EP4267557A1 - Nouveau procédé de synthèse de composés ncas - Google Patents
Nouveau procédé de synthèse de composés ncasInfo
- Publication number
- EP4267557A1 EP4267557A1 EP21839577.0A EP21839577A EP4267557A1 EP 4267557 A1 EP4267557 A1 EP 4267557A1 EP 21839577 A EP21839577 A EP 21839577A EP 4267557 A1 EP4267557 A1 EP 4267557A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- branched
- linear
- aryl
- heteroaryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 197
- 238000000034 method Methods 0.000 title claims abstract description 62
- 230000002194 synthesizing effect Effects 0.000 title 1
- 235000008206 alpha-amino acids Nutrition 0.000 claims abstract description 37
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 195
- 229910052799 carbon Inorganic materials 0.000 claims description 151
- 125000001072 heteroaryl group Chemical group 0.000 claims description 130
- 229910052739 hydrogen Inorganic materials 0.000 claims description 122
- 125000003118 aryl group Chemical group 0.000 claims description 121
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 108
- -1 α-amino acid compound Chemical class 0.000 claims description 98
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 97
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 92
- 125000006239 protecting group Chemical group 0.000 claims description 91
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 77
- 238000002360 preparation method Methods 0.000 claims description 53
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 48
- 239000000203 mixture Substances 0.000 claims description 43
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 claims description 42
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 38
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 37
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 36
- 230000008569 process Effects 0.000 claims description 34
- 150000007530 organic bases Chemical class 0.000 claims description 33
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 32
- 229910052731 fluorine Inorganic materials 0.000 claims description 31
- ZFRKQXVRDFCRJG-UHFFFAOYSA-N skatole Chemical compound C1=CC=C2C(C)=CNC2=C1 ZFRKQXVRDFCRJG-UHFFFAOYSA-N 0.000 claims description 31
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 30
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 29
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 29
- 229910052717 sulfur Inorganic materials 0.000 claims description 24
- 125000005842 heteroatom Chemical group 0.000 claims description 21
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- 125000001153 fluoro group Chemical group F* 0.000 claims description 19
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 18
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 16
- 150000001412 amines Chemical group 0.000 claims description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 239000012453 solvate Substances 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 11
- 229910052794 bromium Inorganic materials 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 238000000354 decomposition reaction Methods 0.000 claims description 10
- 229910052740 iodine Inorganic materials 0.000 claims description 10
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 9
- 150000001721 carbon Chemical group 0.000 claims description 9
- 238000000746 purification Methods 0.000 claims description 9
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 8
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 7
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 150000001732 carboxylic acid derivatives Chemical group 0.000 claims description 7
- 229910052805 deuterium Inorganic materials 0.000 claims description 7
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 claims description 6
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 6
- OKDQKPLMQBXTNH-UHFFFAOYSA-N n,n-dimethyl-2h-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 claims description 6
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 5
- 150000001408 amides Chemical group 0.000 claims description 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 5
- ZRALSGWEFCBTJO-UHFFFAOYSA-N guanidine group Chemical group NC(=N)N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 5
- 229920001184 polypeptide Polymers 0.000 claims description 5
- 150000003573 thiols Chemical group 0.000 claims description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 4
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 4
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 claims description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 4
- 125000003158 alcohol group Chemical group 0.000 claims description 4
- 238000010936 aqueous wash Methods 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 4
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 3
- 239000004475 Arginine Substances 0.000 claims description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims description 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims description 3
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 3
- 235000009697 arginine Nutrition 0.000 claims description 3
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 claims description 3
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 3
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 239000004471 Glycine Substances 0.000 claims description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 2
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 2
- 239000004472 Lysine Substances 0.000 claims description 2
- 102000015636 Oligopeptides Human genes 0.000 claims description 2
- 108010038807 Oligopeptides Proteins 0.000 claims description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims description 2
- 239000004473 Threonine Substances 0.000 claims description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 235000004279 alanine Nutrition 0.000 claims description 2
- 235000009582 asparagine Nutrition 0.000 claims description 2
- 229960001230 asparagine Drugs 0.000 claims description 2
- 235000003704 aspartic acid Nutrition 0.000 claims description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 2
- 235000018417 cysteine Nutrition 0.000 claims description 2
- 239000000412 dendrimer Substances 0.000 claims description 2
- 229920000736 dendritic polymer Polymers 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims description 2
- 235000004554 glutamine Nutrition 0.000 claims description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 2
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims description 2
- 229960000310 isoleucine Drugs 0.000 claims description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 2
- 239000004474 valine Substances 0.000 claims description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims 1
- 101100194706 Mus musculus Arhgap32 gene Proteins 0.000 claims 1
- 101100194707 Xenopus laevis arhgap32 gene Proteins 0.000 claims 1
- 229930182817 methionine Natural products 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 15
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 9
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 150000001371 alpha-amino acids Chemical class 0.000 abstract description 3
- 239000007822 coupling agent Substances 0.000 abstract description 3
- 239000006227 byproduct Substances 0.000 abstract description 2
- 238000005897 peptide coupling reaction Methods 0.000 abstract description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 99
- 238000005481 NMR spectroscopy Methods 0.000 description 36
- 239000007787 solid Substances 0.000 description 27
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 20
- 239000000047 product Substances 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- DTETYCNJKAUROO-UHFFFAOYSA-N 4-methyl-1,3-oxazolidine-2,5-dione Chemical compound CC1NC(=O)OC1=O DTETYCNJKAUROO-UHFFFAOYSA-N 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 229940086542 triethylamine Drugs 0.000 description 4
- JHWZWIVZROVFEM-YFKPBYRVSA-N (4s)-4-(2-methylpropyl)-1,3-oxazolidine-2,5-dione Chemical compound CC(C)C[C@@H]1NC(=O)OC1=O JHWZWIVZROVFEM-YFKPBYRVSA-N 0.000 description 3
- GQBIVYSGPXCELZ-QMMMGPOBSA-N (4s)-4-benzyl-1,3-oxazolidine-2,5-dione Chemical compound O=C1OC(=O)N[C@H]1CC1=CC=CC=C1 GQBIVYSGPXCELZ-QMMMGPOBSA-N 0.000 description 3
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- UGCBVSDSTGUPBC-UHFFFAOYSA-N benzyl 3-(2,5-dioxo-1,3-oxazolidin-4-yl)propanoate Chemical compound C=1C=CC=CC=1COC(=O)CCC1NC(=O)OC1=O UGCBVSDSTGUPBC-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- ZYJPUMXJBDHSIF-NSHDSACASA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZYJPUMXJBDHSIF-NSHDSACASA-N 0.000 description 2
- QVHJQCGUWFKTSE-YFKPBYRVSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound OC(=O)[C@H](C)NC(=O)OC(C)(C)C QVHJQCGUWFKTSE-YFKPBYRVSA-N 0.000 description 2
- XNCNNYXFGGTEMT-UHFFFAOYSA-N 4-propan-2-yl-1,3-oxazolidine-2,5-dione Chemical compound CC(C)C1NC(=O)OC1=O XNCNNYXFGGTEMT-UHFFFAOYSA-N 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 125000005002 aryl methyl group Chemical group 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 150000007942 carboxylates Chemical group 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229910003002 lithium salt Inorganic materials 0.000 description 2
- 159000000002 lithium salts Chemical class 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000007034 nitrosation reaction Methods 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- NSETWVJZUWGCKE-UHFFFAOYSA-N propylphosphonic acid Chemical compound CCCP(O)(O)=O NSETWVJZUWGCKE-UHFFFAOYSA-N 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000000825 ultraviolet detection Methods 0.000 description 2
- JTDGKQNNPKXKII-ZETCQYMHSA-N (1s)-1-(4-methoxyphenyl)ethanamine Chemical compound COC1=CC=C([C@H](C)N)C=C1 JTDGKQNNPKXKII-ZETCQYMHSA-N 0.000 description 1
- WMSUFWLPZLCIHP-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 9h-fluoren-9-ylmethyl carbonate Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)ON1C(=O)CCC1=O WMSUFWLPZLCIHP-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- FUVZDXDCPRQZSQ-UHFFFAOYSA-N 1,5,6,7-tetrahydroindazol-4-one Chemical compound O=C1CCCC2=C1C=NN2 FUVZDXDCPRQZSQ-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical group 0.000 description 1
- 125000001204 arachidyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- MJSHDCCLFGOEIK-UHFFFAOYSA-N benzyl (2,5-dioxopyrrolidin-1-yl) carbonate Chemical compound O=C1CCC(=O)N1OC(=O)OCC1=CC=CC=C1 MJSHDCCLFGOEIK-UHFFFAOYSA-N 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- HLLIDIRDRPSCHN-UHFFFAOYSA-N benzyl n-[4-(2,5-dioxo-1,3-oxazolidin-4-yl)butyl]carbamate Chemical compound C=1C=CC=CC=1COC(=O)NCCCCC1NC(=O)OC1=O HLLIDIRDRPSCHN-UHFFFAOYSA-N 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- ROORDVPLFPIABK-UHFFFAOYSA-N diphenyl carbonate Chemical compound C=1C=CC=CC=1OC(=O)OC1=CC=CC=C1 ROORDVPLFPIABK-UHFFFAOYSA-N 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000005111 flow chemistry technique Methods 0.000 description 1
- IRXSLJNXXZKURP-UHFFFAOYSA-N fluorenylmethyloxycarbonyl chloride Chemical compound C1=CC=C2C(COC(=O)Cl)C3=CC=CC=C3C2=C1 IRXSLJNXXZKURP-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 125000002960 margaryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- KWNIHCJDDYRQFW-UHFFFAOYSA-N n-[4-(2,5-dioxo-1,3-oxazolidin-4-yl)butyl]-2,2,2-trifluoroacetamide Chemical compound FC(F)(F)C(=O)NCCCCC1NC(=O)OC1=O KWNIHCJDDYRQFW-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000009935 nitrosation Effects 0.000 description 1
- 125000001196 nonadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 239000003505 polymerization initiator Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- VTGFSVGZCYYHLO-UHFFFAOYSA-N tert-butyl (2,5-dioxopyrrolidin-1-yl) carbonate Chemical compound CC(C)(C)OC(=O)ON1C(=O)CCC1=O VTGFSVGZCYYHLO-UHFFFAOYSA-N 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/44—Two oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
- C07K1/08—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using activating agents
- C07K1/082—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using activating agents containing phosphorus
Definitions
- the invention relates to a new process for the synthesis of NCAs compounds. It also relates to a novel use of a peptide coupling agent.
- NCAs are chemical derivatives with high added value industrially used in particular in the production of drugs, or polymers. NCAs are, for example, intermediates of choice for the synthesis of peptides under "solvent-free" ecological conditions.
- NCAs compounds are traditionally carried out with phosgene or a phosgene derivative.
- phosgene or a phosgene derivative are problematic and requires special precautions and installations, in particular because of their toxicity and dangerousness.
- this strategy leads to the concomitant formation of HCl, which is difficult to remove from the NCA product, especially during a large-scale process.
- the presence of residual HCl in the NCA product can give rise to side reactions during its use, for example in a polymerization process.
- One of the aims of the invention is to use the reagent propylphosphonic anhydride in the preparation of NCAs compounds.
- One of the aims of the invention is to provide a new process for the synthesis of NCAs compounds, without the concomitant formation of HCl.
- Another object of the invention is to provide a process for the synthesis of NCAs compounds, in the absence of phosgene, or one of its derivatives.
- One of the aims of the invention is to provide NCAs compounds with good chemical and stereochemical purity.
- Another object of the invention is to provide new NCAs compounds. Another object of the invention is to be able to use the NCAs compounds by virtue of their improved chemical purity, in particular as synthesis intermediates in the preparation of a polymer or of an UNCA compound.
- a first object of the present invention is the use of propane-phosphonic acid anhydride for the preparation of an NCA compound, from an ⁇ -amino acid compound N-protected on the amine function at ⁇ by a -C(O)-O-C 1 to C 20 alkyl substituent, linear or branched, in particular by a tert-butyloxycarbonyl group.
- ⁇ -amino acids can be transformed into NCAs compounds, by the action of propylphosphonic anhydride. This transformation thus makes it possible to obtain said NCAs compounds with good yields, and excellent chemical and stereoisomeric purities.
- Figures 1 and 2 attest to the excellent purity with which the NCAs compounds according to the invention are obtained.
- propanephosphonic acid anhydride is meant a molecule whose structure is shown below. It is an anhydride of propylphosphonic acid, which occurs as a cyclic trimer on which propyl groups are attached to phosphorus atoms.
- the reagent is commercially available, under the name T 3 P ® , in 50 w/w% solution in several solvents, such as ethyl acetate, dimethylformamide, toluene, or tetrahydrofuran.
- linear C 1 to C 20 alkyl is meant an alkyl group comprising from 1 to 20 carbon atoms, chosen from: C 1 methyl, C 2 ethyl, C 3 propyl, C 4 butyl, pentyl C 5 , C 6 hexyl, C 7 heptyl, C 8 octyl, C 9 nonyl, C 10 decyl, C 11 undecyl, C 12 dodecyl, C 13 tridecyl, C 14 tetradecyl, C 15 pentadecyl, C 16 hexadecyl, C 17 heptadecyl, C 18 octadecyl, C 19 nonadecyl, C 20 eicosyl, in particular a linear C 1 to C alkyl group 10 , in particular a linear C 1 to C 5 alkyl group.
- branched alkyl it is necessary to understand a linear alkyl group as defined above comprising substituents chosen from the linear alkyl groups defined above, said linear alkyl groups also being capable of being branched.
- branched alkyl groups mention may in particular be made of an iso-propyl, sec-butyl, iso-butyl, tert-butyl, sec-pentyl, iso-pentyl, iso-hexyl, iso-heptyl, iso-octyl, iso-nonyl group. and isodecyl.
- NCAs ⁇ -Amino Acid N-CarboxyAnhydrides
- ⁇ -Amino Acid N-CarboxyAnhydrides have compounds comprising the motif shown below. These compounds can carry one or more substituents on the carbon in ⁇ of the carbonyl function, as well as on the nitrogen atom.
- these NCAs compounds are prepared from an N-protected ⁇ -amino acid compound comprising a unit represented below, and in which R represents a C 1 to C 20 alkyl group, linear or branched.
- the group R is preferably a tert-butyl group, giving rise to an N-protected acid- ⁇ -amino compound whose amine function at ⁇ is protected by a Boc group.
- the carboxylic acid function present in the aforementioned N-protected ⁇ -amino acid compound is optionally in the carboxylate form, in particular in the form of a sodium salt, a potassium salt, or a lithium salt.
- NCAs compounds A specific class of NCAs compounds are UNCAs, or N-Urethane-CarboxyAnhydrides of ⁇ -amino acids. These compounds contain, on the nitrogen atom of the NCA ring, a urethane group. UNCAs compounds, like other NCAs compounds, can include additional substituents on the carbon of the NCA ring.
- the present invention also makes it possible to obtain this specific class of NCAs compounds. It is appropriate in this case, to use an ⁇ -amino acid doubly N-protected on the amine function at a, in the form of dicarbamate.
- an ⁇ -amino acid N-(Boc) 2 , N-(Boc)(Cbz) or N-(Boc)(Fmoc) can for example be used.
- the present invention relates to a use as defined above, in which the preparation of the compound NCA is carried out:
- the preparation of an NCA compound, from an N-protected ⁇ -amino acid compound, according to the present invention is preferably carried out in the presence of an organic base, said base being capable of promoting the reaction.
- the reaction also takes place in the absence of an organic base, but it is slower. In this case, it would be appropriate to heat the reaction medium, in order to increase the kinetics of the reaction, and to obtain reaction times compatible with an industrial process.
- the reaction takes place at "room temperature”, that is to say at a temperature of between 20 and 30°C, in particular around 25°C.
- the present invention relates to a use as defined above, in which the organic base is a nitrogenous base, in particular chosen from triethylamine, 1,8-diazabicyclo[5.4.0]undec- 7-ene, diisopropylethylamine, N-dimethylaminopyridine, N-methylmorpholine or pyridine, preferably pyridine.
- a nitrogenous base in particular chosen from triethylamine, 1,8-diazabicyclo[5.4.0]undec- 7-ene, diisopropylethylamine, N-dimethylaminopyridine, N-methylmorpholine or pyridine, preferably pyridine.
- the present invention relates to a use as defined above, in which the preparation of the compound NCA is carried out: • either in the presence of an organic base, at room temperature, said organic base being chosen in particular from triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, diisopropylethylamine, N-dimethylaminopyridine, N-methylmorpholine or pyridine,
- the present invention relates to a use as defined above, in which the preparation of the NCA compound is carried out in the presence of an organic solvent.
- organic solvents which can be used in the preparation of an NCA compound, according to the present invention, mention may be made, in a non-limiting manner, of ethyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, N,N-dimethylformamide, chlorobenzene, methylene chloride or acetonitrile.
- the organic solvent is chosen in particular according to the commercial availability of the propane-phosphonic acid anhydride reagent, which is in particular marketed in a 50% solution in ethyl acetate, or dimethylformamide.
- the present invention therefore relates to a use as defined above, in which the organic solvent is chosen from ethyl acetate or dimethylformamide, in particular ethyl acetate.
- the present invention relates to a use as defined above, in which the propane-phosphonic acid anhydride is used in a proportion of 1 to 4 molar equivalents with respect to the acid- ⁇ compound -N-protected amino.
- the quantity of propane-phosphonic acid anhydride is in particular 1, 2, or 3 equivalents, in the presence of an organic base, and in particular 2, 3 or 4 equivalents in the absence of an organic base.
- the present invention relates to a use as defined above, in which the preparation of the NCA compound is carried out in the presence of an organic base at a rate of 0.25 to 3 molar equivalents relative to the N-protected ⁇ -amino acid compound, in particular from 1 to 3 molar equivalents, preferably from 3 molar equivalents.
- from 0.25 to 3 molar equivalents also means the following ranges: from 0.25 to 2, from 0.25 to 1, from 0.25 to 0.5, from 0.5 to 3, from 1 to 2, or from 0.5 to 2.
- the present invention relates to a use as defined above, in which:
- the preparation of the NCA compound is carried out in the presence of an organic solvent, chosen in particular from ethyl acetate or dimethylformamide, and/or
- propane-phosphonic acid anhydride is used at a rate of 1 to 4 molar equivalents relative to the N-protected ⁇ -amino acid compound.
- An amount of less than 1 equivalent of base, relative to the N-protected ⁇ -amino acid compound, can be used.
- a stoichiometric quantity, or greater than the stoichiometric value, of organic base makes it possible to increase the kinetics of the reaction, in order to be able to reach reaction times compatible with an industrial process.
- the present invention relates to a use as defined above, in which the NCA compound is of Formula 1: in which :
- R 1 and R 2 independently represent:
- heteroaryl in which the heteroatom is chosen in particular from N, O, and S, in particular 3-methylindole
- ⁇ C 1 to C 20 -alkyl-heteroaryl in which the heteroatom is chosen in particular from N, O, and S,
- halogen in particular a fluorine atom
- said alkyl, alkyl-aryl or alkyl-heteroaryl possibly being substituted on at least one carbon of the alkyl radical by one or more groups chosen from:
- R 4 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, C 3 to C 3 to C 10 , aryl, C 1 to C 20 -alkyl-aryl, heteroaryl, C 1 to C 20 -alkyl-heteroaryl and a protective group, in particular chosen from tBDMS, t-butyl, benzyl, trityl and xanthyl ,
- R 5 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, aryl, C 1 -C 20 -alkyl-aryl, heteroaryl and C 1 -C 20 -alkyl-heteroaryl,
- R 6 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, aryl, C 1 -C 20 -alkyl-aryl, heteroaryl and C 1 -C 20 -alkyl-heteroaryl,
- R 7 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, aryl, C 1 -C 20 -alkyl-aryl, heteroaryl and C 1 -C 20 -alkyl-heteroaryl,
- R 8 and R 9 are independently chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl , C 3 -C 10 heterocycloalkyl, aryl, C 1 -C 20 -alkyl-aryl, heteroaryl and C 1 -C 20 -alkyl-heteroaryl,
- R 10 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, heterocycloalkyl C 3 to C 10 , aryl, C 1 to C 20 -alkyl-aryl, heteroaryl, C 1 to C 20 -alkyl-heteroaryl and a protective group, in particular NO 2 , Pbf, Pmc, Mtr or Boc,
- R 11 and R 12 are independently chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C cycloalkyl 3 to C 10 , C 3 to C 10 heterocycloalkyl, aryl, C 1 to C 20 -linear or branched alkyl-aryl, heteroaryl, C 1 to C 20 -linear or branched C 1 to C 20 -alkyl-heteroaryl, O-C 1 to C 20 linear or branched, C 1 to C 20 -O-alkyl-aryl linear or branched, the -C(O)R 12 radical being in particular a protective group such as Boc, Cbz, Alloc or Fmoc,
- R 13 and R 14 are independently chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, cycloalkyl C 3 to C 10 , C 3 to C 10 heterocycloalkyl, aryl, C 1 to C 20 -alkyl-aryl, heteroaryl and C 1 to C 20 -alkyl-heteroaryl, ⁇ SR 15 , in which R 15 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, C 3 to C 3 to C 10 , aryl, C 1 to C 20 -alkyl-aryl, heteroaryl, C 1 to C 20 -alkyl-heteroaryl and a protective group, in particular trityl or acetamidomethyl (Acm),
- a halogen in particular chosen from F, Cl, Br and I, said aryl, alkyl-aryl, heteroaryl and alkyl-heteroaryl possibly being substituted on the aromatic or heteroaromatic ring by one or more groups chosen from:
- R 16 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, C 3 to C 3 to C 10 , aryl, C 1 to C 20 -alkyl-aryl, heteroaryl, C 1 to C 20 -alkyl-heteroaryl and a protective group, in particular chosen from tBDMS, t-butyl, benzyl, tntyl and xanthyl ,
- R 17 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, aryl, C 1 -C 20 -alkyl-aryl, heteroaryl, C 1 -C 20 -alkyl-heteroaryl,
- R 18 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, aryl, C 1 -C 20 -alkyl-aryl, heteroaryl, C 1 -C 20 -alkyl-heteroaryl,
- R 19 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, aryl, C 1 -C 20 -alkyl-aryl, heteroaryl, C 1 -C 20 -alkyl-heteroaryl,
- R 20 and R 21 are independently chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl , C 3 -C 10 heterocycloalkyl, aryl, C 1 -C 20 -alkyl-aryl, heteroaryl, C 1 -C 20 -alkyl-heteroaryl,
- R 22 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, heterocycloalkyl C 3 to C 10 , aryl, C 1 to C 20 -alkyl-aryl, heteroaryl, C 1 to C 20 -alkyl-heteroaryl and a protective group, in particular NO 2 , Pbf, Pmc, Mtr or Boc,
- R 23 and R 24 are independently chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C cycloalkyl 3 to C 10 , C 3 to C 10 heterocycloalkyl, aryl, C 1 to C 20 -linear or branched alkyl-aryl, heteroaryl, C 1 to C 20 -linear or branched C 1 to C 20 -alkyl-heteroaryl, O-C 1 to C 20 linear or branched, C 1 to C 20 -O-alkyl-aryl linear or branched, the -C(O)R 24 radical being in particular a protective group such as Boc, Cbz, Alloc or Fmoc,
- R 25 and R 26 are independently chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, cycloalkyl C 3 to C 10 , C 3 to C 10 heterocycloalkyl, aryl, C 1 to C 20 -alkyl-aryl, heteroaryl, C 1 to C 20 -alkyl-heteroaryl,
- R 27 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, C 3 to C 3 to C 10 , aryl, C 1 to C 20 -alkyl-aryl, heteroaryl, C 1 to C 20 -alkyl-heteroaryl and a protective group, in particular trityl or acetamidomethyl (Acm),
- ⁇ a halogen chosen in particular from F, Cl, Br and I,
- R 3 represents:
- linear C 2 to C 20 alkenyl group is meant: a linear alkyl chain comprising from two to 20 carbon atoms, comprising one or more carbon-carbon double bond(s). In particular a linear alkyl chain of 3 to 15 carbon atoms, of 3 to 10 carbon atoms, of 5 to 20 carbon atoms, of 10 to 20 carbon atoms, or of 5 to 15 carbon atoms.
- branched alkenyl group is meant an alkenyl group as defined above, comprising substituents chosen from the list of linear alkyl groups defined above, said linear alkyl groups also being able to be branched.
- C 3 to C 10 cycloalkyl group is meant a cycloalkyl group comprising from 3 to 10 carbon atoms, chosen from: C 3 cyclopropyl, C 4 cyclobutyl, C 5 cyclopentyl, C 6 cyclohexyl , cycloheptyl C 7 , C 8 cyclooctyl, C 9 cyclononyl, or C 10 cyclodecyl.
- C 3 to C 10 heterocycloalkyl group is meant a cycloalkyl group comprising from 3 to 10 carbon atoms, and further comprising one or more heteroatoms in the ring, in particular 1 or 2 heteroatom(s).
- aryl denotes an aromatic group comprising 5 to 16 carbon atoms within the aromatic ring, in particular from 6 to 12 carbon atoms, in particular comprising 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 carbon atoms.
- the aryl groups according to the present invention can also be substituted, in particular by one or more substituents chosen from: a linear or branched C 1 to C 10 alkyl group, a linear or branched C 1 to C 10 O-alkyl group.
- Phenyl, anisyl and naphthyl, o-tolyl, m-tolyl, p-tolyl, o-xylyl, m-xylyl, p-xylyl, are examples of aryl groups according to the present invention.
- heteroaryl denotes an aryl group as defined above, comprising atoms other than carbon atoms, in particular N, O or S within the aromatic ring.
- Pyridyl, imidazoyl, indolyl, or fiiranyl are examples of heteroaryl groups according to the present invention.
- R 1 and R 2 capable of forming a ring designates spirocyclic compounds, preferably of 3 to 10 carbon atoms, as follows, for general Formula 3, in which R 3 is as defined above.
- NCAs compounds of Formulas 4, 5 and 6 are specific examples of spirocyclic compounds according to the present invention, respectively comprising a cyclopropyl, cyclopentyl, or cyclohexyl ring.
- the NCA compound comprises a 13 C isotope, or several 13 C isotopes
- said isotope is either on one of the carbonyl functions of the NCA ring, or on the side chain, represented by R 1 and/or R 2 in Formula 1.
- the said isotope(s) is (are) preferably on a non-enolizable position of the NCA ring, or on a non-enolizable position.
- -exchangeable side chain represented by R 1 and/or R 2 in Formula 1.
- the expression "the asymmetric centers of said compound of Formula 1 are of R or S configuration, or a mixture of these configurations” refers to the asymmetric centers formed by the configuration of the R 1 and R 2 groups (Formulas 10 and 11 below ), but also to those optionally present on said R 1 and R 2 groups.
- This situation is illustrated by Formula 12 below, in which the R 1 group is a hydrogen atom, and the R 2 group comprises a racemic asymmetric center.
- the carbon bearing the R 1 and R 2 groups has the S configuration.
- the stereochemistry of NCAs molecules is determined by the stereochemistry of the N-protected ⁇ -amino acid from which the NCA compound is formed.
- the compound of Formula 1 is preferably diastereoisomerically pure, the diastereoisomeric excess being greater than 80%.
- greater than 80% also means greater than 90%, greater than 95%, greater than 98% and in particular greater than 99%.
- the compound of Formula 1 is preferably enantiomerically pure, the enantiomeric excess being greater than 80%, the starting N-protected ⁇ -amino acid being in particular of L configuration.
- the term “greater than 80%” also means greater than 90%, greater than 95%, greater than 98% and in particular greater than 99%.
- the present invention relates to a use as defined above, in which the compound of Formula 1 is such that:
- R 1 and R 2 independently represent:
- heteroaryl in which the heteroatom is chosen in particular from N, O, and S, in particular 3-methylindole,
- alkyl, alkyl-aryl or alkyl-heteroaryl possibly being substituted on at least one carbon of the alkyl radical by one or more groups chosen from:
- R 4 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, C 3 to C 3 to C 10 , aryl, C 1 to C 20 -alkyl-aryl, heteroaryl, C 1 to C 20 -alkyl-heteroaryl and a protective group, in particular chosen from tBDMS, t-butyl, benzyl, trityl and xanthyl ,
- R 8 and R 9 are independently chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl , C 3 -C 10 heterocycloalkyl, aryl, C 1 -C 20 -alkyl-aryl, heteroaryl and C 1 -C 20 -alkyl-heteroaryl,
- R 10 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, heterocycloalkyl C 3 to C 10 , aryl, C 1 to C 20 -alkyl-aryl, heteroaryl, C 1 to C 20 -alkyl-heteroaryl and a protective group, in particular NO 2 , Pbf, Pmc, Mtr or Boc,
- R 11 and R 12 are independently chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C cycloalkyl 3 to C 10 , C 3 to C 10 heterocycloalkyl, aryl, C 1 to C 20 -linear or branched alkyl-aryl, heteroaryl, C 1 to C 20 -linear or branched C 1 to C 20 -alkyl-heteroaryl, O-C 1 to C 20 linear or branched, C 1 to C 20 -O-alkyl-aryl linear or branched, the -C(O)R 12 radical being in particular a protective group such as Boc, Cbz, Alloc or Fmoc,
- R 15 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, C 3 to C 3 to C 10 , aryl, C 1 to C 20 -alkyl-aryl, heteroaryl, C 1 to C 20 -alkyl-heteroaryl and a protective group, in particular trityl or acetamidomethyl (Acm), said aryl, alkyl-aryl, heteroaryl and alkyl-heteroaryl which may be substituted on the aromatic or heteroaromatic ring by one or more groups chosen from:
- R 16 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, C 3 to C 3 to C 10 , aryl, C 1 to C 20 -alkyl-aryl, heteroaryl, C 1 to C 20 -alkyl-heteroaryl and a protective group, in particular chosen from tBDMS, t-butyl, benzyl, trityl and xanthyl ,
- R 20 and R 21 are independently chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl , C 3 -C 10 heterocycloalkyl, aryl, C 1 -C 20 -alkyl-aryl, heteroaryl, C 1 -C 20 -alkyl-heteroaryl,
- R 22 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, heterocycloalkyl C 3 to C 10 , aryl, C 1 to C 20 -alkyl-aryl, heteroaryl, C 1 to C 20 -alkyl-heteroaryl and a protective group, in particular NO 2 , Pbf, Pmc, Mtr or Boc,
- R 23 and R 24 are independently chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C cycloalkyl 3 to C 10 , C 3 to C 10 heterocycloalkyl, aryl, C 1 to C 20 -linear or branched alkyl-aryl, heteroaryl, C 1 to C 20 -linear or branched C 1 to C 20 -alkyl-heteroaryl, O-C 1 to C 20 linear or branched, C 1 to C 20 -O-alkyl-aryl linear or branched, the -C(O)R 24 radical being in particular a protective group such as Boc, Cbz, Alloc or Fmoc,
- R 27 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, C 3 to C 3 to C 10 , aryl, C 1 to C 20 -alkyl-aryl, heteroaryl, C 1 to C 20 -alkyl-heteroaryl and a protective group, in particular trityl or acetamidomethyl (Acm),
- ⁇ a halogen chosen in particular from F, Cl, Br and I,
- R 3 represents:
- the present invention relates to a use as defined above, in which the compound of Formula 1 is such that:
- R 1 and R 2 independently represent:
- heteroaryl in which the heteroatom is chosen in particular from N, O, and S, in particular 3-methylindole, said alkyl or alkyl-aryl possibly being substituted on at least one carbon of the alkyl radical by one or more groups chosen from :
- R 4 is chosen from H, C 1 to C 20 alkyl, linear or branched, and a protective group, in particular chosen from tBDMS, t-butyl, benzyl, tntyl and xanthyl,
- R 8 and R 9 are independently chosen from H, C 1 to C 20 alkyl, linear or branched,
- R 10 is chosen from H, C 1 to C 20 alkyl, linear or branched, and a protective group, in particular Pbf, Pmc, Mtr or Boc,
- R 11 and R 12 are independently chosen from H, C 1 to C 20 alkyl, linear or branched, O-C 1 to C 20 linear or branched alkyl, C 1 at C 20 -O-alkyl- linear or branched aryl, the -C(O)R 12 radical being in particular a protective group such as Boc, Cbz, Alloc or Fmoc,
- R 15 is chosen from H, C 1 to C 20 alkyl, linear or branched, and a protective group, in particular trityl or acetamidomethyl (Acm), said alkyl-aryl or heteroaryl possibly being substituted on the aromatic or heteroaromatic ring by one or more groups chosen from:
- R 16 is chosen from H, C 1 to C 20 alkyl, linear or branched, and a protective group, in particular chosen from tBDMS, t-butyl, benzyl, trityl and xanthyl,
- R 20 and R 21 are independently chosen from H, C 1 to C 20 alkyl, linear or branched,
- R 22 is chosen from H, C 1 to C 20 alkyl, linear or branched, and a protective group, in particular NO 2 , Pbf, Pmc, Mtr or Boc,
- R 23 and R 24 are independently chosen from H, C 1 to C 20 alkyl, linear or branched, O-C 1 to C 20 linear or branched alkyl, C 1 linear or branched C 20 -O-alkylaryl, the -C(O)R 24 radical being in particular a protective group such as Boc, Cbz, Alloc or Fmoc,
- R 27 is chosen from H, C 1 to C 20 alkyl, linear or branched, and a protective group, in particular trityl or acetamidomethyl (Acm),
- R 3 represents:
- the present invention relates to a use as defined above, in which the compound of Formula 1 is such that: R 1 and R 2 independently represent:
- alkyl possibly being substituted by one or more groups chosen from:
- R 10 is chosen from a protective group, in particular NO 2 , Pbf, Pmc, Mtr or Boc,
- R 11 is H
- the -C(O)R 12 radical is a protecting group such as Boc, Cbz, Alloc or Fmoc
- R 3 represents:
- the present invention relates to a use as defined above, in which the compound of Formula 1 is such that R 3 is a hydrogen atom.
- the compound of Formula 1 has the structure of Formula 13: in which R 1 and R 2 are as defined above.
- the present invention relates to a use as defined above, in which the compound of Formula 1 is such that R 1 and R 2 are identical, and are in particular a methyl.
- the present invention relates to a use as defined above, in which the compound of Formula 1 is such that R 1 and R 2 form a cycle.
- the present invention relates to a use as defined above, in which the compound of Formula 1 is such that one of R 1 or R 2 is a hydrogen atom.
- the compound of Formula 1 has the structure of Formula 14, or Formula 14': in which R 1 , R 2 and R 3 are as defined above.
- the present invention relates to a use as defined above, in which at least one of the R 1 or R 2 groups comprises at least one protective group for carboxylic acid functions, amine functions, thiol functions, guanidine functions, amide functions and/or alcohol functions, chosen in particular from tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethyloxycarbonyl (Fmoc), alloc, tert-butyloxy (OtBu), formyl (For), 2,2,4,6,7-pentamethylhydrobenzofuran-5-sulfonyl (Pbf), 2, 2, 5, 7, 8- pentamethylchroman-6-sulfonyl (Pmc), 4-methoxy-2,3,6-trimethylbenzenesulfonyl ( Mtr), trityl (Trt), trifluoroacetyl, acetamidomethyl (Acm), and x
- the protective groups that can be used according to the present invention are any protective group available to those skilled in the art (Greene's Protective Groups in Organic Synthesis, 4th edition, Wiley).
- the present invention relates to a use as defined above, in which the NCA compound is chosen from: alanine-NCA, arginine-NCA, asparagine-NCA, aspartic acid-NCA, cysteine-NCA, glutamine-NCA, glutamic acid-NCA, glycine-NCA, histidine-NCA, isoleucine-NCA, leucine-NCA, lysine-NCA, methionine-NCA, phenylalanine-NCA, proline-NCA, serine-NCA, threonine-NCA, tryptophan-NCA, tyrosine-NCA, valine-NCA, acid-1,2,3,4 - tetrahydro-isoquinoline-3-carboxylic-NCA
- the present invention also relates to a use as defined above, in which the NCA compound is an UNCA compound, in particular an UNCA compound of the following structure: in which R' is chosen from a C 1 to C 20 alkyl group, linear or branched, in particular a tert-butyl, or an aryl-methyl group, in particular a benzyl group or a fluorenylmethyl group, in which R 1 and R 2 are as defined above.
- the present invention relates to a use as defined above, in which the NCA compound is chosen from the following structures:
- a second object of the present invention is a process for the preparation of an NCA compound, comprising:
- the present invention relates to a method as defined above, in which the contacting step comprises: • a stirring step at a temperature of 40 to 80°C, in the absence of said organic base.
- the present invention relates to a method as defined above, in which the contacting step comprises:
- the method of the present invention can be implemented in a flow chemistry device.
- the present invention therefore relates to a method as defined above, said method being implemented in continuous flow.
- the present invention relates to a method as defined above, further comprising, after obtaining the NCA, a step of purification by at least one aqueous wash.
- the aqueous washing makes it possible in particular to eliminate the propylphosphonic acid formed during the reaction.
- the present invention relates to a method as defined above, further comprising a step of purification of the NCA compound, in particular by recrystallization.
- the present invention relates to a method as defined above, in which the contacting step is carried out for a period of 1 to 24 hours, in particular approximately 2 hours.
- the process according to the present invention generally makes it possible to obtain complete conversion after 2 hours of reaction.
- the reaction time may however be longer if the analysis of an aliquot demonstrates the presence of the starting N-protected ⁇ -amino acid.
- the present invention relates to a method as defined above, in the presence of an organic base, said organic base being a nitrogenous base, chosen in particular from triethyl amine, 1,8-diazabicyclo [5.4.0]undec-7-ene, diisopropylethylamine, N-dimethylaminopyridine, diisopropylethylamine or pyridine, preferably pyridine.
- the present invention relates to a process as defined above, in which the organic solvent is chosen from ethyl acetate or dimethylformamide, in particular ethyl acetate.
- the present invention relates to a process as defined above, in which the propane-phosphonic acid anhydride is used in a proportion of 1 to 4 molar equivalents with respect to the acid- ⁇ compound -N-protected amino, in particular of 2 molar equivalents.
- the present invention relates to a process as defined above, in the presence of an organic base at a rate of 0.25 to 3 molar equivalents with respect to the ⁇ -amino acid compound N- protected, in particular from 1 to 3 molar equivalents, preferably from 3 molar equivalents.
- the present invention relates to a process as defined above, in the presence of an organic base, in which the base is pyndine in an amount of 3 molar equivalents relative to the acid- N-protected ⁇ -amino acid, wherein the propane-phosphonic acid anhydride is used at 2 molar equivalents relative to the N-protected ⁇ -amino acid compound, and wherein the agitation step is performed at room temperature.
- the present invention relates to a process as defined above, in which the propane-phosphonic acid anhydride is used at a rate of 4 molar equivalents with respect to the ⁇ -amino acid compound N-protected, and wherein the stirring step is carried out at a temperature of 50 to 80°C, in the absence of an organic base.
- the present invention relates to a process for the preparation of an NCA compound, as defined above, comprising:
- an N-protected ⁇ -amino acid compound into contact with: propane-phosphonic acid anhydride, and optionally an organic base, in particular a nitrogenous base, in particular chosen from triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, diisopropylethylamine, N-dimethylaminopyridine, diisopropylethylamine or pyridine, preferably pyridine, in an organic solvent, chosen in particular from ethyl acetate or dimethylformamide, to obtain said NCA compound, and optionally:
- an organic base in particular a nitrogenous base, in particular chosen from triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, diisopropylethylamine, N-dimethylaminopyridine, diisopropylethylamine or pyridine, preferably pyridine, in an organic solvent, chosen in particular from ethyl
- the present invention relates to a method for preparing an NCA compound, as defined above, in which the contacting step comprises:
- the present invention relates to a process as defined above, in which said NCA compound is of Formula 1-A, prepared from an N-protected ⁇ -amino acid compound of Formula 2-A, according to the following reaction scheme:
- R 1 and R 2 independently represent:
- ⁇ C 3 to C 10 cycloalkyl ⁇ C 3 to C 10 heterocycloalkyl, in which the heteroatom is chosen in particular from N, O and S,
- heteroaryl in which the heteroatom is chosen in particular from N, O, and S, in particular 3-methylindole,
- halogen in particular a fluorine atom
- said alkyl, alkyl-aryl or alkyl-heteroaryl possibly being substituted on at least one carbon of the alkyl radical by one or more groups chosen from:
- R 4 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, C 3 to C 3 to C 10 , aryl, C 1 to C 20 -alkyl-aryl, heteroaryl, C 1 to C 20 -alkyl-heteroaryl and a protective group, in particular chosen from tBDMS, t-butyl, benzyl, tntyl and xanthyl ,
- R 5 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, aryl, C 1 -C 20 -alkyl-aryl, heteroaryl and C 1 -C 20 -alkyl-heteroaryl,
- R 6 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, aryl, C 1 -C 20 -alkyl-aryl, heteroaryl and C 1 -C 20 -alkyl-heteroaryl,
- R 7 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, aryl, C 1 -C 20 -alkyl-aryl, heteroaryl and C 1 -C 20 -alkyl-heteroaryl,
- R 8 and R 9 are independently chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl , C 3 -C 10 heterocycloalkyl, aryl, C 1 -C 20 -alkyl-aryl, heteroaryl and C 1 -C 20 -alkyl-heteroaryl,
- R 10 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, heterocycloalkyl C 3 to C 10 , aryl, C 1 to C 20 -alkyl-aryl, heteroaryl, C 1 to C 20 -alkyl-heteroaryl and a protective group, in particular NO 2 , Pbf, Pmc, Mtr or Boc,
- R 11 and R 12 are independently chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C cycloalkyl 3 to C 10 , C 3 to C 10 heterocycloalkyl, aryl, C 1 to C 20 -linear or branched alkyl-aryl, heteroaryl, C 1 to C 20 -linear or branched C 1 to C 20 -alkyl-heteroaryl, O-C 1 to C 20 linear or branched, C 1 to C 20 -O-alkyl-aryl linear or branched, the -C(O)R 12 radical being in particular a protective group such as Boc, Cbz, Alloc or Fmoc,
- R 13 and R 14 are independently chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, cycloalkyl C 3 to C 10 , C 3 to C 10 heterocycloalkyl, aryl, C 1 to C 20 -alkyl-aryl, heteroaryl and C 1 to C 20 -alkyl-heteroaryl,
- R 15 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, C 3 to C 3 to C 10 , aryl, C 1 to C 20 -alkyl-aryl, heteroaryl, C 1 to C 20 -alkyl-heteroaryl and a protective group, in particular trityl or acetamidomethyl (Acm),
- a halogen in particular chosen from F, Cl, Br and I, said aryl, alkyl-aryl, heteroaryl and alkyl-heteroaryl possibly being substituted on the aromatic or heteroaromatic ring by one or more groups chosen from:
- R 16 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, C 3 to C 3 to C 10 , aryl, C 1 to C 20 -alkyl-aryl, heteroaryl, C 1 to C 20 -alkyl-heteroaryl and a protective group, in particular chosen from tBDMS, t-butyl, benzyl, trityl and xanthyl ,
- R 17 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, aryl, C 1 -C 20 -alkyl-aryl, heteroaryl, C 1 -C 20 -alkyl-heteroaryl,
- R 18 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, aryl, C 1 -C 20 -alkyl-aryl, heteroaryl, C 1 -C 20 -alkyl-heteroaryl,
- R 19 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, aryl, C 1 -C 20 -alkyl-aryl, heteroaryl, C 1 -C 20 -alkyl-heteroaryl,
- R 20 and R 21 are independently chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl , C 3 -C 10 heterocycloalkyl, aryl, C 1 -C 20 -alkyl-aryl, heteroaryl, C 1 -C 20 -alkyl-heteroaryl,
- R 22 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, heterocycloalkyl C 3 to C 10 , aryl, C 1 to C 20 -alkyl-aryl, heteroaryl, C 1 to C 20 -alkyl-heteroaryl and a protective group, in particular NO 2 , Pbf, Pmc, Mtr or Boc,
- R 23 and R 24 are independently chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C cycloalkyl 3 to C 10 , C 3 to C 10 heterocycloalkyl, aryl, C 1 to C 20 -linear or branched alkyl-aryl, heteroaryl, C 1 to C 20 -linear or branched C 1 to C 20 -alkyl-heteroaryl, O-C 1 to C 20 linear or branched, C 1 to C 20 -O-alkyl-aryl linear or branched, the -C(O)R 24 radical being in particular a protective group such as Boc, Cbz, Alloc or Fmoc,
- R 25 and R 26 are independently chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, cycloalkyl C 3 to C 10 , C 3 to C 10 heterocycloalkyl, aryl, C 1 to C 20 -alkyl-aryl, heteroaryl, C 1 to C 20 -alkyl-heteroaryl,
- R 27 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, C 3 to C 3 to C 10 , aryl, C 1 to C 20 -alkyl-aryl, heteroaryl, C 1 to C 20 -alkyl-heteroaryl and a protective group, in particular tntyl or acetamidomethyl (Acm),
- ⁇ a halogen chosen in particular from F, Cl, Br and I,
- R 3 represents:
- the compound of Formula 1-A, or the compound of Formula 2-A comprises a carbon atom
- said carbon atom may be 13 C
- said fluorine atom may be 18 F
- said hydrogen atom may be deuterium
- the asymmetric centers of said compound of Formula 1-A, and of said compound of Formula 2-A are of R or S configuration, or a mixture of these configurations.
- the carboxylic acid function present in the compound of Formula 2-A is optionally in the carboxylate form, in particular in the form of a sodium salt, a potassium salt, or a lithium salt.
- the present invention relates to a process as defined above, in which the compound of Formula 1-A and the compound of Formula 2-A are such that:
- R 1 and R 2 independently represent:
- heteroaryl in which the heteroatom is chosen in particular from N, O, and S, in particular 3-methylindole,
- alkyl, alkyl-aryl or alkyl-heteroaryl possibly being substituted on at least one carbon of the alkyl radical by one or more groups chosen from:
- R 4 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, C 3 to C 3 to C 10 , aryl, C 1 to C 20 -alkyl-aryl, heteroaryl, C 1 to C 20 -alkyl-heteroaryl and a protective group, in particular chosen from tBDMS, t-butyl, benzyl, trityl and xanthyl ,
- R 8 and R 9 are independently chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl , C 3 -C 10 heterocycloalkyl, aryl, C 1 -C 20 -alkyl-aryl, heteroaryl and C 1 -C 20 -alkyl-heteroaryl,
- R 10 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, heterocycloalkyl C 3 to C 10 , aryl, C 1 to C 20 -alkyl-aryl, heteroaryl, C 1 to C 20 -alkyl-heteroaryl and a protective group, in particular NO 2 , Pbf, Pmc, Mtr or Boc,
- R 11 and R 12 are independently chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C cycloalkyl 3 to C 10 , C 3 to C 10 heterocycloalkyl, aryl, C 1 to C 20 -linear or branched alkyl-aryl, heteroaryl, C 1 to C 20 -linear or branched C 1 to C 20 -alkyl-heteroaryl, O-C 1 to C 20 linear or branched, C 1 to C 20 -O-alkyl-aryl linear or branched, the -C(O)R 12 radical being in particular a protective group such as Boc, Cbz, Alloc or Fmoc,
- R 15 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, C 3 to C 3 to C 10 , aryl, C 1 to C 20 -alkyl-aryl, heteroaryl, C 1 to C 10 -alkyl-heteroaryl and a protective group, in particular trityl or acetamidomethyl (Acm), said aryl, alkyl-aryl, heteroaryl and alkyl-heteroaryl which may be substituted on the aromatic or heteroaromatic ring by one or more groups chosen from:
- R 16 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, C 3 to C 3 to C 10 , aryl, C 1 to C 20 -alkyl-aryl, heteroaryl, C 1 to C 20 -alkyl-heteroaryl and a protective group, in particular chosen from tBDMS, t-butyl, benzyl, trityl and xanthyl ,
- R 20 and R 21 are independently chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl , C 3 -C 10 heterocycloalkyl, aryl, C 1 -C 20 -alkyl-aryl, heteroaryl, C 1 -C 20 -alkyl-heteroaryl,
- R 22 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, heterocycloalkyl C 3 to C 10 , aryl, C 1 to C 20 -alkyl-aryl, heteroaryl, C 1 to C 20 -alkyl-heteroaryl and a protective group, in particular NO 2 , Pbf, Pmc, Mtr or Boc,
- R 23 and R 24 are independently chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C cycloalkyl 3 to C 10 , C 3 to C 10 heterocycloalkyl, aryl, C 1 to C 20 -linear or branched alkyl-aryl, heteroaryl, C 1 to C 20 -linear or branched C 1 to C 20 -alkyl-heteroaryl, O-C 1 to C 20 linear or branched, C 1 to C 20 -O-alkyl-aryl linear or branched, the -C(O)R 24 radical being in particular a protective group such as Boc, Cbz, Alloc or Fmoc,
- R 27 is chosen from H, C 1 to C 20 alkyl, linear or branched, C 1 to C 20 heteroalkyl, linear or branched, C 3 to C 10 cycloalkyl, heterocycloalkyl C 3 to C 10 aryl, C 1 to C 20 -alkyl-aryl, heteroaryl, C 1 to C 20 -alkyl-heteroaryl and a protective group, in particular trityl or acetamidom ethyl (Acm),
- ⁇ a halogen chosen in particular from F, Cl, Br and I,
- R 3 represents:
- R 33 represents a linear or branched C 1 to C 20 alkyl group, in particular a tert-butyl, said compound of Formula 1-A possibly being in the form of a solvate or a hydrate, said NR 8 R groups 9 .
- the present invention relates to a process as defined above, in which the compound of Formula 1-A and the compound of Formula 2-A are such that:
- R 1 and R 2 independently represent:
- heteroaryl in which the heteroatom is chosen in particular from N, O, and S, in particular 3-methylindole, said alkyl or alkyl-aryl possibly being substituted on at least one carbon of the alkyl radical by one or more groups chosen from:
- R 4 is chosen from H, C 1 to C 20 alkyl, linear or branched, and a protective group, in particular chosen from tBDMS, t-butyl, benzyl, trityl and xanthyl,
- R 8 and R 9 are independently chosen from H, C 1 to C 20 alkyl, linear or branched,
- R 10 is chosen from H, C 1 to C 20 alkyl, linear or branched, and a protective group, in particular NO 2 , Pbf, Pmc, Mtr or Boc,
- R 11 and R 12 are independently chosen from H, C 1 to C 20 alkyl, linear or branched, O-C 1 to C 20 linear or branched alkyl, C 1 linear or branched C 20 -O-alkylaryl, the -C(O)R 12 radical being in particular a protective group such as Boc, Cbz, Alloc or Fmoc,
- R 15 is chosen from H, C 1 to C 20 alkyl, linear or branched, and a protective group, in particular tntyl or acetamidomethyl (Acm), said alkyl-aryl or heteroaryl possibly being substituted on the aromatic or heteroaromatic ring by one or more groups chosen from:
- R 16 is chosen from H, C 1 to C 20 alkyl, linear or branched, and a protective group, in particular chosen from tBDMS, t-butyl, benzyl, trityl and xanthyl,
- R 20 and R 21 are independently chosen from H, C 1 to C 20 alkyl, linear or branched,
- R 22 is chosen from H, C 1 to C 20 alkyl, linear or branched, and a protective group, in particular NO 2 , Pbf, Pmc, Mtr or Boc,
- R 23 and R 24 are independently chosen from H, C 1 to C 20 alkyl, linear or branched, O-C 1 to C 20 linear or branched alkyl, C 1 linear or branched C 20 -O-alkylaryl, the -C(O)R 24 radical being in particular a protective group such as Boc, Cbz, Alloc or Fmoc,
- R 27 is chosen from H, C 1 to C 20 alkyl, linear or branched, and a protective group, in particular trityl or acetamidomethyl (Acm),
- R 3 represents:
- R 33 represents a linear or branched C 1 to C 20 alkyl group, in particular a tert-butyl, said compound of Formula 1-A possibly being in the form of a solvate or a hydrate, said NR 8 R groups 9 (NH)CNHR 10 , NR 20 R 21 and (NH)CNHR 22 , and/or heteroaryl of the compound of Formula 1-A possibly being in a salified form, the asymmetric centers of said compound of Formula 1-A, and of said compound of Formula 2-A, are of R or S configuration, or a mixture of these configurations.
- the present invention relates to a process as defined above, in which the compound of Formula 1-A and the compound of Formula 2-A are such that:
- R 1 and R 2 independently represent:
- alkyl possibly being substituted by one or more groups chosen from:
- R 10 is chosen from a protective group, in particular NO 2 , Pbf, Pmc, Mtr or Boc,
- R 11 is H
- the -C(O)R 12 radical is a protecting group such as Boc, Cbz, Alloc or Fmoc
- R 3 represents:
- R 33 represents a tert-butyl group, said compound of Formula 1-A possibly being in the form of a solvate or a hydrate, said NR 8 R 9 , (NH)CNHR 10 , NR 20 R 21 and (NH)CNHR 22 and/or 3-methylindole groups, of the compound of Formula 1 -A possibly being in a salified form, the asymmetric centers of said compound of Formula 1-A, and said compound of Formula 2-A, are of R or S configuration, or a mixture of these configurations.
- the present invention relates to a process as defined above, in which R 3 is a hydrogen atom.
- the present invention relates to a process as defined above, in which R 1 and R 2 are identical, and in particular represent a methyl.
- the present invention relates to a process as defined above, in which one of R 1 or R 2 is a hydrogen atom.
- the present invention relates to a method as defined above, in which R 1 or R 2 form a cycle.
- the present invention relates to a process as defined above, in which at least one of the R 1 or R 2 groups comprises at least one protective group, carboxylic acid functions, amine functions, thiol functions, guanidine functions, amide functions and/or alcohol functions, chosen in particular from tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethyloxycarbonyl (Fmoc), alloc, tert-butyloxy (OtBu), formyl (For), 2,2,4,6,7-pentamethylhydrobenzofuran-5-sulfonyl (Pbf), 2, 2, 5, 7, 8- pentamethylchroman-6-sulfonyl (Pmc), 4-methoxy-2,3,6-trimethylbenzenesulfonyl ( Mtr), trityl (Trt), trifluoroacetyl, acetamidomethyl (Acm), and x
- the present invention relates to a method as defined above, comprising:
- the present invention relates to a process as defined above, in which the ⁇ -amino acid compound is chosen from: alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine isoleucine, leucine, lysine, amethionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, l 1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-amino-2-methylpropanoic acid (Aib), and norleucine (NIe), said acid- ⁇ - amine being N-protected on the amine function at a by a -C(O)-O- C 1 to C 20 alkyl substituent, linear or branched, in particular by a -tert-butyloxycarbonyl group, the said amino acids
- the present invention also relates to a process as defined above, in which the NCA compound is an UNCA compound, in particular an UNCA compound of the following structure: in which R' is chosen from a C 1 to C 20 alkyl group, linear or branched, in particular a tert-butyl, or an aryl-methyl group, in particular a benzyl group or a fluorenylmethyl group, in which R 1 and R 2 are as defined above.
- a third object of the present invention is an NCA compound, as obtained by the process as defined above.
- the process for preparing an NCA compound according to the invention makes it possible to have NCA compounds of excellent purity, and devoid of phosgene decomposition products, of decomposition of diphosgene and decomposition products of triphosgene, in particular devoid of hydrochloric acid.
- the process also makes it possible to avoid the contaminations observed when the NCA compound is prepared under nitrosation conditions.
- NCA compounds can be detrimental in certain uses of NCA compounds, in particular in the synthesis of a peptide, where the presence of hydrochloric acid residues, for example, is troublesome.
- such compounds according to the present invention can be salified, after their isolation, during a salification step in which the NCA compound is placed in the presence of an acid, for example such as hydrochloric acid or triflic acid. , non-nucleophilic.
- an acid for example such as hydrochloric acid or triflic acid.
- non-nucleophilic non-nucleophilic.
- it is the salification of a salifiable function on the side chain, and not the nitrogen of the NCA cycle, the salified forms of which are unstable.
- a fourth object of the present invention is a new NCA compound, chosen from the following structures:
- the invention also relates to a novel NCA compound of the following structure: According to another particular embodiment, the present invention relates to a new NCA compound as defined below, chosen from:
- a fifth object of the present invention is a solution comprising an NCA compound prepared according to the process as defined above, or an NCA compound as defined above, said solution being free of phosgene decomposition products, of decomposition of diphosgene and decomposition products of triphosgene, in particular devoid of hydrochloric acid.
- a sixth object of the present invention is the use of an NCA compound prepared according to the process as defined above, or of an NCA compound as defined below, in the preparation of a polypeptide, an oligopeptide or a dendrimer.
- a seventh object of the present invention is a method for preparing a polypeptide, comprising a step of bringing into contact an NCA compound prepared according to the method as defined above, or an NCA compound as defined above above, with a polymerization initiator, chosen in particular from amines, in particular arginine.
- An eighth object of the present invention is a polypeptide, as obtained by the process for preparing a polypeptide as defined above.
- a ninth object of the present invention is a process for the preparation of an UNCA compound, comprising a step of bringing into contact an NCA compound prepared according to the process as defined above, or an NCA compound as defined above, with:
- a reagent allowing the introduction of a benzyloxycarbonyl protective group, chosen in particular from Cbz-Cl and Cbz-OSu, to obtain an UNCA compound protected on the nitrogen atom of the NCA cycle by a -Cbz group, • or a reagent making it possible to introduce a protective group fhiorényhnéthyloxycarbonyle, chosen in particular from Fmoc-Cl and Fmoc-OSu, to obtain an UNCA compound protected on the nitrogen atom of the NCA ring by an -Fmoc group.
- the starting NCA compound comprises an NCA ring in which the nitrogen atom is in the -NH form, making it possible to introduce a substituent.
- Figures 1 represent the analytical data obtained for the compound (L)Trp(Boc)-NCA of example 2.
- Figure 1A represents the NMR spectrum of the proton
- Figure 1B shows the LC chromatogram
- Figure 1C shows the mass spectrum
- Figures 2 represent an analysis by chiral HPLC on the diastereoisomers obtained according to example 22.
- Figure 2A represents the LC chromatogram of the racemic mixture
- Figure 2B represents the LC chromatogram of the diastereoisomer S, S, and
- Figure 2C shows the LC chromatogram of the R,S diastereoisomer.
- the LC/MS analyzes were carried out using a reversed phase Chromolith Flash 25 x 4.6 mm C 18 column. A flow rate of 3 ml/min and a gradient of (0 to 100%) of B on 2.5 min was used. Eluent A: water/0.1% HCO 2 H; eluent B: acetonitrile/0.1% HCO 2 H. UV detection was carried out at 214 nm. Electrospray mass spectra were acquired at a solvent flow rate of 200 ⁇ L/min. Nitrogen was used for both nebulizing and drying gas. Data was obtained in a scan mode ranging from 100 to 1000 m/z or 250 to 1500 m/z at 0.7 s intervals.
- Example 1 General procedure for the synthesis of NCAs compounds - in the presence of pyridine
- Boc-AA-OH (1 eq), was dissolved in ethyl acetate or dimethylformamide. Pyridine (3 eq) was added, followed by T3P® /Ac0Et 50% (2 eq), drop by drop. The reaction mixture was stirred at room temperature for 2 hours, and the progress of the reaction was analyzed by HPLC and LC/MS. The reaction mixture was diluted in ethyl acetate and washed twice with cold water, then with saturated aqueous NaCl solution. The organic phase was dried over anhydrous magnesium sulphate, filtered and concentrated under vacuum. The expected product was purified by recrystallization.
- Boc-(L)leu-OH (10g) was dissolved in ethyl acetate (300ml). T 3 P ® (2 equivalents), in solution in ethyl acetate was added dropwise, followed by pyridine (3 equivalents). The reaction mixture was stirred for 1 hour at room temperature. Water/ice (300 ml) was added, and the organic phase was recovered, washed twice with a cooled saturated aqueous NaCl solution (2 ⁇ 300 ml), dried over MgSO 4 , filtered and concentrated under vacuum. Hexane (50 mL) was added to the oily residue, causing crystallization.
- Boc-(L)Phe-OH (20g) was dissolved in ethyl acetate (1500ml). T 3 P ® (2 equivalents), in solution in ethyl acetate was added dropwise, followed by pyridine (3 equivalents). The reaction mixture was stirred for 1 hour at room temperature. Water/ice (1000 ml) was added, and the organic phase was recovered, washed twice with a cooled saturated aqueous NaCl solution (2 ⁇ 500 ml), dried over MgSO 4 . filtered and concentrated under vacuum. Hexane (100 mL) was added to the oily residue, causing crystallization.
- Boc-(L)Glu(OBzl)-OH 25g was dissolved in ethyl acetate (1500ml). T 3 P ® (2 equivalents), in solution in ethyl acetate was added dropwise, followed by pyridine (3 equivalents). The reaction mixture was stirred for 1 hour at room temperature. Water/ice (1000 ml) was added, and the organic phase was recovered, washed twice with a cooled saturated aqueous NaCl solution (2 ⁇ 500 ml), dried over MgSO 4 , filtered and concentrated under vacuum. Hexane (100 mL) was added to the oily residue, causing crystallization.
- Boc-(L)Lys-(Boc)-OH (10g) was dissolved in ethyl acetate (300ml). T 3 P ® (2 equivalents), in solution in ethyl acetate was added dropwise, followed by pyridine (3 equivalents). The reaction mixture was stirred for 1 hour at room temperature. Water/ice (300 ml) was added, and the organic phase was recovered, washed twice with a cooled saturated aqueous NaCl solution (2 ⁇ 300 ml), dried over MgSO 4 , filtered and concentrated under vacuum. Hexane (50 mL) was added to the oily residue, causing crystallization. The expected product was recrystallized from an AcOEt/hexane mixture to obtain (L)Lys-(Boc)-NCA (6.3g), which was stored under argon at -20°C. Yield 80%.
- Example 1 The general procedure of Example 1 was used, replacing the pyridine with the bases Et 3 N, iPr 2 EtN or DBU. After 2 hours of stirring at ambient temperature in ethyl acetate, the expected NCA product has formed predominantly, as analyzed by LC. 3 DBU 63
- Boc-(L)-Arg(Pbf)-OH (1 eq) was dissolved in ethyl acetate or dimethylformamide.
- the reaction mixture was stirred at 70°C for 2 hours, and the progress of the reaction was analyzed by HPLC and LC/MS.
- the reaction mixture was diluted in ethyl acetate and washed twice with cold water, then with saturated aqueous NaCl solution. The organic phase was dried over anhydrous magnesium sulphate, filtered and concentrated under vacuum. The expected product was purified by recrystallization.
- the purpose of this test is to confirm that the process according to the present invention is not racemizing and makes it possible to isolate the NCAs compounds with retention of the enantiomeric excess.
- the compounds (L)Asp(OBzl)-NCA and (D)Asp(OBzl)-NCA were prepared according to the procedure of Example 1, from Boc-(L)Asp(OBzl)-OH and Boc (D)Asp(OBzl)-OH respectively. Dimethylformamide was used as reaction solvent.
- NCAs compounds thus obtained were then reacted with (S)-1-(4-methoxyphenyl)ethan-1-amine to obtain the S,S and R,S diastereoisomers.
- Figure 2 shows the chromatograms thus obtained. A single peak was observed in both cases ( Figures 2B and 2C), confirming the retention of stereochemistry during the process. This result was also confirmed by 1 H-NMR analysis of the S,S and R,S diastereoisomers.
- Example 23 Comparative example - DCC versus T 3 P ®
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Indole Compounds (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR2014040A FR3118035A1 (fr) | 2020-12-23 | 2020-12-23 | Nouveau procédé de synthèse de composés NCAs |
PCT/EP2021/086981 WO2022136366A1 (fr) | 2020-12-23 | 2021-12-21 | Nouveau procédé de synthèse de composés ncas |
Publications (1)
Publication Number | Publication Date |
---|---|
EP4267557A1 true EP4267557A1 (fr) | 2023-11-01 |
Family
ID=75438935
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP21839577.0A Pending EP4267557A1 (fr) | 2020-12-23 | 2021-12-21 | Nouveau procédé de synthèse de composés ncas |
Country Status (4)
Country | Link |
---|---|
US (1) | US20240109875A1 (fr) |
EP (1) | EP4267557A1 (fr) |
FR (1) | FR3118035A1 (fr) |
WO (1) | WO2022136366A1 (fr) |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3951741A (en) * | 1973-07-10 | 1976-04-20 | Peter Pfaender | Process and apparatus for the synthesis of peptides by use of n-carboxyanhydrides |
DE2901843A1 (de) * | 1979-01-18 | 1980-07-31 | Hoechst Ag | Verfahren zur herstellung von carbonsaeureamiden und peptiden |
NL1015169C2 (nl) * | 2000-05-12 | 2001-11-13 | Dsm Nv | Werkwijze voor de bereiding van N-carboxy-t-leucineanhydride. |
US7829709B1 (en) * | 2007-08-10 | 2010-11-09 | Marquette University | Cysteine prodrugs to treat schizophrenia and drug addiction |
FR3016879A1 (fr) * | 2014-01-29 | 2015-07-31 | Guillaume Laconde | Procede de preparation de benzotriazole n-acyles |
EP3506999A1 (fr) * | 2016-09-05 | 2019-07-10 | Drei Lilien PVG GmbH & Co. KG | Membrane à pores ouverts dotée d'un réseau structural polymère interne s'étendant dans l'espace, destinée à la séparation sélective en matière par voie électrophorétique, ainsi que procédé de fabrication et utilisation |
-
2020
- 2020-12-23 FR FR2014040A patent/FR3118035A1/fr active Pending
-
2021
- 2021-12-21 EP EP21839577.0A patent/EP4267557A1/fr active Pending
- 2021-12-21 WO PCT/EP2021/086981 patent/WO2022136366A1/fr active Application Filing
- 2021-12-21 US US18/259,089 patent/US20240109875A1/en active Pending
Also Published As
Publication number | Publication date |
---|---|
FR3118035A1 (fr) | 2022-06-24 |
WO2022136366A1 (fr) | 2022-06-30 |
US20240109875A1 (en) | 2024-04-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4803352B2 (ja) | アミノ酸−n−カルボキシ無水物の製造方法 | |
EP1201659B1 (fr) | Procédé de préparation des N-carboxyanhydrides | |
WO2020167831A1 (fr) | Procédé de préparation d'un promédicament don à partir d'acide l-glutamique | |
CA2387464C (fr) | Procede de preparation des n-carboxyanhydrides | |
EP4267557A1 (fr) | Nouveau procédé de synthèse de composés ncas | |
EP0154581B1 (fr) | Nouveaux carbonates alpha-chlorés, leur procédé de fabrication et leur application à la protection des fonctions amines des amino-acides | |
EP2139910B1 (fr) | Procede de synthese de peptides sans solvant | |
JP4852282B2 (ja) | N−カルボン酸無水物の製造方法 | |
BE1007184A3 (fr) | Procede de preparation d'un amide d'alpha-aminoacide, utilisable en synthese peptidique. | |
US6670447B2 (en) | Amino acid N-carboxyanhydrides with acyl substituents on nitrogen atoms thereof | |
EP0155862B1 (fr) | Procédé de préparation de dérivés de l'acide carbamique | |
EP0318338B1 (fr) | Procédé de préparation de synthons peptidiques | |
BE660945A (fr) | ||
CA2694320C (fr) | Procede de fabrication d'un derive de n-(halopropyl)amino acide optiquement actif | |
FR2616784A1 (fr) | Composes guanidiniques comprenant un ion tetraphenylborate, procede d'obtention de ces composes et utilisation des composes lors de la synthese peptidique | |
FR2858976A1 (fr) | Procede d'obtention de n-carboxyanhydrides d'alpha-aminoacides a protection urethane | |
FR2666086A1 (fr) | Fluorures d'acides amines et leur utilisation pour la preparation des peptides. | |
FR2559767A1 (fr) | Procede de fabrication d'amino-acide a fonction amine protegee | |
FR2589860A1 (fr) | Nouveau procede de preparation des n-nitrosourees | |
FR2585354A1 (fr) | Procede stereoselectif de preparation de derives de la proline | |
FR2805811A1 (fr) | Urethane n-carboxyanhydrides issus de beta-aminoacides, leur procede de preparation et leurs utilisations | |
WO2019066578A1 (fr) | Procédé de préparation d'un composé intermédiaire pour une synthèse pharmaceutique | |
CH688149A5 (fr) | Procédé de synthèse de 1-alkyl-3-hydroxy-5-halogéno-1,2,4-triazoles et nouveaux dérivés d'hydrazine. | |
FR2652082A1 (fr) | Procede de preparation de l'acide-1 cyclopropanecarboxylique ou d'un de ses sels, produits de depart et leurs procedes de preparation. | |
FR2881741A1 (fr) | Procede de synthese de derives de la cysteine, notamment thiocarbaester, utiles en tant que produits intermediaires dans la synthese de medicaments |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: UNKNOWN |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE |
|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
17P | Request for examination filed |
Effective date: 20230615 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
DAV | Request for validation of the european patent (deleted) | ||
DAX | Request for extension of the european patent (deleted) | ||
RAP3 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (CNRS) Owner name: UNIVERSITE DE MONTPELLIER (UM) Owner name: ECOLE NATIONALE SUPERIEURE DE CHIMIE DE MONTPELLIER (ENSCM) |