl, 2-buteny
- said palladium catalyst is formed in situ from: i) a palladium source selected from palladium bis(dibenzylideneacetone) (Pd(dba)2), (Pd 2 (dba) 3 ), bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh 3 ) 2 Cl 2 ), palladium acetate (Pd(OAc) 2 , palladium trifluoracetate (Pd(TFA) 2 ), palladium chloride (PdCl2), palladium bromide (PdBr2),palladium iodide (PdI2), palladium bis acetylacetonate (Pd(acac)2), (Pd(PPh3)4), bis(acetonitrile)-palladium(II) dichloride (PdCl 2 (CH 3 CN) 2 ), cyclopentadien
- said mono- and diphosphine ligands are selected from PtBu3, PAd 3 , AmPhos, cataCXiumA, PtBu 2 Bu, PtBu 2 Ph, PtBu 2 -p-C 6 H 4 CF 3 , cataCXium POMeCy, CPhos, RuPhos, SPhos, dppf, dcypf, dippf, and dtbpf.
- said palladium catalyst is selected from Pd(PPh 3 ) 4 , CPhosPdG3, Pd 2 (dba) 3 + CPhos, and PdCl 2 (dtbpf).
- the palladium catalyst PdCl2(dtbpf) works particularly well in the Suzuki coupling according to the invention.
- the Suzuki coupling with PdCl 2 (dtbpf) requires only a very low catalyst loading (2 mol% or less) and a small excess of boronic acid 2, which results in reduced amount of contamination of the final product with palladium and organic impurities, reduced cost and reduced waste.
- said palladium catalyst is PdCl 2 (dtbpf).
- said palladium catalyst is present in an amount of 1 mol% to 10 mol% relative to aryl bromide 1. In one embodiment of step (a) of the process according to the invention, said palladium catalyst is present in an amount of 1 mol% to 5 mol% relative to aryl bromide 1. In a preferred embodiment of step (a) of the process according to the invention, said palladium catalyst is present in an amount of 1 mol% to 3 mol% relative to aryl bromide 1. In a particularly preferred embodiment of step (a) of the process according to the invention, said palladium catalyst is present in an amount of 2 mol% relative to aryl bromide 1.
- said palladium catalyst is PdCl 2 (dtbpf) and is present in an amount of 1 mol% to 10 mol% relative to aryl bromide 1.
- said palladium catalyst is PdCl2(dtbpf) and is present in an amount of 1 mol% to 5 mol% relative to aryl bromide 1.
- said palladium catalyst is PdCl 2 (dtbpf) and is present in an amount of 1 mol% to 3 mol% relative to aryl bromide 1.
- said palladium catalyst is PdCl 2 (dtbpf) and is present in an amount of 2 mol% relative to aryl bromide 1.
- said base is selected from inorganic bases and alcoholates.
- said base is selected from Na2CO3, Ba(OH)2, K3PO4, Cs2CO3, K2CO3, TlOH, KF, CsF, Bu4F, and NaOH.
- said base is selected from K3PO4 and K2CO3.
- step (a) of the process according to the invention said base is K 3 PO 4 .
- said base is K2CO3.
- step (a) of the process according to the invention 1 to 4 equivalents of said base relative to aryl bromide 1 are used.
- step (a) of the process according to the invention 1 to 3 equivalents of said base relative to aryl bromide 1 are used.
- step (a) of the process according to the invention 1 to 2 equivalents of said base relative to aryl bromide 1 are used.
- step (a) of the process according to the invention 1.5 equivalents of said base relative to aryl bromide 1 are used.
- One advantage of the Suzuki coupling of process step (a) according to the invention is that it performs very well in toluene, as opposed to the toxic dioxane described in WO2019206853. This is of particular importance when conducting the reaction on an industrial scale and in view of the fact that the final antibiotic product of formula (I) is for administration to mammals, where traces of toxic solvents are not acceptable.
- step (a) is conducted in an aromatic solvent.
- said aromatic solvent is selected from toluene, xylenes (o-xylene, p- xylene, m-xylene or a mixture thereof), ethylbenzene, anisole, cumene, and cymene.
- said aromatic solvent is toluene. It was found that the methyl ester moiety of boronic acid building block 2 is prone to hydrolysis under the reaction conditions used. However, it was surprisingly found that adding water to the reaction mixture prevents said hydrolysis, allowing to employ fewer equivalents of this building block. Thus, in one embodiment of step (a) of the process according to the invention, the process is conducted in the further presence of water.
- step (a) of the process according to the invention the process is conducted in the further presence of 1 to 30 equivalents of water relative to aryl bromide 1. In one embodiment of step (a) of the process according to the invention, the process is conducted in the further presence of 1 to 20 equivalents of water relative to aryl bromide 1. In one embodiment of step (a) of the process according to the invention, the process is conducted in the further presence of 5 to 25 equivalents of water relative to aryl bromide 1. In a preferred embodiment of step (a) of the process according to the invention, the process is conducted in the further presence of 10 to 25 equivalents of water relative to aryl bromide 1.
- step (a) of the process according to the invention is conducted in the further presence of 12.5 to 25 equivalents of water relative to aryl bromide 1. In a particularly preferred embodiment of step (a) of the process according to the invention, the process is conducted in the further presence of 25 equivalents of water relative to aryl bromide 1. In one embodiment of step (a) of the process according to the invention, the process is conducted in the further presence of 5 to 15 equivalents of water relative to aryl bromide 1. In one embodiment of step (a) of the process according to the invention, the process is conducted in the further presence of 10 to 15 equivalents of water relative to aryl bromide 1.
- step (a) of the process according to the invention the process is conducted in the further presence of 12.5 equivalents of water relative to aryl bromide 1.
- the process is conducted in the further presence of water, wherein the water is continuously added over a period of 2-8 h to the reaction mixture comprising aryl bromide 1, boronic acid 2, palladium catalyst and base.
- the process is conducted in the further presence of water, wherein the water is continuously added over a period of 2-7 h to the reaction mixture comprising aryl bromide 1, boronic acid 2, palladium catalyst and base.
- step (a) of the process according to the invention the process is conducted in the further presence of water, wherein the water is continuously added over a period of 3-6 h to the reaction mixture comprising aryl bromide 1, boronic acid 2, palladium catalyst and base.
- step (a) of the process according to the invention the process is conducted in the further presence of water, wherein the water is continuously added over a period of 2-5 h to the reaction mixture comprising aryl bromide 1, boronic acid 2, palladium catalyst and base.
- step (a) of the process according to the invention the process is conducted in the further presence of water, wherein the water is continuously added over a period of 2-4 h to the reaction mixture comprising aryl bromide 1, boronic acid 2, palladium catalyst and base.
- step (a) of the process according to the invention the process is conducted in the further presence of water, wherein the water is continuously added over a period of 6 h to the reaction mixture comprising aryl bromide 1, boronic acid 2, palladium catalyst and base.
- step (a) of the process according to the invention the process is conducted in the further presence of water, wherein the water is continuously added over a period of 3 h to the reaction mixture comprising aryl bromide 1, boronic acid 2, palladium catalyst and base.
- the new Suzuki coupling according to the invention allows the use of less equivalents of boronic acid 2 compared to the amound of boronic acid that is used in the process described in WO2019206853.
- 1 to ⁇ 1.5 equivalents of boronic acid 2 are used relative to aryl bromide 1.
- step (a) of the process according to the invention 1 to 1.4 equivalents of boronic acid 2 are used relative to aryl bromide 1. In a further preferred embodiment of step (a) of the process according to the invention, 1 to 1.3 equivalents of boronic acid 2 are used relative to aryl bromide 1. In a further preferred embodiment of step (a) of the process according to the invention, 1.05 to 1.2 equivalents of boronic acid 2 are used relative to aryl bromide 1. In a further preferred embodiment of step (a) of the process according to the invention, 1 to 1.2 equivalents of boronic acid 2 are used relative to aryl bromide 1.
- step (a) of the process according to the invention 1 to 1.1 equivalents of boronic acid 2 are used relative to aryl bromide 1. In a particularly preferred embodiment of step (a) of the process according to the invention, 1.2 equivalents of boronic acid 2 are used relative to aryl bromide 1. In a particularly preferred embodiment of step (a) of the process according to the invention, 1.05 equivalents of boronic acid 2 are used relative to aryl bromide 1. If desired, the level of palladium contamination of compound 3 may be reduced, typically to a level of ⁇ 10 ppm, by treating compound 3 with N-acetylcysteine or ammonium pyrrolidinedithiocarbamate in situ.
- the process for manufacturing compound 3, or a salt thereof, according to the invention optionally further comprises: (b) adding ammonium pyrrolidinedithiocarbamate or an aqueous solution of N- acetylcysteine to the reaction mixture obtained from step (a). In one embodiment, the process for manufacturing compound 3, or a salt thereof, according to the invention optionally further comprises: (b) adding an aqueous solution of N-acetylcysteine to the reaction mixture obtained from step (a). In one embodiment, the process for manufacturing compound 3, or a salt thereof, according to the invention optionally further comprises: (b) adding ammonium pyrrolidinedithiocarbamate to the reaction mixture obtained from step (a).
- the present invention provides a process for manufacturing compound 4, or a salt thereof, comprising steps (a) and (b) as described herein, and further comprising: (c) reacting compound 3 described herein with sodium hydroxide to afford said compound 4.
- step (c) is performed in a solvent being an alcohol, preferably in methanol.
- the present invention provides a process for manufacturing compound 4, or a salt thereof, comprising steps (a) and (b) as described herein, and further comprising: (c) reacting compound 3 according to claim 1 with 2 to 10 equivalents, preferably 3 to 8 equivalents, more preferably 4 to 7 equivalents, in particular 7 equivalents of sodium hydroxide to afford said compound 4, wherein said sodium hydroxide is added as a 5% w/w to 30% w/w, preferably 10% w/w to 20% w/w, in particular a 16% w/w aqueous solution to a solution of compound 3 in an alcoholic solvent or a mixture of water and an alcoholic solvent.
- said alcoholic solvent is methanol.
- the process for manufacturing compound 4 according to the invention optionally further comprises: (d) crystallizing said compound 4.
- said crystallizing of said compound 4 is crystallizing of said compound 4 from a mixture of an alcohol and acetone.
- said alcohol is selected from 2-propanol and 1-propanol.
- said alcohol is 1-propanol.
- the present invention provides a process for manufacturing the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprising process steps (a)-(d) described herein, and further comprising: (e) reacting compound 4 described herein with an acid, to afford said compound of formula (I).
- said acid is hydrochloric acid.
- step (e) is performed in a solvent mixture selected from acetone/water, THF/water, and acetonitrile/water.
- 2 to 6 equivalents of acid relative to compound 4 are used in step (e) of the process according to the invention.
- step (e) of the process according to the invention 3 to 5 equivalents of acid relative to compound 4 are used in step (e) of the process according to the invention.
- 4 to 5 equivalents of acid relative to compound 4 are used in step (e) of the process according to the invention.
- 3.5 to 4.5 equivalents of acid relative to compound 4 are used in step (e) of the process according to the invention.
- 4 to 4.1 equivalents of acid relative to compound 4 are used in step (e) of the process according to the invention.
- 4 equivalents of acid relative to compound 4 are used in step (e) of the process according to the invention.
- step (e) of the process according to the invention is performed between room temperature and reflux. In a preferred embodiment, step (e) of the process according to the invention is performed between 30 °C and reflux. In a further preferred embodiment, step (e) of the process according to the invention is performed between 35 °C and 65 °C. In a particularly preferred embodiment, step (e) of the process according to the invention is performed between 35 °C and 60 °C. In a further aspect, the present invention provides the use of the process for manufacturing compound 3 described herein in the manufacture of the compound of formula (I).
- the present invention provides the use of the process for manufacturing compound 4 described herein in the manufacture of the compound of formula (I).
- Compounds of the Invention relates to certain synthetic intermediates that are useful for manufacturing the novel antibiotic of formula (I) described herein.
- the present invention also relates to certain compounds when manufactured according to the novel chemical processes described herein.
- the present invention provides a compound, which is tert- butyl 3-[[(11S,14S,17S)-14-[4-(tert-butoxycarbonylamino)butyl]-11-[3-(tert- butoxycarbonylamino)propyl]-22-(4-methoxycarbonylphenyl)-16-methyl-12,15,18-trioxo- 2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-17- yl]methyl]indole-1-carboxylate (3), or a salt thereof .
- the present invention provides a compound, which is 4-[(11S,14S,17S)- 14-[4-(tert-butoxycarbonylamino)butyl]-11-[3-(tert-butoxycarbonylamino)propyl]-17-(1H- indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-22-yl]benzoic acid (4), or a salt thereof .
- the present invention relates to compound 3 when manufactured according to the processes for manufacturing compound 3 described herein. In a further aspect, the present invention relates to compound 3 when manufactured according to the processes for manufacturing compound 3 described herein. In a further aspect, the present invention relates to the compound of formula (I) when manufactured according to the processes for manufacturing the compound of formula (I) described herein. In a further aspect, the present invention relates to the use of compound 3 described herein in the manufacture of the compound of formula (I). In a further aspect, the present invention relates to the use of compound 4 described herein in the manufacture of the compound of formula (I). Examples The invention will be more fully understood by reference to the following examples. The claims should not, however, be construed as limited to the scope of the examples.
- the organic layer was treated with activated charcoal at room temperature.
- the mixture was distilled under reduced pressure an the solvent was swapped to methanol and concentrated to a final volume of 80 ml.
- Methanol (221 ml, 7.4 vol) and water (70 ml, 2.3vol) are added.
- the mixture is heated to 50°C and 32% w/w aq.
- sodium hydroxide (25.0 g, 200.0 mmol, 7.0 eq) is added.
- the mixture is stirred for 5h and then cooled to 20°C.
- Methanol is distilled off under reduced pressure.
- Example 1a Preparation of 4-[(11S,14S,17S)-14-[4-(tert-butoxycarbonylamino)butyl]-11-[3-(tert- butoxycarbonylamino)propyl]-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-22- yl]benzoic acid
- Ammonium pyrrolidinedithiocarbamate (237 mg, 1.43 mmol, 0.3 eq) is added. The mixture was stirred for at least 1 h at 85-90°C, then the phases were split. The organic phase was extracted with water. The organic layer was distilled under reduced pressure and methanol (12.5 ml, 2.5 vol) is added. The mixture is cooled to 40°C. A 16% w/w aqueous soludion of sodium hydroxide (8.33 g, 33.33 mmol, 7.0 eq) is added. The mixture is stirred for at least 5 h and then cooled to 20°C.
- a 35% w/w aqueous solution of citric acid (13.07 g, 23.81 mmol, 5.0 eq) is charged to the residue at 20°C and the mixture is distilled under reduced pressure.
- the residue is extracted with ethyl acetate.
- the organic phase is extracted with water, dried over sodium sulfate and diluted with ethyl acetate (15 ml).
- the solution is heated to 60°C and stirred for ca.1h.
- the resulting suspension is cooled in 12h to 0°C and stirred at least 2h.
Abstract
The invention relates to a novel process for manufacturing 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid (I), or a pharmaceutically acceptable salt thereof. The invention further relates to certain synthetic intermediates that are useful for the novel process according to the invention. The process according to the invention is particularly suitable for large-scale manufacturing of the compound of formula (I) under GMP conditions.
Description
F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland Case: P37469 PROCESS FOR MANUFACTURING AN ANTIBIOTIC MACROCYCLIC PEPTIDE Field of the Invention The invention relates to a novel process for manufacturing 4-[(11S,14S,17S)-14-(4- Aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2- thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid (I), or a pharmaceutically acceptable salt thereof.
The invention further relates to certain synthetic intermediates that are useful for the novel process according to the invention. The process according to the invention is particularly suitable for large-scale manufacturing of the compound of formula (I) under GMP conditions. Background of the Invention The compound of formula (I) is a potent antibiotic with selective action against Acinetobacter baumannii, as discussed in WO2019206853. The compound of formula (I) is also known under the INN zosurabalpin (WHO Drug Information, Vol.36, No.2, 2022). WO2019206853 discloses a laboratory scale synthesis of the compound of formula (I), which relies on a Suzuki coupling reaction that is characterized by a high catalyst loading (about 20 mol%) and a relatively high amount of a boronic acid building block (about 1.5 equivalents). The high catalyst loading, in addition to generating high costs, also leads to CNE/13.07.2023
palladium impurities in the final product that are difficult to remove. Similarly, the use of high amounts of boronic acid results in the formation of organic impurities. Furthermore, the process disclosed in WO2019206853 involves the use of the toxic solvent dioxane, and relies on chromatography to purify certain intermediates, as well as the final product. In summary, the process for making the compound of formula (I) as described in WO2019206853 is not well suited for an industrial scale synthesis of said compound of formula (I). Accordingly, there is a high unmet need for a new process for manufacturing the compound of formula (I), in order to provide patients with this new treatment option for infections with Acinetobacter baumannii and resulting diseases. Summary of the Invention The present invention provides an improved process for manufacturing the compound of formula (I), which overcomes the problems outlined above. The present invention also provides certain synthetic intermediates that are useful in the new process. Detailed Description of the Invention Definitions Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims and the abstract), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims and the abstract), or to any novel one, or any novel combination, of the steps of any method or process so disclosed. The term “palladium catalyst” as used herein refers to any palladium catalyst that enables the reaction of aryl bromide 1 as described herein with (4-carbomethoxyphenyl)boronic acid (2) to afford compound 3 as defined herein on an industrial scale. The palladium catalyzed reaction according to the invention requires a zero valent palladium species
(Pd(0)). Exemplary catalytically active Pd(0) species may be applied directly or may be formed in situ from a palladium source in combination with a phosphine ligand. In some embodiments, the palladium catalyst is a preformed palladium catalyst. Examples of preformed catalytically active Pd(0) reagents include: Pd(PPh3)4 and Pd(L)2, wherein L is selected from PBu3, AmPhos, CPhos, RuPhos, and SPhos. Further examples of preformed palladium catalysts include: [Pd(L)XCl] (L = ligand as defined above, X = allyl, 2-butenyl, 2-methylallyl, 1-phenylallyl, p-tert-butylindenyl); [Pd(L)X]trifluoromethanesulfonate (L = ligand as defined above, X = as defined above), [Pd(L)(2-(2′-amino-1,1′-biphenyl)Cl] (L = as defined above); [Pd(L)(2-(2′-amino-1,1′-biphenyl)]methanesulfonate (L = as defined above), [Pd(L)(2-(2′-methylamino-1,1′-biphenyl)]methanesulfonate (L = as defined above), [Pd(L)(2-(2-aminoethyl)phenyl)Cl] (L = as defined above), PdLCl2, PdL2Cl2 (L =PtBu3, AmPhos, PtBu2Bu, PtBu2Ph, PtBu2-p-C6H4CF3)2, dppf, dcypf, dippf, dtbpf. [PdI(L)]2 (L = PtBu3, AmPhos). Examples of palladium sources that form a palladium catalyst in situ in combination with a suitable ligand include: palladium bis(dibenzylideneacetone) (Pd(dba)2), (Pd2(dba)3), bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), palladium acetate (Pd(OAc)2, palladium trifluoracetate (Pd(TFA)2), palladium chloride (PdCl2), palladium bromide (PdBr2),palladium iodide (PdI2), palladium bis acetylacetonate (Pd(acac)2), (Pd(PPh3)4), bis(acetonitrile)- palladium(II) dichloride (PdCl2(CH3CN)2), cyclopentadienyl allyl palladium, allylpalladium(II) chloride dimer (Pd(allyl)Cl)2), (2-butenyl)chloropalladium dimer, (2- methylallyl) palladium(II) chloride dimer, palladium(1-phenylallyl)chloride dimer,(p-tert- butylindenyl) palladium(II) chloride dimer, di-μ-chlorobis[2′-(amino-N)[1,1′-biphenyl]-2- yl-C]dipalladium(II), di-μ-mesylbis[2′-(amino-N)[1,1′-biphenyl]-2-yl-C]dipalladium(II), di-μ-mesylbis[2′-(methylamino-N)[1,1′-biphenyl]-2-yl-C]dipalladium(II), and di-μ- chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium(II). Examples of ligands that form palladium catalysts in situ in combination with a palladium source described above include: mono or diphosphines such as PtBu3, PAd3, AmPhos, cataCXiumA, PtBu2Bu, PtBu2Ph, PtBu2-p-C6H4CF3, cataCXium POMeCy, CPhos, RuPhos, SPhos, dppf, dcypf, dippf, and dtbpf. The term “salt” as used herein refers to any kind of salts formed by reacting the compounds disclosed herein with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic
acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, N-acetylcystein and the like. Where the compounds disclose herein contain a free acidic moiety, salts may also be prepared by addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins and the like. Manufacturing Process In a first aspect, the present invention provides a process for manufacturing compound 3, or a salt thereof,
3 comprising: (a) reacting aryl bromide 1 +
with (4-carbomethoxyphenyl)boronic acid (2)
in the presence of a palladium catalyst and a base, to afford said compound 3. In a further aspect, the present invention provides a process for manufacturing compound 3, or a salt thereof,
3 comprising: (a) reacting aryl bromide 1 +
with (4-carbomethoxyphenyl)boronic acid (2)
in the presence of a palladium catalyst and a base in an aromatic solvent, to afford said compound 3; wherein said palladium catalyst is selected from: i) a preformed catalyst selected from Pd(PPh3)4, Pd(L1)2, [Pd(L1)XCl], [Pd(L1)X]trifluoromethanesulfonate, [Pd(L1)(2-(2′-amino-1,1′-biphenyl)Cl]; [Pd(L1)(2-(2′-amino-1,1′-biphenyl)]methanesulfonate, [Pd(L1)(2-(2′-
methylamino-1,1′-biphenyl)]methanesulfonate, [Pd(L1)(2-(2- aminoethyl)phenyl)Cl], Pd(L2)Cl2, Pd(L2)2Cl2, and [PdI(L3)]2; wherein X is selected from allyl, 2-butenyl, 2-methylallyl, 1-phenylallyl, p-tert- butylindenyl; L1 is selected from PBu3, AmPhos, CPhos, RuPhos, and SPhos; L2 is selected from PtBu3, AmPhos, PtBu2Bu, PtBu2Ph, PtBu2-p-C6H4CF3)2, dppf, dcypf, dippf, and dtbpf; and L3 is selected from PtBu3, AmPhos; and ii) a catalyst that is formed in situ from: iia) a palladium source selected from palladium bis(dibenzylideneacetone) (Pd(dba)2), (Pd2(dba)3), bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), palladium acetate (Pd(OAc)2, palladium trifluoracetate (Pd(TFA)2), palladium chloride (PdCl2), palladium bromide (PdBr2),palladium iodide (PdI2), palladium bis acetylacetonate (Pd(acac)2), (Pd(PPh3)4), bis(acetonitrile)-palladium(II) dichloride (PdCl2(CH3CN)2), cyclopentadienyl allyl palladium, allylpalladium(II) chloride dimer (Pd(allyl)Cl)2), (2-butenyl)chloropalladium dimer, (2- methylallyl) palladium(II) chloride dimer, palladium(1- phenylallyl)chloride dimer,(p-tert-butylindenyl) palladium(II) chloride dimer, di-μ-chlorobis[2′-(amino-N)[1,1′-biphenyl]-2-yl- C]dipalladium(II), di-μ-mesylbis[2′-(amino-N)[1,1′-biphenyl]-2-yl- C]dipalladium(II), di-μ-mesylbis[2′-(methylamino-N)[1,1′-biphenyl]-2- yl-C]dipalladium(II), and di-μ-chlorobis[2- [(dimethylamino)methyl]phenyl-C,N]dipalladium(II); and iib) a ligand selected from mono- and diphosphines, in particular a ligand selected from PtBu3, PAd3, AmPhos, cataCXiumA, PtBu2Bu, PtBu2Ph, PtBu2-p-C6H4CF3, cataCXium POMeCy, CPhos, RuPhos, SPhos, dppf, dcypf, dippf, and dtbpf; and said base is selected from inorganic bases and alcoholates, preferably wherein said base is selected from Na2CO3, Ba(OH)2, K3PO4, Cs2CO3, K2CO3, TlOH, KF, CsF, Bu4F, and NaOH, more preferably wherein said base is K3PO4 or K2CO3. Suzuki coupling of aryl bromide 1 with (4-carbomethoxyphenyl)boronic acid (2) instead of with (4-(tert-Butoxycarbonyl)phenyl)boronic acid as described in WO2019206853 affords the new intermediate 3, which can be partially deprotected under basic conditions
to afford new intermediate 4 (vide infra). This is in contrast to the gobal deprotection under acidic conditions (trifluoroacetic acid) described in WO2019206853. Importantly, new intermediate 4 is crystalline and can thus be conveniently purified by crystallization, replacing the need for chromatography as described in WO2019206853. In one embodiment of step (a) of the process according to the invention, said palladium catalyst is selected from: i) a preformed catalyst selected from Pd(PPh3)4, Pd(L1)2, [Pd(L1)XCl], [Pd(L1)X]trifluoromethanesulfonate, [Pd(L1)(2-(2′-amino-1,1′-biphenyl)Cl]; [Pd(L1)(2-(2′-amino-1,1′-biphenyl)]methanesulfonate, [Pd(L1)(2-(2′-methylamino- 1,1′-biphenyl)]methanesulfonate, [Pd(L1)(2-(2-aminoethyl)phenyl)Cl], Pd(L2)Cl2, Pd(L2)2Cl2, and [PdI(L3)]2; wherein X is selected from allyl, 2-butenyl, 2- methylallyl, 1-phenylallyl, p-tert-butylindenyl; L1 is selected from PBu3, AmPhos, CPhos, RuPhos, and SPhos; L2 is selected from PtBu3, AmPhos, PtBu2Bu, PtBu2Ph, PtBu2-p-C6H4CF3)2, dppf, dcypf, dippf, and dtbpf; and L3 is selected from PtBu3, AmPhos; and ii) a catalyst that is formed in situ from: iia) a palladium source selected from palladium bis(dibenzylideneacetone) (Pd(dba)2), (Pd2(dba)3), bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), palladium acetate (Pd(OAc)2, palladium trifluoracetate (Pd(TFA)2), palladium chloride (PdCl2), palladium bromide (PdBr2),palladium iodide (PdI2), palladium bis acetylacetonate (Pd(acac)2), (Pd(PPh3)4), bis(acetonitrile)-palladium(II) dichloride (PdCl2(CH3CN)2), cyclopentadienyl allyl palladium, allylpalladium(II) chloride dimer (Pd(allyl)Cl)2), (2- butenyl)chloropalladium dimer, (2-methylallyl) palladium(II) chloride dimer, palladium(1-phenylallyl)chloride dimer,(p-tert-butylindenyl) palladium(II) chloride dimer, di-μ-chlorobis[2′-(amino-N)[1,1′-biphenyl]-2-yl- C]dipalladium(II), di-μ-mesylbis[2′-(amino-N)[1,1′-biphenyl]-2-yl- C]dipalladium(II), di-μ-mesylbis[2′-(methylamino-N)[1,1′-biphenyl]-2-yl- C]dipalladium(II), and di-μ-chlorobis[2-[(dimethylamino)methyl]phenyl- C,N]dipalladium(II); and iib) a ligand selected from mono- and diphosphines, in particular a ligand selected from PtBu3, PAd3, AmPhos, cataCXiumA, PtBu2Bu, PtBu2Ph, PtBu2-p-
C6H4CF3, cataCXium POMeCy, CPhos, RuPhos, SPhos, dppf, dcypf, dippf, and dtbpf. In one embodiment of step (a) of the process according to the invention, said palladium catalyst is selected from Pd(PPh3)4, Pd(L1)2, [Pd(L1)XCl], [Pd(L1)X]trifluoromethanesulfonate, [Pd(L1)(2-(2′-amino-1,1′-biphenyl)Cl]; [Pd(L1)(2-(2′- amino-1,1′-biphenyl)]methanesulfonate, [Pd(L1)(2-(2′-methylamino-1,1′- biphenyl)]methanesulfonate, [Pd(L1)(2-(2-aminoethyl)phenyl)Cl], Pd(L2)Cl2, Pd(L2)2Cl2, and [PdI(L3)]2; wherein X is selected from allyl, 2-butenyl, 2-methylallyl, 1-phenylallyl, p- tert-butylindenyl; L1 is selected from PBu3, AmPhos, CPhos, RuPhos, and SPhos; L2 is selected from PtBu3, AmPhos, PtBu2Bu, PtBu2Ph, PtBu2-p-C6H4CF3)2, dppf, dcypf, dippf, and dtbpf; and L3 is selected from PtBu3, AmPhos. In one embodiment of step (a) of the process according to the invention, said palladium catalyst is formed in situ from: i) a palladium source selected from palladium bis(dibenzylideneacetone) (Pd(dba)2), (Pd2(dba)3), bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), palladium acetate (Pd(OAc)2, palladium trifluoracetate (Pd(TFA)2), palladium chloride (PdCl2), palladium bromide (PdBr2),palladium iodide (PdI2), palladium bis acetylacetonate (Pd(acac)2), (Pd(PPh3)4), bis(acetonitrile)-palladium(II) dichloride (PdCl2(CH3CN)2), cyclopentadienyl allyl palladium, allylpalladium(II) chloride dimer (Pd(allyl)Cl)2), (2-butenyl)chloropalladium dimer, (2-methylallyl) palladium(II) chloride dimer, palladium(1-phenylallyl)chloride dimer,(p-tert- butylindenyl) palladium(II) chloride dimer, di-μ-chlorobis[2′-(amino-N)[1,1′- biphenyl]-2-yl-C]dipalladium(II), di-μ-mesylbis[2′-(amino-N)[1,1′-biphenyl]-2-yl- C]dipalladium(II), di-μ-mesylbis[2′-(methylamino-N)[1,1′-biphenyl]-2-yl- C]dipalladium(II), and di-μ-chlorobis[2-[(dimethylamino)methyl]phenyl- C,N]dipalladium(II); and ii) a ligand selected from mono- and diphosphines. In a preferred embodiment, said mono- and diphosphine ligands are selected from PtBu3, PAd3, AmPhos, cataCXiumA, PtBu2Bu, PtBu2Ph, PtBu2-p-C6H4CF3, cataCXium POMeCy, CPhos, RuPhos, SPhos, dppf, dcypf, dippf, and dtbpf.
In a preferred embodiment of step (a) of the process according to the invention, said palladium catalyst is selected from Pd(PPh3)4, CPhosPdG3, Pd2(dba)3 + CPhos, and PdCl2(dtbpf). It has been found that the palladium catalyst PdCl2(dtbpf) works particularly well in the Suzuki coupling according to the invention. Thus, the Suzuki coupling with PdCl2(dtbpf) requires only a very low catalyst loading (2 mol% or less) and a small excess of boronic acid 2, which results in reduced amount of contamination of the final product with palladium and organic impurities, reduced cost and reduced waste. Those are all important aspects when manufacturing chemicals on an industrial scale, especially when manufacturing pharmaceutical products. Thus, in a particularly preferred embodiment of step (a) of the process according to the invention, said palladium catalyst is PdCl2(dtbpf). In one embodiment of step (a) of the process according to the invention, said palladium catalyst is present in an amount of 1 mol% to 10 mol% relative to aryl bromide 1. In one embodiment of step (a) of the process according to the invention, said palladium catalyst is present in an amount of 1 mol% to 5 mol% relative to aryl bromide 1. In a preferred embodiment of step (a) of the process according to the invention, said palladium catalyst is present in an amount of 1 mol% to 3 mol% relative to aryl bromide 1. In a particularly preferred embodiment of step (a) of the process according to the invention, said palladium catalyst is present in an amount of 2 mol% relative to aryl bromide 1. In a preferred embodiment of step (a) of the process according to the invention, said palladium catalyst is PdCl2(dtbpf) and is present in an amount of 1 mol% to 10 mol% relative to aryl bromide 1. In a further preferred embodiment of step (a) of the process according to the invention, said palladium catalyst is PdCl2(dtbpf) and is present in an amount of 1 mol% to 5 mol% relative to aryl bromide 1.
In a further preferred embodiment of step (a) of the process according to the invention, said palladium catalyst is PdCl2(dtbpf) and is present in an amount of 1 mol% to 3 mol% relative to aryl bromide 1. In a particularly preferred embodiment of step (a) of the process according to the invention, said palladium catalyst is PdCl2(dtbpf) and is present in an amount of 2 mol% relative to aryl bromide 1. In one embodiment of step (a) of the process according to the invention, said base is selected from inorganic bases and alcoholates. In a preferred embodiment of step (a) of the process according to the invention, said base is selected from Na2CO3, Ba(OH)2, K3PO4, Cs2CO3, K2CO3, TlOH, KF, CsF, Bu4F, and NaOH. In a preferred embodiment of step (a) of the process according to the invention, said base is selected from K3PO4 and K2CO3. In a particularly preferred embodiment of step (a) of the process according to the invention, said base is K3PO4. In a particularly preferred embodiment of step (a) of the process according to the invention, said base is K2CO3. In one embodiment of step (a) of the process according to the invention 1 to 4 equivalents of said base relative to aryl bromide 1 are used. In a preferred embodiment of step (a) of the process according to the invention 1 to 3 equivalents of said base relative to aryl bromide 1 are used. In a further preferred embodiment of step (a) of the process according to the invention 1 to 2 equivalents of said base relative to aryl bromide 1 are used. In a particularly preferred embodiment of step (a) of the process according to the invention 1.5 equivalents of said base relative to aryl bromide 1 are used. One advantage of the Suzuki coupling of process step (a) according to the invention is that it performs very well in toluene, as opposed to the toxic dioxane described in
WO2019206853. This is of particular importance when conducting the reaction on an industrial scale and in view of the fact that the final antibiotic product of formula (I) is for administration to mammals, where traces of toxic solvents are not acceptable. Thus, in one embodiment of step (a) of the process according to the invention, step (a) is conducted in an aromatic solvent. In one embodiment, said aromatic solvent is selected from toluene, xylenes (o-xylene, p- xylene, m-xylene or a mixture thereof), ethylbenzene, anisole, cumene, and cymene. In a preferred embodiment said aromatic solvent is toluene. It was found that the methyl ester moiety of boronic acid building block 2 is prone to hydrolysis under the reaction conditions used. However, it was surprisingly found that adding water to the reaction mixture prevents said hydrolysis, allowing to employ fewer equivalents of this building block. Thus, in one embodiment of step (a) of the process according to the invention, the process is conducted in the further presence of water. In one embodiment of step (a) of the process according to the invention, the process is conducted in the further presence of 1 to 30 equivalents of water relative to aryl bromide 1. In one embodiment of step (a) of the process according to the invention, the process is conducted in the further presence of 1 to 20 equivalents of water relative to aryl bromide 1. In one embodiment of step (a) of the process according to the invention, the process is conducted in the further presence of 5 to 25 equivalents of water relative to aryl bromide 1. In a preferred embodiment of step (a) of the process according to the invention, the process is conducted in the further presence of 10 to 25 equivalents of water relative to aryl bromide 1. In a further preferred embodiment of step (a) of the process according to the invention, the process is conducted in the further presence of 12.5 to 25 equivalents of water relative to aryl bromide 1.
In a particularly preferred embodiment of step (a) of the process according to the invention, the process is conducted in the further presence of 25 equivalents of water relative to aryl bromide 1. In one embodiment of step (a) of the process according to the invention, the process is conducted in the further presence of 5 to 15 equivalents of water relative to aryl bromide 1. In one embodiment of step (a) of the process according to the invention, the process is conducted in the further presence of 10 to 15 equivalents of water relative to aryl bromide 1. In a particularly preferred embodiment of step (a) of the process according to the invention, the process is conducted in the further presence of 12.5 equivalents of water relative to aryl bromide 1. In one embodiment of step (a) of the process according to the invention, the process is conducted in the further presence of water, wherein the water is continuously added over a period of 2-8 h to the reaction mixture comprising aryl bromide 1, boronic acid 2, palladium catalyst and base. In one embodiment of step (a) of the process according to the invention, the process is conducted in the further presence of water, wherein the water is continuously added over a period of 2-7 h to the reaction mixture comprising aryl bromide 1, boronic acid 2, palladium catalyst and base. In a preferred embodiment of step (a) of the process according to the invention, the process is conducted in the further presence of water, wherein the water is continuously added over a period of 3-6 h to the reaction mixture comprising aryl bromide 1, boronic acid 2, palladium catalyst and base. In one embodiment of step (a) of the process according to the invention, the process is conducted in the further presence of water, wherein the water is continuously added over a period of 2-5 h to the reaction mixture comprising aryl bromide 1, boronic acid 2, palladium catalyst and base. In a preferred embodiment of step (a) of the process according to the invention, the process is conducted in the further presence of water, wherein the water is continuously added over
a period of 2-4 h to the reaction mixture comprising aryl bromide 1, boronic acid 2, palladium catalyst and base. In a particularly preferred embodiment of step (a) of the process according to the invention, the process is conducted in the further presence of water, wherein the water is continuously added over a period of 6 h to the reaction mixture comprising aryl bromide 1, boronic acid 2, palladium catalyst and base. In a particularly preferred embodiment of step (a) of the process according to the invention, the process is conducted in the further presence of water, wherein the water is continuously added over a period of 3 h to the reaction mixture comprising aryl bromide 1, boronic acid 2, palladium catalyst and base. As mentioned above, the new Suzuki coupling according to the invention allows the use of less equivalents of boronic acid 2 compared to the amound of boronic acid that is used in the process described in WO2019206853. Thus, in one embodiment of step (a) of the process according to the invention, 1 to <1.5 equivalents of boronic acid 2 are used relative to aryl bromide 1. In a preferred embodiment of step (a) of the process according to the invention, 1 to 1.4 equivalents of boronic acid 2 are used relative to aryl bromide 1. In a further preferred embodiment of step (a) of the process according to the invention, 1 to 1.3 equivalents of boronic acid 2 are used relative to aryl bromide 1. In a further preferred embodiment of step (a) of the process according to the invention, 1.05 to 1.2 equivalents of boronic acid 2 are used relative to aryl bromide 1. In a further preferred embodiment of step (a) of the process according to the invention, 1 to 1.2 equivalents of boronic acid 2 are used relative to aryl bromide 1. In a further preferred embodiment of step (a) of the process according to the invention, 1 to 1.1 equivalents of boronic acid 2 are used relative to aryl bromide 1. In a particularly preferred embodiment of step (a) of the process according to the invention, 1.2 equivalents of boronic acid 2 are used relative to aryl bromide 1.
In a particularly preferred embodiment of step (a) of the process according to the invention, 1.05 equivalents of boronic acid 2 are used relative to aryl bromide 1. If desired, the level of palladium contamination of compound 3 may be reduced, typically to a level of <10 ppm, by treating compound 3 with N-acetylcysteine or ammonium pyrrolidinedithiocarbamate in situ. Thus, in one embodiment, the process for manufacturing compound 3, or a salt thereof, according to the invention optionally further comprises: (b) adding ammonium pyrrolidinedithiocarbamate or an aqueous solution of N- acetylcysteine to the reaction mixture obtained from step (a). In one embodiment, the process for manufacturing compound 3, or a salt thereof, according to the invention optionally further comprises: (b) adding an aqueous solution of N-acetylcysteine to the reaction mixture obtained from step (a). In one embodiment, the process for manufacturing compound 3, or a salt thereof, according to the invention optionally further comprises: (b) adding ammonium pyrrolidinedithiocarbamate to the reaction mixture obtained from step (a). In a further aspect, the present invention provides a process for manufacturing compound 4, or a salt thereof,
comprising steps (a) and (b) as described herein, and further comprising: (c) reacting compound 3 described herein with sodium hydroxide to afford said compound 4.
In one embodiment, step (c) is performed in a solvent being an alcohol, preferably in methanol. In a further aspect, the present invention provides a process for manufacturing compound 4, or a salt thereof, comprising steps (a) and (b) as described herein, and further comprising: (c) reacting compound 3 according to claim 1 with 2 to 10 equivalents, preferably 3 to 8 equivalents, more preferably 4 to 7 equivalents, in particular 7 equivalents of sodium hydroxide to afford said compound 4, wherein said sodium hydroxide is added as a 5% w/w to 30% w/w, preferably 10% w/w to 20% w/w, in particular a 16% w/w aqueous solution to a solution of compound 3 in an alcoholic solvent or a mixture of water and an alcoholic solvent. In one embodiment, said alcoholic solvent is methanol. A major advantage of new compound 4 according to the invention is its crystallinity, allowing it to be purified by crystallization. Especially on an industrial scale, crystallization is a convenient means of purification of chemicals, as opposed to other purification techniques, such as chromatography. Thus, in one embodiment, the process for manufacturing compound 4 according to the invention optionally further comprises: (d) crystallizing said compound 4. In a preferred embodiment of step (d) of the process according to the invention, said crystallizing of said compound 4 is crystallizing of said compound 4 from a mixture of an alcohol and acetone. In a preferred embodiment, said alcohol is selected from 2-propanol and 1-propanol. In a particularly preferred embodiment said alcohol is 1-propanol. In a further aspect, the present invention provides a process for manufacturing the compound of formula (I), or a pharmaceutically acceptable salt thereof,
comprising process steps (a)-(d) described herein, and further comprising: (e) reacting compound 4 described herein with an acid, to afford said compound of formula (I). In a preferred embodiment of step (e) of the process according to the invention, said acid is hydrochloric acid. In one embodiment, step (e) is performed in a solvent mixture selected from acetone/water, THF/water, and acetonitrile/water. In one embodiment, 2 to 6 equivalents of acid relative to compound 4 are used in step (e) of the process according to the invention. In a preferred embodiment, 3 to 5 equivalents of acid relative to compound 4 are used in step (e) of the process according to the invention. In a further preferred embodiment, 4 to 5 equivalents of acid relative to compound 4 are used in step (e) of the process according to the invention. In a further preferred embodiment, 3.5 to 4.5 equivalents of acid relative to compound 4 are used in step (e) of the process according to the invention. In a particularly preferred embodiment, 4 to 4.1 equivalents of acid relative to compound 4 are used in step (e) of the process according to the invention. In a further particularly preferred embodiment, 4 equivalents of acid relative to compound 4 are used in step (e) of the process according to the invention. In a further particularly preferred embodiment, 4.1 equivalents of acid relative to compound 4 are used in step (e) of the process according to the invention.
In one embodiment, step (e) of the process according to the invention is performed between room temperature and reflux. In a preferred embodiment, step (e) of the process according to the invention is performed between 30 °C and reflux. In a further preferred embodiment, step (e) of the process according to the invention is performed between 35 °C and 65 °C. In a particularly preferred embodiment, step (e) of the process according to the invention is performed between 35 °C and 60 °C. In a further aspect, the present invention provides the use of the process for manufacturing compound 3 described herein in the manufacture of the compound of formula (I). In a further aspect, the present invention provides the use of the process for manufacturing compound 4 described herein in the manufacture of the compound of formula (I). Compounds of the Invention The present invention relates to certain synthetic intermediates that are useful for manufacturing the novel antibiotic of formula (I) described herein. The present invention also relates to certain compounds when manufactured according to the novel chemical processes described herein. In more detail, in one aspect, the present invention provides a compound, which is tert- butyl 3-[[(11S,14S,17S)-14-[4-(tert-butoxycarbonylamino)butyl]-11-[3-(tert- butoxycarbonylamino)propyl]-22-(4-methoxycarbonylphenyl)-16-methyl-12,15,18-trioxo- 2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-17- yl]methyl]indole-1-carboxylate (3), or a salt thereof
. In a further aspect, the present invention provides a compound, which is 4-[(11S,14S,17S)- 14-[4-(tert-butoxycarbonylamino)butyl]-11-[3-(tert-butoxycarbonylamino)propyl]-17-(1H- indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-22-yl]benzoic acid (4), or a salt thereof
. In a further aspect, the present invention relates to compound 3 when manufactured according to the processes for manufacturing compound 3 described herein. In a further aspect, the present invention relates to compound 3 when manufactured according to the processes for manufacturing compound 3 described herein. In a further aspect, the present invention relates to the compound of formula (I) when manufactured according to the processes for manufacturing the compound of formula (I) described herein. In a further aspect, the present invention relates to the use of compound 3 described herein in the manufacture of the compound of formula (I).
In a further aspect, the present invention relates to the use of compound 4 described herein in the manufacture of the compound of formula (I). Examples The invention will be more fully understood by reference to the following examples. The claims should not, however, be construed as limited to the scope of the examples. The following abbreviations are used in the present text: PdCl2(dtbpf) = [1,1′-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (CAS 95408-45-0); HCl = hydrochloric acid; PPh3 = triphenylphosphine; PtBu3 = tri-tert- butylphosphine; PAd3 = tri(1-adamantyl)phosphine; AmPhos = (4-(N,N- dimethylamino)phenyl)di-tert-butyl phosphine; cataCXiumA = di(1-adamantyl)-n- butylphosphine; PtBu2Bu = di-t-butyl(n-butyl)phosphine; PtBu2Ph = di-t- butyl(phenyl)phosphine; PtBu2-p-C6H4CF3 = di-t-butyl(4-trifluoromethyl phenyl)phosphine; cataCXium POMeCy = 1-(2-Methoxyphenyl)-2- (dicyclohexylphosphino)pyrrole; CPhos = 2-dicyclohexylphosphino-2′,6′-bis(N,N- dimethylamino)biphenyl; RuPhos = 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl; SPhos = 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl; dppf = 1,1′-Ferrocenediyl- bis(diphenylphosphine); dcypf = 1,1′-Ferrocenediyl-bis(dicyclohexylphosphine); dippf = 1,1′-Ferrocenediyl-bis(diisopropylphosphine); dtbpf = 1,1′-Bis(di-tert- butylphosphino)ferrocene; Pd(PPh3)4 = tetrakis (triphenyl-phosphino) palladium; CPhosPdG3 = [(2-Dicyclohexylphosphino-2′,6′-bis(N,N-dimethylamino) -1,1′-biphenyl)- 2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate; Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0). Example 1 Preparation of 4-[(11S,14S,17S)-14-[4-(tert-butoxycarbonylamino)butyl]-11-[3-(tert- butoxycarbonylamino)propyl]-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-22- yl]benzoic acid
To a dry, Ar-flushed flask were charged 3-[[(11S,14S,17S)-22-bromo-14-[4-(tert- butoxycarbonylamino)butyl]-11-[3-(tert-butoxycarbonylamino)propyl]-12,15,18-triketo- 16-methyl-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23- hexaen-17-yl]methyl]indole-1-carboxylic acid tert-butyl ester (1) (30.0 g, 28.57 mmol, 1.0 eq), tripotassium phosphate (9.10 g , 42.85 mmol, 1.5 eq) and toluene (300 ml, 10 vol). The mixture was degassed and heated to 90°C. To the hot mixture were added (4- carbomethoxyphenyl)boronic acid (2) (5.4 g, 30.00 mmol, 1.05 eq) and PdCl2(dtbpf) (372 mg, 0.571 mmol, 0.02 eq). To the resulting suspension water (6.43 g, 357.1 mmol, 12.5 eq) was charged over 3 h via syringe pump. The mixture was stirred for 4h. The mixture was cooled to 60°C and 9% w/w aq. N-acetylcysteine was added. The mixture was stirred for 1h at 60°C, then the phases were split. The organic phase was extracted with water. The organic layer was treated with activated charcoal at room temperature. The mixture was distilled under reduced pressure an the solvent was swapped to methanol and concentrated to a final volume of 80 ml. Methanol (221 ml, 7.4 vol) and water (70 ml, 2.3vol) are added. The mixture is heated to 50°C and 32% w/w aq. sodium hydroxide (25.0 g, 200.0 mmol, 7.0 eq) is added. The mixture is stirred for 5h and then cooled to 20°C. Methanol is distilled off under reduced pressure. Ethyl acetate (250 ml, 8.3 vol) and a solution of citric acid (27.8 g) in water (60 ml, 2 vol) are charged to the residue at room temperature. The organic phase is extracted with a solution of sodium bicarbonate (4.88 g) in water (150 ml) and then with water (150 ml). The organic phase is concentrated to 3 vol under reduced pressure. The solvent is switched to 1-propanol to a final volume of ca.3.3 vol. The residue is heated to 60°C. Acetone (198 g, 250 ml, 8.33 vol) is added in 1.5h. The
resulting suspension is cooled to 20°C in 5h. The solids are recovered by suction filtration and rinsed with a solution of 1-propanol (20 g) and acetone (60 g) and dried under reduced pressure.23.1 g (81.4% yield) of crude 4-[(11S,14S,17S)-14-[4-(tert- butoxycarbonylamino)butyl]-11-[3-(tert-butoxycarbonylamino)propyl]-17-(1H-indol-3- ylmethyl)-12,15,18-triketo-16-methyl-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-22-yl]benzoic acid (4) as off-white solid is obtained. Example 1a Preparation of 4-[(11S,14S,17S)-14-[4-(tert-butoxycarbonylamino)butyl]-11-[3-(tert- butoxycarbonylamino)propyl]-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-22- yl]benzoic acid
To a dry, Ar-flushed flask were charged 3-[[(11S,14S,17S)-22-bromo-14-[4-(tert- butoxycarbonylamino)butyl]-11-[3-(tert-butoxycarbonylamino)propyl]-12,15,18-triketo- 16-methyl-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23- hexaen-17-yl]methyl]indole-1-carboxylic acid tert-butyl ester (1) (5.0 g, 4.76 mmol, 1.0 eq), potassium carbonate (0.987 g , 7.14 mmol, 1.5 eq) and toluene (50 ml, 10 vol). The mixture was degassed and heated to 90°C. To the hot mixture were added (4- carbomethoxyphenyl)boronic acid (2) (1.0 g, 5.56 mmol, 1.2 eq) and toluene (25 ml, 5 vol). The mixture is distilled under reduced pressure, until 25 ml distillate are collected. PdCl2(dtbpf) (62 mg, 0.095 mmol, 0.02 eq) is added and the mixture is stirred ca.30 min
at 85-90°C. Water (2.14 g, 119.03 mmol, 25.0 eq) was charged over 6 h via syringe pump. The mixture was stirred for at least 2h. Ammonium pyrrolidinedithiocarbamate (237 mg, 1.43 mmol, 0.3 eq) is added. The mixture was stirred for at least 1 h at 85-90°C, then the phases were split. The organic phase was extracted with water. The organic layer was distilled under reduced pressure and methanol (12.5 ml, 2.5 vol) is added. The mixture is cooled to 40°C. A 16% w/w aqueous soludion of sodium hydroxide (8.33 g, 33.33 mmol, 7.0 eq) is added. The mixture is stirred for at least 5 h and then cooled to 20°C. A 35% w/w aqueous solution of citric acid (13.07 g, 23.81 mmol, 5.0 eq) is charged to the residue at 20°C and the mixture is distilled under reduced pressure. The residue is extracted with ethyl acetate. The organic phase is extracted with water, dried over sodium sulfate and diluted with ethyl acetate (15 ml). The solution is heated to 60°C and stirred for ca.1h. The resulting suspension is cooled in 12h to 0°C and stirred at least 2h. The solids are recovered by suction filtration and rinsed with cold ethyl acetate.3.2 g (80.4% yield) of 4-[(11S,14S,17S)-14-[4-(tert-butoxycarbonylamino)butyl]-11-[3-(tert- butoxycarbonylamino)propyl]-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2- thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-22- yl]benzoic acid (4) as off-white solid is obtained. Example 2 Preparation of 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3- ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-22-yl]benzoic acid
4-[(11S,14S,17S)-14-[4-(tert-butoxycarbonylamino)butyl]-11-[3-(tert- butoxycarbonylamino)propyl]-17-(1H-indol-3-ylmethyl)-12,15,18-triketo-16-methyl-2- thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-22-
yl]benzoic acid (4) (200 g, 201.78 mmol, 1 eq), tetrahydrofuran (455 ml), and water (320 mL) were charged into a 2000 mL four-necked reaction vessel and stirred at 35°C. A solution of HCl 25% (99.8 mL, 821 mmol, 4.1 eq.) and water (200 mL) was added within 10 minutes at 35 to 50°C. The addition funnel was rinsed with water (50 mL) and the reaction mixture was stirred at 60°C for 4 hours. Following basic workup and crystallization at pH 10, the title compound was obtained as a white powder (158.3 g, 98.5%).
Claims
CLAIMS 1. A compound, which is tert-butyl 3-[[(11S,14S,17S)-14-[4-(tert- butoxycarbonylamino)butyl]-11-[3-(tert-butoxycarbonylamino)propyl]-22-(4- methoxycarbonylphenyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-17- yl]methyl]indole-1-carboxylate (3), or a salt thereof
. 2. A compound, which is 4-[(11S,14S,17S)-14-[4-(tert-butoxycarbonylamino)butyl]- 11-[3-(tert-butoxycarbonylamino)propyl]-17-(1H-indol-3-ylmethyl)-16-methyl- 12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa- 1(25),3,5,7,21,23-hexaen-22-yl]benzoic acid (4), or a salt thereof
. 3. A process for manufacturing compound 3 according to claim 1, or a salt thereof, comprising: (a) reacting aryl bromide 1
+ with (4-carbomethoxyphenyl)boronic acid (2)
in the presence of a palladium catalyst and a base in an aromatic solvent, to afford said compound 3; wherein said palladium catalyst is selected from: i) a preformed catalyst selected from Pd(PPh3)4, Pd(L1)2, [Pd(L1)XCl], [Pd(L1)X]trifluoromethanesulfonate, [Pd(L1)(2-(2′-amino-1,1′-biphenyl)Cl]; [Pd(L1)(2-(2′-amino-1,1′-biphenyl)]methanesulfonate, [Pd(L1)(2-(2′- methylamino-1,1′-biphenyl)]methanesulfonate, [Pd(L1)(2-(2- aminoethyl)phenyl)Cl], Pd(L2)Cl2, Pd(L2)2Cl2, and [PdI(L3)]2; wherein X is selected from allyl, 2-butenyl, 2-methylallyl, 1-phenylallyl, p-tert- butylindenyl; L1 is selected from PBu3, AmPhos, CPhos, RuPhos, and SPhos; L2 is selected from PtBu3, AmPhos, PtBu2Bu, PtBu2Ph, PtBu2-p-C6H4CF3)2, dppf, dcypf, dippf, and dtbpf; and L3 is selected from PtBu3, AmPhos; and ii) a catalyst that is formed in situ from: iia) a palladium source selected from palladium bis(dibenzylideneacetone) (Pd(dba)2), (Pd2(dba)3), bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), palladium acetate (Pd(OAc)2, palladium trifluoracetate (Pd(TFA)2), palladium chloride (PdCl2), palladium bromide (PdBr2),palladium iodide (PdI2), palladium bis acetylacetonate (Pd(acac)2), (Pd(PPh3)4), bis(acetonitrile)-palladium(II) dichloride (PdCl2(CH3CN)2), cyclopentadienyl allyl palladium, allylpalladium(II) chloride dimer (Pd(allyl)Cl)2), (2-butenyl)chloropalladium dimer, (2- methylallyl) palladium(II) chloride dimer, palladium(1- phenylallyl)chloride dimer,(p-tert-butylindenyl) palladium(II) chloride
dimer, di-μ-chlorobis[2′-(amino-N)[1,1′-biphenyl]-2-yl- C]dipalladium(II), di-μ-mesylbis[2′-(amino-N)[1,1′-biphenyl]-2-yl- C]dipalladium(II), di-μ-mesylbis[2′-(methylamino-N)[1,1′-biphenyl]-2- yl-C]dipalladium(II), and di-μ-chlorobis[2- [(dimethylamino)methyl]phenyl-C,N]dipalladium(II); and iib) a ligand selected from mono- and diphosphines, in particular a ligand selected from PtBu3, PAd3, AmPhos, cataCXiumA, PtBu2Bu, PtBu2Ph, PtBu2-p-C6H4CF3, cataCXium POMeCy, CPhos, RuPhos, SPhos, dppf, dcypf, dippf, and dtbpf; and said base is selected from inorganic bases and alcoholates, preferably wherein said base is selected from Na2CO3, Ba(OH)2, K3PO4, Cs2CO3, K2CO3, TlOH, KF, CsF, Bu4F, and NaOH, more preferably wherein said base is K3PO4 or K2CO3. 4. The process according to claim 3, wherein said palladium catalyst is present in an amount of 1 mol% to 10 mol%, preferably 1 mol% to 5 mol%, more preferably 1 mol% to 3 mol%, most preferably 2 mol% relative to aryl bromide 1. 5. The process according to claim 3 or 4, wherein 1 to 4 equivalents, preferably 1 to 3 equivalents, more preferably 1 to 2 equivalents, most preferably 1.5 equivalents of said base relative to aryl bromide 1 are used. 6. The process according to any one of claims 3 to 5, wherein said aromatic solvent is selected from toluene, xylenes (o-xylene, p-xylene, m-xylene or a mixture thereof), ethylbenzene, anisole, cumene, and cymene. 7. The process according to claim 6, wherein said aromatic solvent is toluene. 8. The process according to any one of claims 3 to 7, wherein the process is conducted in the further presence of water, preferably 1 to 30 equivalents, more preferably 5 to 25 equivalents, most preferably 10 to 25 equivalents, in particular 12.5 to 25 equivalents of water relative to aryl bromide 1. 9. The process according to claim 8, wherein the water is continuously added over a period of 2-8 h, preferably over a period of 2-7 h, most preferably over a period of 3-
6 h to the reaction mixture comprising aryl bromide 1, boronic acid 2, palladium catalyst and base. 10. The process according to any one of claims 3 to 9, wherein 1 to <1.5 equivalents, preferably 1 to 1.3 equivalents, more preferably 1 to 1.2 equivalents, more preferably 1.05 to 1.2 equivalents of boronic acid 2 are used relative to aryl bromide 1. 11. The process according to any one of claims 3 to 10, optionally further comprising: (b) adding ammonium pyrrolidinedithiocarbamate or an aqueous solution of N- acetylcysteine to the reaction mixture obtained from step (a). 12. A process for manufacturing compound 4 according to claim 2, or a salt thereof, comprising the process according to any one of claims 3 to 11, and further comprising: (c) reacting compound 3 according to claim 1 with 2 to 10 equivalents, preferably 3 to 8 equivalents, more preferably 4 to 7 equivalents, in particular 7 equivalents of sodium hydroxide to afford said compound 4, wherein said sodium hydroxide is added as a 5% w/w to 30% w/w, preferably 10% w/w to 20% w/w, in particular a 16% w/w aqueous solution to a solution of compound 3 in an alcoholic solvent or a mixture of water and an alcoholic solvent. 13. The process according to claim 12, wherein said alcoholic solvent in step (c) is methanol. 14. The process according to claim 12 or 13, optionally further comprising: (d) crystallizing said compound 4, preferably from a mixture of 1-propanol and acetone. 15. A process for manufacturing the compound of formula (I), or a pharmaceutically acceptable salt thereof,
comprising the process according to any one of claims 12 to 14, and further comprising: (e) reacting compound 4 according to claim 2 with an acid, preferably with hydrochloric acid, to afford said compound of formula (I). 16. The process according to claim 15, wherein step (e) is performed in a solvent mixture selected from acetone/water, THF/water, and acetonitrile/water. 17. The process according to any one of claims 15 or 16, wherein 2 to 6 equivalents, preferably 3 to 5 equivalents, more preferably 4 to 5 equivalents, more preferably 3.5 to 4.5 equivalents, in particular 4.1 equivalents of acid relative to compound 4 are used in step (e). 18. The process according to any one of claims 15 to 17, wherein the process is performed between room temperature and reflux, preferably between 30 °C and reflux, more preferably between 35 °C and 65 °C, most preferably between 35 °C and 60 °C. 19. Compound 3 according to claim 1, or a salt thereof, when manufactured according to the process of any one of claims 3 to 11. 20. Compound 4 according to claim 2, or a salt thereof, when manufactured according to the process of any one of claims 12 to 14. 21. Compound of formula (I), or a pharmaceutically acceptable salt thereof,
when manufactured according to the process of any one of claims 15 to 18. 22. Use of the process according to any one of claims 3 to 14 in the manufacture of the compound of formula (I),
or a pharmaceutically acceptable salt thereof. 23. Use of compound 3 according to claim 1 in the manufacture of the compound of formula (I). 24. Use of compound 4 according to claim 2 in the manufacture of the compound of formula (I). 25. The invention as described hereinbefore.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP22189412 | 2022-08-09 | ||
| EP22189412.4 | 2022-08-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2024033278A1 true WO2024033278A1 (en) | 2024-02-15 |
Family
ID=82851819
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2023/071759 WO2024033278A1 (en) | 2022-08-09 | 2023-08-07 | Process for manufacturing an antibiotic macrocyclic peptide |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2024033278A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017072062A1 (en) * | 2015-10-27 | 2017-05-04 | F. Hoffmann-La Roche Ag | Peptide macrocycles against acinetobacter baumannii |
| WO2019206853A1 (en) | 2018-04-23 | 2019-10-31 | F. Hoffmann-La Roche Ag | Peptide macrocycles against acinetobacter baumannii |
-
2023
- 2023-08-07 WO PCT/EP2023/071759 patent/WO2024033278A1/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017072062A1 (en) * | 2015-10-27 | 2017-05-04 | F. Hoffmann-La Roche Ag | Peptide macrocycles against acinetobacter baumannii |
| WO2019206853A1 (en) | 2018-04-23 | 2019-10-31 | F. Hoffmann-La Roche Ag | Peptide macrocycles against acinetobacter baumannii |
Non-Patent Citations (1)
| Title |
|---|
| WHO DRUG INFORMATION, vol. 36, no. 2, 2022 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3847156B1 (en) | Salts of methyl 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylate and preparation process thereof | |
| WO2000008032A1 (en) | Catalyst ligands useful for cross-coupling reactions | |
| EP1838673A1 (en) | Process for making substituted piperidines | |
| KR20180095894A (en) | Metal complex | |
| EP1070075A1 (en) | Chiral phosphorated ligands useful in catalysts | |
| JP2008505903A (en) | Formation of tetrasubstituted enamides and this stereoselective reduction. | |
| WO2008077560A1 (en) | Process for the preparation of optically active 2-amino-1-phenylethanols | |
| Lage et al. | Intramolecular Palladium‐Catalyzed Direct Arylation vs. Heck Reactions: Synthesis of Pyrroloisoquinolines and Isoindoles | |
| WO2024033278A1 (en) | Process for manufacturing an antibiotic macrocyclic peptide | |
| JPH0632780A (en) | Asymmetric reduction method | |
| CN112675920B (en) | Mono-chiral center catalyst, preparation thereof and method for catalytically synthesizing chiral alcohol compound and chiral alpha-allyl alcohol | |
| JP5099830B2 (en) | Method for producing dibenzoxepin derivative | |
| AU2021302965A1 (en) | Preparation of a pyrimidinyl-3,8-diazabicyclo(3.2.1)octanylmethanone derivative and salt thereof | |
| US10947170B2 (en) | Process for the preparation of deuterated ethanol from D2O | |
| JP2003522744A (en) | Method for producing polycyclic aromatic compound | |
| US20230348390A1 (en) | Method for preparing methyl(s)-2-amino-3-(4-(2,3-dimethylpyridin-4-yl)phenylpropionate and salt thereof | |
| WO2008095678A1 (en) | Process for the preparation of optically active 2-amino-1-phenylethanols | |
| CA3107270A1 (en) | Method for producing tetracyclic compound | |
| EP2762467B1 (en) | Method for producing an optically active 2-arylpiperidinium salt | |
| WO2008044702A1 (en) | Process for production of azabicycloalkanol derivative | |
| Ku et al. | A Highly Efficient Synthesis of a Naphthalenoid Histamine‐3 Antagonist | |
| US20100261905A1 (en) | Ruthenium Catalysts for the Production of Hydrocodone, Hydromorphone or a Derivative Thereof | |
| Ruan | C− H Alkylations and Alkynylations Using Ruthenium, Nickel and Manganese Complexes | |
| US8344161B2 (en) | Process for the preparation of pyrollidine-3-carboxylic acids | |
| JP2007537144A (en) | Catalytic production of hydrocodone and hydromorphone. |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 23753892 Country of ref document: EP Kind code of ref document: A1 |