US20070105760A1 - Process for the preparation of echinocandin derivatives - Google Patents
Process for the preparation of echinocandin derivatives Download PDFInfo
- Publication number
- US20070105760A1 US20070105760A1 US11/591,898 US59189802A US2007105760A1 US 20070105760 A1 US20070105760 A1 US 20070105760A1 US 59189802 A US59189802 A US 59189802A US 2007105760 A1 US2007105760 A1 US 2007105760A1
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- US
- United States
- Prior art keywords
- formula
- compound
- carried out
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- hours
- 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.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title abstract description 31
- 230000008569 process Effects 0.000 title abstract description 23
- 238000002360 preparation method Methods 0.000 title abstract description 13
- 108010049047 Echinocandins Proteins 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 68
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 5
- 239000000543 intermediate Substances 0.000 abstract description 5
- 230000000843 anti-fungal effect Effects 0.000 abstract description 4
- 229940121375 antifungal agent Drugs 0.000 abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 40
- 239000000047 product Substances 0.000 description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 238000013019 agitation Methods 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 28
- 239000007787 solid Substances 0.000 description 26
- 239000000203 mixture Substances 0.000 description 21
- 239000004473 Threonine Substances 0.000 description 20
- 229960003104 ornithine Drugs 0.000 description 20
- 229960002898 threonine Drugs 0.000 description 20
- 230000009471 action Effects 0.000 description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- 229960001153 serine Drugs 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 17
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 15
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 108010062092 echinocandin B Proteins 0.000 description 14
- FAUOJMHVEYMQQG-HVYQDZECSA-N echinocandin B Chemical compound C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3C[C@H](C)[C@H](O)[C@H]3C(=O)N[C@H](O)[C@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCC\C=C/C\C=C/CCCCC)[C@@H](C)O)=CC=C(O)C=C1 FAUOJMHVEYMQQG-HVYQDZECSA-N 0.000 description 14
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 13
- 238000001914 filtration Methods 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 238000004587 chromatography analysis Methods 0.000 description 12
- 238000006297 dehydration reaction Methods 0.000 description 12
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 0 *C(=O)N[C@H]1CC(NCCN)CNC(=O)[C@]2([H])[C@@H](O)[C@@H](C)CN2C(=O)[C@]([H])(CO)NC(=O)[C@]([H])([C@H](O)CC2=CC=C(O)C=C2)NC(=O)[C@]2([H])C[C@@H](O)CN2C(=O)[C@]([H])([C@@H](C)O)NC1=O Chemical compound *C(=O)N[C@H]1CC(NCCN)CNC(=O)[C@]2([H])[C@@H](O)[C@@H](C)CN2C(=O)[C@]([H])(CO)NC(=O)[C@]([H])([C@H](O)CC2=CC=C(O)C=C2)NC(=O)[C@]2([H])C[C@@H](O)CN2C(=O)[C@]([H])([C@@H](C)O)NC1=O 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 9
- 230000008025 crystallization Effects 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- OOKAXSHFTDPZHP-UHFFFAOYSA-N (1-bromo-2-methyl-1-oxopropan-2-yl) acetate Chemical compound CC(=O)OC(C)(C)C(Br)=O OOKAXSHFTDPZHP-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 238000005917 acylation reaction Methods 0.000 description 8
- 238000005576 amination reaction Methods 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- BLQJIBCZHWBKSL-UHFFFAOYSA-L magnesium iodide Chemical compound [Mg+2].[I-].[I-] BLQJIBCZHWBKSL-UHFFFAOYSA-L 0.000 description 8
- 229910001641 magnesium iodide Inorganic materials 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 208000005156 Dehydration Diseases 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 230000018044 dehydration Effects 0.000 description 6
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 5
- 229910020889 NaBH3 Inorganic materials 0.000 description 5
- 230000010933 acylation Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 5
- 239000012429 reaction media Substances 0.000 description 5
- 239000000377 silicon dioxide Substances 0.000 description 5
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 5
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 4
- CNPSFBUUYIVHAP-AKGZTFGVSA-N (2s)-3-methylpyrrolidine-2-carboxylic acid Chemical compound CC1CCN[C@@H]1C(O)=O CNPSFBUUYIVHAP-AKGZTFGVSA-N 0.000 description 4
- BMTZEAOGFDXDAD-UHFFFAOYSA-M 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium;chloride Chemical compound [Cl-].COC1=NC(OC)=NC([N+]2(C)CCOCC2)=N1 BMTZEAOGFDXDAD-UHFFFAOYSA-M 0.000 description 4
- LOOZZTFGSTZNRX-VIFPVBQESA-N L-Homotyrosine Chemical compound OC(=O)[C@@H](N)CCC1=CC=C(O)C=C1 LOOZZTFGSTZNRX-VIFPVBQESA-N 0.000 description 4
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 4
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 4
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 4
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 4
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 4
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 4
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 4
- 229910003074 TiCl4 Inorganic materials 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 125000005447 octyloxy 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])O* 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- KKJQZEWNZXRJFG-UHFFFAOYSA-N trans-4-methylproline Natural products CC1CNC(C(O)=O)C1 KKJQZEWNZXRJFG-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 description 3
- PMMYEEVYMWASQN-BKLSDQPFSA-N 4-hydroxy-L-proline Chemical compound OC1C[NH2+][C@H](C([O-])=O)C1 PMMYEEVYMWASQN-BKLSDQPFSA-N 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
- VJLPJZYNVYQBHK-RGQRDNOZSA-N [H][C@@]1(CO)NC(=O)[C@]([H])([C@H](O)CC2=CC=C(O)C=C2)NC(=O)[C@]2([H])C[C@@H](O)CN2C(=O)[C@]([H])([C@@H](C)O)NC(=O)[C@@H](NC(=O)C2=CC=C(C3=CC=C(OCCCCCCCC)C=C3)C=C2)CC(O)C(OC)NC(=O)[C@]2([H])[C@@H](O)[C@@H](C)CN2C1=O Chemical compound [H][C@@]1(CO)NC(=O)[C@]([H])([C@H](O)CC2=CC=C(O)C=C2)NC(=O)[C@]2([H])C[C@@H](O)CN2C(=O)[C@]([H])([C@@H](C)O)NC(=O)[C@@H](NC(=O)C2=CC=C(C3=CC=C(OCCCCCCCC)C=C3)C=C2)CC(O)C(OC)NC(=O)[C@]2([H])[C@@H](O)[C@@H](C)CN2C1=O VJLPJZYNVYQBHK-RGQRDNOZSA-N 0.000 description 3
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- 238000004821 distillation Methods 0.000 description 3
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 3
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- XCUCLODHJSRDGC-UHFFFAOYSA-N 1-octoxy-2-phenylbenzene Chemical group CCCCCCCCOC1=CC=CC=C1C1=CC=CC=C1 XCUCLODHJSRDGC-UHFFFAOYSA-N 0.000 description 2
- IXPLQJZRAGHCNI-UHFFFAOYSA-N CCCCCCCCOC1=CC=C(C2=CC=C(C)C=C2)C=C1 Chemical compound CCCCCCCCOC1=CC=C(C2=CC=C(C)C=C2)C=C1 IXPLQJZRAGHCNI-UHFFFAOYSA-N 0.000 description 2
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- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
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- 125000003158 alcohol group Chemical group 0.000 description 2
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- DJOFHRNSSUAQQK-OERVALRRSA-N [H][C@@]1(CO)NC(=O)[C@]([H])([C@H](O)CC2=CC=C(O)C=C2)NC(=O)[C@]2([H])C[C@@H](O)CN2C(=O)[C@]([H])([C@@H](C)O)NC(=O)[C@@H](N)CC(O)C(O)NC(=O)[C@]2([H])[C@@H](O)[C@@H](C)CN2C1=O Chemical compound [H][C@@]1(CO)NC(=O)[C@]([H])([C@H](O)CC2=CC=C(O)C=C2)NC(=O)[C@]2([H])C[C@@H](O)CN2C(=O)[C@]([H])([C@@H](C)O)NC(=O)[C@@H](N)CC(O)C(O)NC(=O)[C@]2([H])[C@@H](O)[C@@H](C)CN2C1=O DJOFHRNSSUAQQK-OERVALRRSA-N 0.000 description 1
- KIAJRIXCJUNMAZ-QEWOSQOLSA-N [H][C@@]1(CO)NC(=O)[C@]([H])([C@H](O)CC2=CC=C(O)C=C2)NC(=O)[C@]2([H])C[C@@H](O)CN2C(=O)[C@]([H])([C@@H](C)O)NC(=O)[C@@H](NC(=O)C2=CC=C(C3=CC=C(OC)C=C3)C=C2)CC(=O)CNC(=O)[C@]2([H])[C@@H](O)[C@@H](C)CN2C1=O Chemical compound [H][C@@]1(CO)NC(=O)[C@]([H])([C@H](O)CC2=CC=C(O)C=C2)NC(=O)[C@]2([H])C[C@@H](O)CN2C(=O)[C@]([H])([C@@H](C)O)NC(=O)[C@@H](NC(=O)C2=CC=C(C3=CC=C(OC)C=C3)C=C2)CC(=O)CNC(=O)[C@]2([H])[C@@H](O)[C@@H](C)CN2C1=O KIAJRIXCJUNMAZ-QEWOSQOLSA-N 0.000 description 1
- UMNFJRNUJIBDSK-NMVZEWDOSA-N [H][C@@]1(CO)NC(=O)[C@]([H])([C@H](O)CC2=CC=C(O)C=C2)NC(=O)[C@]2([H])C[C@@H](O)CN2C(=O)[C@]([H])([C@@H](C)O)NC(=O)[C@@H](NC(=O)C2=CC=C(C3=CC=C(OCCCCCCCC)C=C3)C=C2)CC(NCCN)CNC(=O)[C@]2([H])[C@@H](O)[C@@H](C)CN2C1=O Chemical compound [H][C@@]1(CO)NC(=O)[C@]([H])([C@H](O)CC2=CC=C(O)C=C2)NC(=O)[C@]2([H])C[C@@H](O)CN2C(=O)[C@]([H])([C@@H](C)O)NC(=O)[C@@H](NC(=O)C2=CC=C(C3=CC=C(OCCCCCCCC)C=C3)C=C2)CC(NCCN)CNC(=O)[C@]2([H])[C@@H](O)[C@@H](C)CN2C1=O UMNFJRNUJIBDSK-NMVZEWDOSA-N 0.000 description 1
- JNKXREYDRTYMFD-KVHYQBFCSA-N [H][C@@]1(CO)NC(=O)[C@]([H])([C@H](O)CC2=CC=C(O)C=C2)NC(=O)[C@]2([H])C[C@@H](O)CN2C(=O)[C@]([H])([C@@H](C)O)NC(=O)[C@@H](NC(=O)C2=CC=C(C3=CC=C(OCCCCCCCC)C=C3)C=C2)CC(O)C(O)NC(=O)[C@]2([H])[C@@H](O)[C@@H](C)CN2C1=O Chemical compound [H][C@@]1(CO)NC(=O)[C@]([H])([C@H](O)CC2=CC=C(O)C=C2)NC(=O)[C@]2([H])C[C@@H](O)CN2C(=O)[C@]([H])([C@@H](C)O)NC(=O)[C@@H](NC(=O)C2=CC=C(C3=CC=C(OCCCCCCCC)C=C3)C=C2)CC(O)C(O)NC(=O)[C@]2([H])[C@@H](O)[C@@H](C)CN2C1=O JNKXREYDRTYMFD-KVHYQBFCSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- GLRAHDCHUZLKKC-UHFFFAOYSA-N acetonitrile;2,2,2-trifluoroacetic acid;hydrate Chemical compound O.CC#N.OC(=O)C(F)(F)F GLRAHDCHUZLKKC-UHFFFAOYSA-N 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- XEKAUTDWPYQNFU-UHFFFAOYSA-N chlorane Chemical compound Cl.Cl.Cl XEKAUTDWPYQNFU-UHFFFAOYSA-N 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 108010063315 deoxymulundocandin Proteins 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 150000002222 fluorine compounds Chemical class 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- QYRFJLLXPINATB-UHFFFAOYSA-N hydron;2,4,5,6-tetrafluorobenzene-1,3-diamine;dichloride Chemical compound Cl.Cl.NC1=C(F)C(N)=C(F)C(F)=C1F QYRFJLLXPINATB-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-N sodium;hydron;carbonate Chemical compound [Na+].OC(O)=O UIIMBOGNXHQVGW-UHFFFAOYSA-N 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/50—Cyclic peptides containing at least one abnormal peptide link
- C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
- C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
Definitions
- a subject of the present invention is a process for the preparation of echinocandin derivatives, the intermediates and the products obtained and their use as an antifungal medicament.
- the objective of the present invention is to provide a new process for the preparation of echinocandin derivatives and to obtain new salts of the latter.
- Echinocandin can be presented in the form of two epimers called isomer A and isomer B corresponding to the R and S configurations of the substituent in position 4.
- One of the subjects of the present invention is to obtain during the process, a majority of one of the two isomers, i.e. at least greater than 50% (isomer called form A, corresponding to the pharmacologically active compound of formula (I), which is not the case for the process according to WO99/29716 during which the active isomer A obtained during the process before purification on a chromatographic column is in the minority.
- Another objective of the present invention is to avoid purifications of the intermediate products by chromatography and to obtain crystallized products which allows a significant improvement in yields.
- a subject of the invention is a process for the preparation of compounds of formula (I) in which R represents a linear or branched or cyclic chain containing up to 30 carbon atoms, optionally containing one or more heteroatoms and one or more heterocycles comprising the following stages a) A compound of formula (II) is subjected to the action of an acid of formula R—CO 2 H, R being as defined above, said acid being, if appropriate, in an isolated or non isolated activated form, in order to obtain the compound of formula (III) b) if appropriate, the compound of formula (III) is subjected to an alkylation reaction of the alcohol in position 5 by the action of an alcohol of formula Alk—OH in the presence of PPTS, Alk being an Alkyl radical containing 1 to 4 carbon atoms, in order to obtain the compound of formula (III′) c) the compound of formula (III) or (III′) is subjected to a dehydration reaction, in order to obtain a compound of formula (IV) d)
- a subject of the invention is a process as defined previously in which the compounds of formulae (I), (III), (III′) or (IV) contain an R radical representing the following groups:
- a subject of the invention is a process as defined previously in which the compounds of formulae (I), (III), (III′) or (IV) contain an R radical representing the following group:
- the compound of formula (II) is prepared according to the method described in the International Application WO99/29716 page 18 (Preparation 2, “nucleus of deoxymulundocandin”).
- Activation of the acid of formula R—CO 2 H is carried out according to standard methods known to a person skilled in the art (Journet M. et al, J. Org. Chem. (1999), 64, 2411-2417; Pöchlauer P. et al. Tetrahedron 54(1998) 3489-3494; Kunushima et al. Tetrahedron (1999) 55 13159-13170).
- pentaflurophenol is used in order to obtain the activated ester of pentafluorophenol which is isolated before being used in the acylation reaction of the amine.
- Another method is the use of N-hydroxysuccinimide (optionally N-hydroxybenzotriazole) in order to obtain the activated ester of N-hydroxysuccinimide (optionally N-hydroxybenzotriazole) which is also isolated.
- the acylation stage which follows in order to obtain a compound of formula (III) is carried out in the presence of a base according to methods known to a person skilled in the art and is illustrated in the examples described hereafter. It is also possible to carry out the acylation without isolating the active ester and without an added base by operating in the presence of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-myl-morpholinium chloride (DMTMM). This last alternative has the advantage of suppressing an isolation stage and therefore of improving yields.
- DTMM 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-myl-morpholinium chloride
- the compound obtained after the dehydration reaction is then purified by crystallization from a mixture of DMF (dimethylformamide)/MeCN (acetonitile). Mixtures of the following solvents: DMF/acetone and DMF/AcOEt (ethyl acetate) can also be used.
- DMF dimethylformamide
- MeCN acetonitile
- ethylenediamine is used in the presence of NaBH 3 CN by coupling with TiCl 4 or any other Lewis acid or in the presence of NaBH(OCOR′)3, OCOR′ representing Boc-L-Pro, Bzl-L-Pro or any other optically active amino acid as well as any other chiral or non chiral carboxylic acid.
- Coupling the reduction reagent NaBH 3 CN with a Lewis acid, in particular TiCl 4 is an essential element for selectivity and therefore in order to obtain a mixture of isomer A and isomer B in which the active isomer A is in the majority.
- a ratio of isomer A of greater than 70%, and in particular comprised between 80 and 85% is obtained. The situation is similar with the other reagents mentioned above.
- reaction intermediate before reduction can if appropriate, be isolated, and is therefore a subject of the present invention. It is an imidazolidine of formula (IV′) or (IV′a) when R represents a —Ph—Ph—O— C 8 H 17 group
- the salification reaction is carried out according to the usual methods known to a person skilled in the art.
- Preparation of the hydrochloride or of the di-hydrochloride is carried out in the presence of hydrochloric acid in methanol.
- a subject of the present invention is a process for the preparation of the compounds of formula (Ia) comprising the following stages a) A compound of formula (II) is subjected to the action of an acid of formula C 8 H 17 —O—Ph—Ph—CO 2 H, said acid being, if appropriate, in an activated, isolated or non isolated form, in order to obtain the compound of formula (IIIa) b) if appropriate the compound of formula (IIIa) is subjected to an alkylation reaction of the alcohol in position 5 by the action of methanol in the presence of PPTS in order to obtain the compound of formula (IIIa′) c) the compound of formula (IIIa) or (IIIa′) is subjected to a dehydration reaction, in order to obtain a compound of formula (IVa), d) the compound of formula (IVa) is subjected to a reducing amination reaction by the action of ethylene diamine in the presence of a reducing agent such as NaBH 3 CN coupled with TiC
- the compound of formula (Ia) can be found in the form of a mixture of two epimers (asymmetrical carbon in position 4) which are called isomer A or isomer B.
- the compound of formula (I) obtained according to the process as defined above allows a mixture of isomer A/isomer B of approximately 70-85%/30-15% to be obtained.
- the compound of formula (Ia) is purified by chromatography on silica then by reversed-phase chromatography using a mixture of organic solvents, water and trifluoroacetic acid in order to obtain the trifluoroacetic acid salt of the compound of formula (Ia).
- This salt is then subjected to the action of a base, for example by the action of an aqueous solution of sodium bicarbonate, in order to obtain the compound of formula (Ia) in the form of a base.
- the base obtained is salified by the action of hydrochloric acid in order to obtain the corresponding salt namely the dihydrochloride of the compound of formula (Ia).
- a quite particular subject of the invention is a process as defined previously characterized in that the activation reaction of the acid is carried out in the presence of pentafluorophenol, N-hydroxysuccinimide or optionally N-hydroxybenzotriazole.
- a quite particular subject of the invention is a process as defined previously characterized in that the acylation reaction in the presence of an isolated activated acid, is carried out in the presence of diisopropylethylamine.
- a quite particular subject of the invention is a process as defined previously characterized in that the activation reaction then the acylation reaction in the presence of an isolated activated acid, is carried out in the presence of N-methyl pyrrolidone and DMTMM.
- a quite particular subject of the invention is a process as defined previously characterized in that the dehydration reaction is carried out in the presence of AIBB and if appropriate MgI 2 .
- a quite particular subject of the invention is a process as defined previously characterized in that the dehydration reaction is carried out in the presence of HBr-AcOH and MgI 2 .
- a quite particular subject of the invention is a process as defined previously characterized in that the product originating from the dehydration is purified by crystallization from a dimethylformamide (DMF)/acetonitrile, DMF/acetone or DMF/AcOEt mixture.
- DMF dimethylformamide
- a quite particular subject of the invention is a process as defined previously characterized in that the reducing amination reaction is carried out in the presence of a reducing agent chosen from NaBH 3 CN coupled with TiCl 4 , NaBH(Boc-L-Pro) 3 or NaBH(Bzl-L-Pro) 3 .
- a reducing agent chosen from NaBH 3 CN coupled with TiCl 4 , NaBH(Boc-L-Pro) 3 or NaBH(Bzl-L-Pro) 3 .
- a subject of the invention is also the dihydrochloride of 1-[4-[(2-aminoethyl)amino]-N-2-[[4′-(octyloxy)[1,1 ′-biphenyl]-4-yl]carbonyl]-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandin B in 4S or 4R form or in the form of a mixture of the two stereoisomers.
- a subject of the invention is also the dihydrochloride of 1-[4-[(2-aminoethyl)amino]-N2-[[4′-(octyloxy)[1,1 ′-biphenyl]-4-yl]carbonyl]-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandin B in the form of the active isomer A obtained by the process as described previously.
- a subject of the invention is also the dihydrochloride of 1-[4-[(2-aminoethyl)amino]-N2-[[4′-(octyloxy)[1,1′-biphenyl]-4-yl]carbonyl]-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandin B in 4S or 4R form or in the form of a mixture of the two stereoisomers, as a medicament and in particular as and antifungal medicament.
- a subject of the invention is the pharmaceutical compositions containing the dihydrochloride of 1-[4-[(2-aminoethyl)amino]-N2-[[4′-(octyloxy)[1,1′-biphenyl]-4-yl]carbonyl]-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandin B in 4S or 4R form or in the form of a mixture of the two stereoisomers and a pharmaceutically acceptable vehicle.
- Threonine 8.16 (1H), 4.85 (1H), 4.41 (1H), 1.13 (3H); ⁇ Hydroxyproline: 4.42 (1H), 1.92-2.28 (2H), 4.44 (1H), 3.86-3.70 (2H); ⁇ Hydroxy homo tyrosine 7.36 (1H), 4.23 (1H), 4.20 (1H), 2.53-2.46 (2H), 6.98 (2H), 6.68 (2H); Serine: 7.40 (1H), 4.86 (1H), 3.66-3.60 (2H), ⁇ Hydroxy ⁇ methyl proline: 4.27 (1H), 4.03 (1H), 2.38 (1H), 0.99 (3H), 3.25-3.93 (2H), ⁇ ornithine >>: 7.98 (1H), 5.16 (1H), 3.96 (1H), 8.54 (1H), 4.44 (1H), 1.98 (2H); Aromatic and octyloxy chain: 7.98 (2H), 7.71 (2H), 7.68 (2H), 7.02 (2H), 4.00 (2H), 1.72 (2H), 1.41 (2H), 1.
- deoxymuluncandin prepared according to Preparation 2 of WO 99/29716
- 8.3 ml of N-myl pyrolidone 1.12 g of octyloxybiphenyl acid and 0.95 g of 4-(4,6-Dimoxy-1,3,5-triazin-2-yl)-4-m-yl-morpholinium chloride (DMTMM) is added.
- DTMM 4-(4,6-Dimoxy-1,3,5-triazin-2-yl)-4-m-yl-morpholinium chloride
- the reaction medium is poured into 133 ml of water under agitation. Agitated is carried out for 20 minutes, the solid is filtered and rinsed 3 times with water (3 times 7 ml). After drying under vacuum at 40° C., 2.66 g of expected product 4 is obtained in the form of beige solid.
- Second Stage Dehydration (Obtaining a Compound of Formula (IVa)
- the Product is Crystallized According to the Preparation Described below.
- Route 2 Starting from Product (IIIa) Obtained in Stage a by the Action of AIBB/MgI 2 /dioxane
- Agitation is carried out for 2 hours, followed by distilling under vacuum to a residual volume of 250 ml at an internal temperature of less than 35° C. Atmospheric pressure of nitrogen is reestablished, and 200 ml of dimethylformamide is added, followed by distilling under vacuum to a residual volume of 250 ml and this solution is poured at ambient temperature into 2.8 litres of water. After rinsing with DMF, agitation is carried out for 1 hour. The solid is filtered and rinsed with water. The solid is dried for 24 hours under vacuum at 30° C. 46 g of expected product is obtained in the form of beige solid.
- the Product is then Crystallized According to the Method Described below.
- Route 3 Starting From Product IIIa Obtained in the First Stage by the Action of HBr-AcOH/MgI 2 /MEK
- Agitating is carried out for 10 minutes, followed by decanting, reextracting the aqueous phase with a mixture of ethyl acetate/methanol and distilling all the organic phases under vacuum to a residual volume of 40 ml.
- 40 ml of DMF is introduced and distilling is continued to a residual volume of 60 ml.
- This solution is poured into 320 ml of water over 20 minutes and agitated for 15 hours at ambient temperature. If necessary the pH is adjusted to 9-9.5 with dilute soda, followed by filtering and rinsing with an aqueous solution of 1.2 g of sodium bicarbonate (pH 9-9.5). After drying the solid in an oven under vacuum at 30 C. for 18 hours, 8.55 g of expected crude base is obtained in the form of a white solid.
- Hyflosupercel Kieselguhr filtration agent 20 g is added to the suspension and agitation is carried out for 16 hours at ambient temperature, followed by filtering and washing with water. The cake is dissolved by passing through 100 ml of methanol four times. The methanolic filtrate is concentrated to dryness under vacuum without exceeding 40° C. 21.25 g of expected product is obtained.
- a suspension of the product of formula (IVa) obtained in Stage II) in 40 ml of dichloromethane and 0.32 ml of ethylene diamine is agitated for 18 hours.
- 80 ml of diethyl ether is added and agitation is carried out for 5 hours.
- the solid is filtered and rinsed several times with diethyl ether. After drying in an oven under vacuum for 15 hours at ambient temperature, 076 g of expected compound is obtained in the form of a white solid.
- This intermediate is then subjected to the action of a reducing reaction according to preceding routes 1 or 2.
- This isolated compound is new and forms part of the present invention
- a Prochrom LC 200 column is conditioned with 2.5 g of merck 11763 silica using a methylene chloride (43)-acetonitrile (50)-methanol (7)-water (5)-trifluoroacetic acid (1) mixture as mobile phase.
- 24 g of the compound obtained above (Stage III, route 1) is dissolved in 126 ml of a mixture composed of acetonitrile (50)-methanol (7)-water (5)-TFA (1).
- the solution is filtered and 86 ml of methylene chloride is added. This solution is injected into the column. Elution is carried out a flow rate of 76 1/h and a pressure of 14 bars.
- a Prochrom LC 50 column is conditioned with 300 g of reversed-phase Daisogel SP 120 n° 5/1502 silica, using a water (90)-acetonitrile (10)-trifluoroacetic acid (0.1) mixture as mobile phase. 36.75 g of the salt obtained above in the first chromatography is dissolved in a mixture comprising 57.3 ml of water (90)-acetonitrile (10)-trifluoroacetic acid (0.1) and 26.8 ml of pure acetonitrile. The solution is filtered and this solution is injected into the column.
- Elution is carried out with water (90)-acetonitrile (10)-trifluoroacetic acid (0.1) in the first instance to remove the mineral salts, then with water (50)-acetonitrile (50)-trifluoroacetic acid (0.1) to remove the product.
- the fractions collected are distilled under vacuum at an external temperature of less than 40° C.
- the resultant limpid aqueous solution is lyophilized. 15.59 g of expected product is obtained in the form of a Lacty white solid di-salt of TFA.
- 10.53 g of compound obtained in the preceding stage is dissolved in 263 ml of methanol whilst agitating for 30 minutes at ambient temperature, followed by filtering and rinsing with twice 31.6 ml of methanol.
- 2.1 ml of 36% hydrochloric acid is added agitation and under nitrogen at ambient temperature. Agitation is carried out for 30 minutes, followed by distilling to dryness under vacuum without exceeding 35° C.
- the dry extract is taken up in 105.3 ml of diisopropyl oxide.
- the suspension obtained is agitated for 2 hours, followed by filtering and washing with twice 21.1 ml of diisopropyl oxide. After drying the solid in an oven under vacuum at 40.° C., 10.52 g of expected product is obtained in the form of a white powder.
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract
A subject of the invention is a process for the preparation of the compounds of formula (I):
R being as defined in the description as well as their salts, the intermediates, the use of the dihydrochloride as a medicament and the pharmaceutical compositions containing them. The process for preparing formula (I) leads to greater than 50% yield of isomer A, and its intended use, e.g. as an antifungal medicament.
Description
- This is a divisional application of U.S. patent application Ser. No. 10/867,070, filed Jun. 14, 2004, which is a continuation of Serial No. PCT/FR02/04308, filed Dec. 12, 2002, which claims priority to FR 0116230, filed Dec. 14, 2001, all of which are incorporated by reference herein.
- A subject of the present invention is a process for the preparation of echinocandin derivatives, the intermediates and the products obtained and their use as an antifungal medicament.
- Numerous compounds having an antifungal activity are known in the prior art. In particular the echinocandin derivatives as defined in International Application WO99/29716 can be mentioned.
- The objective of the present invention is to provide a new process for the preparation of echinocandin derivatives and to obtain new salts of the latter.
- Echinocandin can be presented in the form of two epimers called isomer A and isomer B corresponding to the R and S configurations of the substituent in position 4. One of the subjects of the present invention is to obtain during the process, a majority of one of the two isomers, i.e. at least greater than 50% (isomer called form A, corresponding to the pharmacologically active compound of formula (I), which is not the case for the process according to WO99/29716 during which the active isomer A obtained during the process before purification on a chromatographic column is in the minority.
- Moreover another objective of the present invention is to avoid purifications of the intermediate products by chromatography and to obtain crystallized products which allows a significant improvement in yields.
- Therefore a subject of the invention is a process for the preparation of compounds of formula (I)
in which R represents a linear or branched or cyclic chain containing up to 30 carbon atoms, optionally containing one or more heteroatoms and one or more heterocycles comprising the following stages
a) A compound of formula (II)
is subjected to the action of an acid of formula R—CO2H, R being as defined above, said acid being, if appropriate, in an isolated or non isolated activated form, in order to obtain the compound of formula (III)
b) if appropriate, the compound of formula (III) is subjected to an alkylation reaction of the alcohol in position 5 by the action of an alcohol of formula Alk—OH in the presence of PPTS, Alk being an Alkyl radical containing 1 to 4 carbon atoms, in order to obtain the compound of formula (III′)
c) the compound of formula (III) or (III′) is subjected to a dehydration reaction, in order to obtain a compound of formula (IV)
d) the compound of formula (IV) is subjected to a reducing amination reaction by the action of ethylene diamine in the presence of a reducing agent such as NaBH3CN in the presence of a Lewis acid, or NaBH(OCOR′3), OCOR′ representing Boc-L-Pro, Bzl-L-Pro or any other optically active amino acid as well as any other chiral or non chiral carboxylic acid, in order to obtain the compound of formula (I) as defined above, comprising a majority of one of the active isomers, said compound of formula (I) then being subjected, if appropriate, and in any appropriate order to the one or more of the following operations -
- purification by chromatography
- purification by crystallization
- the action of a base
- salification.
-
-
- The compound of formula (II) is prepared according to the method described in the International Application WO99/29716 page 18 (Preparation 2, “nucleus of deoxymulundocandin”).
- Activation of the acid of formula R—CO2H is carried out according to standard methods known to a person skilled in the art (Journet M. et al, J. Org. Chem. (1999), 64, 2411-2417; Pöchlauer P. et al. Tetrahedron 54(1998) 3489-3494; Kunushima et al. Tetrahedron (1999) 55 13159-13170). In particular pentaflurophenol is used in order to obtain the activated ester of pentafluorophenol which is isolated before being used in the acylation reaction of the amine. Another method is the use of N-hydroxysuccinimide (optionally N-hydroxybenzotriazole) in order to obtain the activated ester of N-hydroxysuccinimide (optionally N-hydroxybenzotriazole) which is also isolated.
- The acylation stage which follows in order to obtain a compound of formula (III) is carried out in the presence of a base according to methods known to a person skilled in the art and is illustrated in the examples described hereafter. It is also possible to carry out the acylation without isolating the active ester and without an added base by operating in the presence of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-myl-morpholinium chloride (DMTMM). This last alternative has the advantage of suppressing an isolation stage and therefore of improving yields.
- The dehydration stage of the compound of formula (III) in order to obtain a compound of formula (IV) can be carried out in the following way:
-
- The dehydration stage is carried out in the presence of a hydrohalogenated acid such as HBr in the presence of MgI2. In this case, it is not necessary to pass via the intermediate of formula (III′).
- By way of a variant, it can be desirable to alkylate the hydroxyl group in position 5 before proceeding to the dehydration stage. For example methylation can be carried out with methanol in the presence of PPTS (Pyridinium Paratoluene Sulphonate) in order to obtain a compound of formula (III′) with Alk representing a methyl.
- Finally, this dehydration reaction can also be carried out in the presence of α-acetoxy isobutyryl bromide (AIBB) in dioxane. In this latter case the operation can be carried out either on the compound of formula (III′) or directly on the compound of formula (III) in the presence of MgI2.
- Preferably, the compound obtained after the dehydration reaction is then purified by crystallization from a mixture of DMF (dimethylformamide)/MeCN (acetonitile). Mixtures of the following solvents: DMF/acetone and DMF/AcOEt (ethyl acetate) can also be used.
- The reducing amination reaction of the compounds of formula (IV) in order to obtain the echinocandin of formula (I) is carried out according to the methods described in the literature and known to a person skilled in the art (Yamada K. et al. J. Chem. Soc. Perkin Trans I (1983) 265-270; Hutchins R. et al. Org. prep. Proc. Int. 11(5) (1979) 201-246). In particular ethylenediamine is used in the presence of NaBH3CN by coupling with TiCl4 or any other Lewis acid or in the presence of NaBH(OCOR′)3, OCOR′ representing Boc-L-Pro, Bzl-L-Pro or any other optically active amino acid as well as any other chiral or non chiral carboxylic acid.
- Coupling the reduction reagent NaBH3CN with a Lewis acid, in particular TiCl4, is an essential element for selectivity and therefore in order to obtain a mixture of isomer A and isomer B in which the active isomer A is in the majority. In general a ratio of isomer A of greater than 70%, and in particular comprised between 80 and 85% is obtained. The situation is similar with the other reagents mentioned above.
- In particular, for the compound of formula (Ia), in this stage an isomer A/isomer B ratio is obtained of 80-85%/20-15% respectively whereas the process as described in WO 97/29716 leads to a mixture in which isomer A is in the minority or equivalent (racemic A and B mixture).
-
- It can be desirable to purify the product or products obtained by chromatography or by recrystallization. This operation is carried out according to the usual methods known to a person skilled in the art. When the product obtained is in particular in the form of a trifluoroacetic acid salt following chromatography, it is desirable to eliminate this salt by the action of a base in order to obtain the compound of formula (I) in the form of a base.
- The salification reaction is carried out according to the usual methods known to a person skilled in the art. Preparation of the hydrochloride or of the di-hydrochloride is carried out in the presence of hydrochloric acid in methanol.
- Quite particularly, a subject of the present invention is a process for the preparation of the compounds of formula (Ia)
comprising the following stages
a) A compound of formula (II)
is subjected to the action of an acid of formula C8H17—O—Ph—Ph—CO2H, said acid being, if appropriate, in an activated, isolated or non isolated form, in order to obtain the compound of formula (IIIa)
b) if appropriate the compound of formula (IIIa) is subjected to an alkylation reaction of the alcohol in position 5 by the action of methanol in the presence of PPTS in order to obtain the compound of formula (IIIa′)
c) the compound of formula (IIIa) or (IIIa′) is subjected to a dehydration reaction, in order to obtain a compound of formula (IVa),
d) the compound of formula (IVa) is subjected to a reducing amination reaction by the action of ethylene diamine in the presence of a reducing agent such as NaBH3CN coupled with TiCl4, NaBH(Boc-L-Pro)3 or NaBH(Bzl-L-Pro)3 in order to obtain the compound of formula (Ia) as defined above, comprising a majority of one of the active isomers, said compound of formula (Ia) being subjected to one or more of the following operations in an appropriate order. -
- chromatography
- crystallization
- the action of a base
- salification by the action of hydrochloric acid.
- The compound of formula (Ia) can be found in the form of a mixture of two epimers (asymmetrical carbon in position 4) which are called isomer A or isomer B. The compound of formula (I) obtained according to the process as defined above allows a mixture of isomer A/isomer B of approximately 70-85%/30-15% to be obtained.
- The purification/crystallization and salification stages which are carried out after the reducing amination reaction allows the active epimer A of the compound of formula (Ia) to be obtained selectively.
- Preferably, the compound of formula (Ia) is purified by chromatography on silica then by reversed-phase chromatography using a mixture of organic solvents, water and trifluoroacetic acid in order to obtain the trifluoroacetic acid salt of the compound of formula (Ia). This salt is then subjected to the action of a base, for example by the action of an aqueous solution of sodium bicarbonate, in order to obtain the compound of formula (Ia) in the form of a base. Then, the base obtained is salified by the action of hydrochloric acid in order to obtain the corresponding salt namely the dihydrochloride of the compound of formula (Ia).
- Therefore a quite particular subject of the invention is a process as defined previously characterized in that the compound of formula (Ia) is subjected successively to the following operations:
- a) purification by chromatography on silica then by reversed-phase chromatography using a mixture of organic solvents, water and trifluoroacetic acid in order to obtain the trifluoroacetic acid salt of the compound of formula (Ia)
- b) the action of a base, for example, by the action of an aqueous solution of sodium bicarbonate, in order to obtain the compound of formula (Ia) in the form of a base
- c) salification by the action of hydrochloric acid in order to obtain the corresponding salt namely the dihydrochloride of the compound of formula (Ia).
- Therefore a quite particular subject of the invention is a process as defined previously characterized in that the activation reaction of the acid is carried out in the presence of pentafluorophenol, N-hydroxysuccinimide or optionally N-hydroxybenzotriazole.
- Therefore a quite particular subject of the invention is a process as defined previously characterized in that the acylation reaction in the presence of an isolated activated acid, is carried out in the presence of diisopropylethylamine.
- Therefore a quite particular subject of the invention is a process as defined previously characterized in that the activation reaction then the acylation reaction in the presence of an isolated activated acid, is carried out in the presence of N-methyl pyrrolidone and DMTMM.
- Therefore a quite particular subject of the invention is a process as defined previously characterized in that the dehydration reaction is carried out in the presence of AIBB and if appropriate MgI2.
- Therefore a quite particular subject of the invention is a process as defined previously characterized in that the dehydration reaction is carried out in the presence of HBr-AcOH and MgI2.
- Therefore a quite particular subject of the invention is a process as defined previously characterized in that the product originating from the dehydration is purified by crystallization from a dimethylformamide (DMF)/acetonitrile, DMF/acetone or DMF/AcOEt mixture.
- Therefore a quite particular subject of the invention is a process as defined previously characterized in that the reducing amination reaction is carried out in the presence of a reducing agent chosen from NaBH3CN coupled with TiCl4, NaBH(Boc-L-Pro)3 or NaBH(Bzl-L-Pro)3.
- Therefore a subject of the invention is also the dihydrochloride of 1-[4-[(2-aminoethyl)amino]-N-2-[[4′-(octyloxy)[1,1 ′-biphenyl]-4-yl]carbonyl]-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandin B in 4S or 4R form or in the form of a mixture of the two stereoisomers.
- The process as described previously allows isomer A of the compound of formula (I) or (Ia) to be obtained in the majority before separation of the isomers by chromatography.
- Therefore a subject of the invention is also the dihydrochloride of 1-[4-[(2-aminoethyl)amino]-N2-[[4′-(octyloxy)[1,1 ′-biphenyl]-4-yl]carbonyl]-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandin B in the form of the active isomer A obtained by the process as described previously.
- A subject of the invention is also the dihydrochloride of 1-[4-[(2-aminoethyl)amino]-N2-[[4′-(octyloxy)[1,1′-biphenyl]-4-yl]carbonyl]-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandin B in 4S or 4R form or in the form of a mixture of the two stereoisomers, as a medicament and in particular as and antifungal medicament.
- Finally, a subject of the invention is the pharmaceutical compositions containing the dihydrochloride of 1-[4-[(2-aminoethyl)amino]-N2-[[4′-(octyloxy)[1,1′-biphenyl]-4-yl]carbonyl]-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandin B in 4S or 4R form or in the form of a mixture of the two stereoisomers and a pharmaceutically acceptable vehicle.
- 1-[4-[(2-aminoethyl)amino]-N2-[[4′-(octyloxy)[1,1′-biphenyl]-4-yl]-carbonyl]-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandin B is prepared in WO 99/29716 in the form of a base or the trifluoroacetic acid salt (Example 14). The dihydrochloride has the advantage of having a better stability and solubility in water. Moreover, the dihydrochloride is the preferred pharmaceutically acceptable salt which is a subject of the present invention.
- I): First Stage: Acylation of the Compound of Formula (II) and Obtaining a Compound of Formula (IIIa)
- Route 1: by the Activated Ester of Isolated Pentaflurophenol
- Stage 1: Preparation of the Activated Ester
- 100 g of 4-octyloxybiphenyl-4′carboxylic acid and 62 g of pentafluorophenol are introduced into 1 litre of dichloromethane. Agitation is carried out for 15 minutes and 69.6 g of N,N′-dicyclohexylcarbodiimide in solution in 500 ml of dichloromethane is added over 15 minutes. The dark beige suspension is agitated for 20 hours at ambient temperature. The dicyclohexylurea is filtered and the filtrate is concentrated. Distillation to constant volume is carried out by the regular addition of ethanol up to the vapour temperature of 74° C. The reaction medium is cooled down to ambient temperature, followed by agitating for one hour, filtering then washing with ethanol. After drying, 145.7 g of sought product is obtained in the form of crystals.
- Yield 96.5% NMR (CDCl3): 8.23-7.72 (AA′BB′) 4H; 7.01-7.60 (AA′BB′) 4H; 4.02 (t) 2H; 1.82 (quint) 2H; 1.48 (quint) 2H; 1.32 (m) 8H; 0.89 (t) 3H.
- Stage 2: Acylation
- 23.2 g of the compound of formula (II) (“nucleus of deoxymuluncandin” prepared according to Preparation 2 of WO 99/29716) and 14.1 g of the ester obtained above in 60 ml of DMF are introduced. 6.7 ml of diisopropylethylamine is introduced into the suspension and agitation is carried out for 24 hours under a nitrogen atmosphere at ambient temperature. The homogenous reaction medium is poured into one litre of water over 10 minutes whilst moderate agitation is carried out, the suspension is agitated for 2 hours, filtered and the solid washed with water. The solid is dried under vacuum at room temperature then taken to reflux in 100 ml of methylene chloride, under nitrogen whilst agitating for 2 hours (40° C.), followed by cooling down to ambient temperature over 1 hour, agitating for 1 hour, filtering the solid and rinsing it three times with methylene chloride and drying under vacuum at room temperature. 26.9 g of expected product is obtained in the form of a beige solid.
- Yield 91.5% TLC: Rf:0.13 silica plate; development UV 254 nm; eluant: CH2Cl2-MeOH-water: 86-13-1 NMR: (DMSO)
- Threonine: 8.16 (1H), 4.85 (1H), 4.41 (1H), 1.13 (3H); γHydroxyproline: 4.42 (1H), 1.92-2.28 (2H), 4.44 (1H), 3.86-3.70 (2H); βHydroxy homo tyrosine 7.36 (1H), 4.23 (1H), 4.20 (1H), 2.53-2.46 (2H), 6.98 (2H), 6.68 (2H); Serine: 7.40 (1H), 4.86 (1H), 3.66-3.60 (2H), βHydroxy γmethyl proline: 4.27 (1H), 4.03 (1H), 2.38 (1H), 0.99 (3H), 3.25-3.93 (2H), <<ornithine >>: 7.98 (1H), 5.16 (1H), 3.96 (1H), 8.54 (1H), 4.44 (1H), 1.98 (2H); Aromatic and octyloxy chain: 7.98 (2H), 7.71 (2H), 7.68 (2H), 7.02 (2H), 4.00 (2H), 1.72 (2H), 1.41 (2H), 1.28 (2H), 1.25 (2H), 1.31 (2H), 1.27 (2H), 0.86 (3H).
- Route 2: by the Activated Ester of Isolated hOSu
- Stage 1: Synthesis of the Activated Ester
- 9.3 g of octyloxybiphenyl acid, 93 ml of dichloromethane, 3.8 g of N-hydroxysuccinimide, 6.3 g of EDC are introduced and agitation is carried out for 3 hours at ambient temperature. 6 ml of water is added, agitation is carried out for 10 minutes, followed by decanting and reextracting with 45 ml of dichloromethane. The organic phase is washed with water (3 times 45 ml) and dried over sodium sulphate. After bringing to dryness under vacuum, 12.05 g of expected product is obtained in the form of crystals.
- Yield: 99.9% NMR: CDCl3: 8.2-7.65 (AA′BB′) 4H; 7.6-6.97 (AA′BB′) 4H; 4.02 (t, 2H); 2.93 (broad) 4H; 1.83 (quint 2H); 1.45 (m) 2H; 1.3 (m) 8H; 0.9 (t) 3H.
- Stage 2: Acylation
- 1.43 g of succinimidic ester as prepared above is dissolved in 6 ml of DMF. 2.42 g of “nucleus of deoxymuluncandin” (prepared according to Preparation 2 of WO 99/29716) and 0.66 ml of diisopropylethylamine are introduced. The solution is agitated for 18 hours at ambient temperature. 35 ml of water is introduced and agitated is carried out for 2 hours at ambient temperature. After filtering, the solid is taken up in 30 ml of water under agitation for 2 hours in a reaction vessel, followed by filtering and rinsing with water. The solid is dried under vacuum at ambient temperature and 2.75 g of expected product is obtained in the form of beige solid.
- Yield 98.2%
- Route 3: Synthesis by Direct Activation with DMTMM
- 2.8 g of deoxymuluncandin (prepared according to Preparation 2 of WO 99/29716) is dissolved in 8.3 ml of N-myl pyrolidone. 1.12 g of octyloxybiphenyl acid and 0.95 g of 4-(4,6-Dimoxy-1,3,5-triazin-2-yl)-4-m-yl-morpholinium chloride (DMTMM) is added. After agitation for 24 hours at ambient temperature, the reaction medium is poured into 133 ml of water under agitation. Agitated is carried out for 20 minutes, the solid is filtered and rinsed 3 times with water (3 times 7 ml). After drying under vacuum at 40° C., 2.66 g of expected product 4 is obtained in the form of beige solid.
- Yield 73.5%
- II). Second Stage: Dehydration (Obtaining a Compound of Formula (IVa)
- Route 1: via the Compound of Formula (III′a)
- Stage 1: Alkylation
- 283 g of product IIIa obtained in the first stage is dissolved in 5.67 liters of methanol. 22.7 g of pyridinium p-toluene sulphonate is added in one go whilst agitating and agitation is carried out for 6 hours under reflux (42° C.) and for 12 hours at ambient temperature. Concentration is carried out under vacuum to two residual volumes then 1.2 litres of water is added. The suspension is agitated for 18 hours. The solid is filtered and rinsed twice with water. After drying in an oven under vacuum at ambient temperature, 270.5 g of expected product is obtained in the form of a beige powder.
- Yield 94.2% NMR: (DMSO) Threonine: 8.11 (1H), 4.84 (1H), 4.41 (1H), 1.11 (3H); γHydroxyproline: 4.40 (1H), 1.91-2.27 (2H), 4.42 (1H), 3.67-3.87 (2H); βHydroxy homo tyrosine 7.32 (1H), 4.22 (1H), 4.18 (1H), 2.51-2.44 (2H), 6.96 (2H), 6.65 (2H), 9.03 (1H); Serine: 7.36 (1H), 4.87 (1H), 3.58-3.63 (2H), βHydroxy γmethyl proline: 4.32 (1H), 4.05 (1H), 2.37 (1H), 1.00 (3H), 3.27-3.94 (2H), <<ornithine >>: 7.88 (1H), 4.94 (1H), 4.06 (1H), 8.50 15 (1H), 4.43 (1H), 3.16 (3H); 1.93-2.03 (2H); Aromatic and octyloxy chain: 7.97 (2H), 7.70 (2H), 7.65 (2H), 7.02 (2H), 4.00 (2H), 1.73 (2H), 1.43 (2H), 1.32 (2H), 1.27-1.28 (6H), 0.87 (3H).
- Stage 2: Dehydration
- 265.3 g of methoxylated product (III′a) obtained above is dissolved in 5.3 litres of dioxane. 71.8 ml of α-acetoxyisobutyryl bromide (AIBB) is added over 20 minutes. The medium is agitated for 7 hours. 4.1 litres of a saturated aqueous solution of sodium bicarbonate (NaHCO3) is added over 15 minutes. Agitation is carried out for 15 minutes and the dioxane is distilled under vacuum at a temperature which does not exceed 30° C. 3.2 litres of water is added and agitation is carried out for 15 hours at ambient temperature. The solid is filtered and rinsed twice with water. After drying in an oven under vacuum, 251.2 g of expected product is obtained in the form of an ochre solid.
- Yield 97.5%
- The Product is Crystallized According to the Preparation Described Below.
- Route 2: Starting from Product (IIIa) Obtained in Stage a by the Action of AIBB/MgI2/dioxane
- 23.26 g of anhydrous magnesium iodide is suspended in 500 ml of dioxane and agitation is carried out for 30 minutes. 12.25 ml of α-acetoxyisobutyryl bromide (AIBB) is introduced and the ochre suspension is agitated at ambient temperature for 45 minutes. A solution of 50 g of product (IIIa) obtained in the first stage, dissolved in 400 ml of dioxane is added over 1 hour and the addition funnel is rinsed with 25 ml of dioxane. The suspension is agitated for 19 hours at ambient temperature. A solution of 5 g of sodium bicarbonate dissolved in 50 ml of water is introduced over 30 minutes (pH 5-6 at the end of the addition). Agitation is carried out for 2 hours, followed by distilling under vacuum to a residual volume of 250 ml at an internal temperature of less than 35° C. Atmospheric pressure of nitrogen is reestablished, and 200 ml of dimethylformamide is added, followed by distilling under vacuum to a residual volume of 250 ml and this solution is poured at ambient temperature into 2.8 litres of water. After rinsing with DMF, agitation is carried out for 1 hour. The solid is filtered and rinsed with water. The solid is dried for 24 hours under vacuum at 30° C. 46 g of expected product is obtained in the form of beige solid.
- Yield: 98.6%
- The Product is then Crystallized According to the Method Described Below.
- Route 3: Starting From Product IIIa Obtained in the First Stage by the Action of HBr-AcOH/MgI2/MEK
- 10 g of product obtained in Stage a) is dissolved in 180 ml of methylethyl ketone (MEK). 4.65 g of anhydrous magnesium iodide and 10 ml of MEK are introduced. Agitation is carried out for 35 minutes at ambient temperature, followed by cooling down to 20° C. 3 ml of a 33% solution of HBr in AcOH is introduced. The suspension is agitated for 4 hours at 20° C. 10 ml of a saturated aqueous solution of NaHCO3 (sodium bicarbonate) is added. Agitation is carried out for 1 hour at 20° C. (dissolution). The solution is poured into 700 ml of water over 2 hours whilst distilling the MEK under vacuum at 40° C. Distillation is carried out to residual volume of 430 ml. 100 ml of water is added and distillation is continued to a residual volume of 430 ml. The operation is repeated twice. The suspension is taken to ambient temperature and agitated overnight. The solid is filtered and washed with 3 times 50 ml of water. After drying under vacuum at ambient temperature, 9.3 g of expected product is obtained in the form of a beige powder. The product is purified by crystallization according to the method described below
- Yield 94.5% solvents not considered
- Crystallization of the Product of Formula (IVa) Obtained Above (Route 1, 2 or 3)
- 10 g of 1-[(N2-[4′-(octyloxy)-[1,1′-biphenyl]-4-yl]carbonyl]-4-oxo-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine-echinocandin B (obtained above, route 1, 2 or 3) is dissolved over 1 hour, under agitation and at ambient temperature in 30 ml of dimethylformamide (DMF). 51 mg of initiator (crystals of the product obtained according to routes 1, 2 or 3) is introduced and agitation is carried out for 2 hours. Then 67 ml of acetonitrile is introduced regularly over 2 hours. At the end of the introduction, agitation is carried out for 19 hours, followed by filtering and rinsing with 3 times 10 ml of acetonitrile. After drying under vacuum at ambient temperature, 7.10 g of expected product is obtained in the form of white crystals.
- Yield: 71% TLC: rf=0.28 Silica gel 60F254, UV 254 nm Mobile phase: CH2Cl2/MeOH/water 86/13/1 NMR: (DMSO) Threonine: 7.94 (1H), 4.50 (1H), 4.25 (1H), 1.18 (3H); .γHydroxyproline: 4.39 (1H), 1.93-2.20 (2H), 4.40 (1H), 3.85-3.71 (2H); βHydroxy homo tyrosine 7.53 (1H), 4.06 (1H), 4.25 (1H), 2.44-2.53 (2H), 6.96 (2H), 6.66 (2H), 9.06 (1H); Serine: 7.74 (1H), 4.96 (1H), 3.72 (2H), βHydroxy .γmethyl proline: 4.33 (1H), 3.98 (1H), 2.31 (1H), 0.99 (3H), 3.26-4.0 (2H), <<ornithine >>: 8.37 (1H), 3.84-3.64 (2H), 8.11 (1H), 4.83 (1H), 2.82-3.11 (2H); Aromatic and octyloxy chain: 7.91 (2H), 7.69 (2H), 7.66 (2H), 7.02 (2H), 4.02 (2H), 1.74 (2H), 1.43 (2H), 1.32-1.28 (6H), 1.28 (2H), 0.87 (3H).
- III: Third Stage: Reducing Amination of the Compound of Formula (IVa) and Obtaining a Compound of Formula (Ia)
- Route 1:
- 8 g of product of formula (IVa) obtained according to Stage II and 2.52 ml of ethylene diamine are dissolved in 80 ml of tetrahydrofuran (THF) whilst agitating for 30 minutes to 1 hour under nitrogen and at ambient temperature. A solution of 0.36 g of titanium tetrachloride dissolved in 80 ml of THF is added over 30 minutes. Agitation is carried out for 1 hour followed by cooling down to 5° C. 3.2 ml of glacial acetic acid dissolved in 16 ml of THF is added. Agitation is carried out for 1 hour at 5° C., followed by cooling down to 0° C. and a solution of 1.04 g of sodium cyanoborohydride dissolved in 24 ml of THF is added over 15 minutes. The reaction medium is left to rise to 5° C. over 30 minutes and agitated for 30 minutes at this temperature. Then left to rise to ambient temperature whilst agitating for 3 hours, followed by distilling under vacuum to 40 ml of the volume, adding a solution of 7.2 g of sodium bicarbonate dissolved in 80 ml of water, distilling under vacuum to a residual volume of 80 ml then 32 ml of methanol and 128 ml of ethyl acetate are added. Agitating is carried out for 10 minutes, followed by decanting, reextracting the aqueous phase with a mixture of ethyl acetate/methanol and distilling all the organic phases under vacuum to a residual volume of 40 ml. 40 ml of DMF is introduced and distilling is continued to a residual volume of 60 ml. This solution is poured into 320 ml of water over 20 minutes and agitated for 15 hours at ambient temperature. If necessary the pH is adjusted to 9-9.5 with dilute soda, followed by filtering and rinsing with an aqueous solution of 1.2 g of sodium bicarbonate (pH 9-9.5). After drying the solid in an oven under vacuum at 30 C. for 18 hours, 8.55 g of expected crude base is obtained in the form of a white solid.
- Yield: 100% Isomeric ratio A/B=80/20
- Route 2:
- 10 g of the product of formula (IV) obtained in Stage II) is introduced under agitation and a nitrogen atmosphere into 600 ml of THF. 20 g of 3 Åmolecular sieve then 3.16 ml of ethylene diamine and finally 110.4 g of sodium tri-benzyl-L-proline-borohydride are added. The homogeneous solution is agitated at ambient temperature for 6 hours, followed by filtering the molecular sieve and rinsing with THF. The filtrate is distilled to dryness under vacuum at an internal temperature of less than 40° C. 600 ml of a saturated aqueous solution of sodium bicarbonate is added slowly onto the resin obtained whilst agitating. 20 g of Hyflosupercel Kieselguhr filtration agent is added to the suspension and agitation is carried out for 16 hours at ambient temperature, followed by filtering and washing with water. The cake is dissolved by passing through 100 ml of methanol four times. The methanolic filtrate is concentrated to dryness under vacuum without exceeding 40° C. 21.25 g of expected product is obtained.
- Route 3
- Isolation of the intermediate of the reducing amination reaction (compound of formula IV′a) 1-[4-[N,N′-imidazolidine]-N2-[[4′-(octyloxy)[-1,1′-biphenyl]-4-yl]carbonyl]-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandin B
- A suspension of the product of formula (IVa) obtained in Stage II) in 40 ml of dichloromethane and 0.32 ml of ethylene diamine is agitated for 18 hours. 80 ml of diethyl ether is added and agitation is carried out for 5 hours. The solid is filtered and rinsed several times with diethyl ether. After drying in an oven under vacuum for 15 hours at ambient temperature, 076 g of expected compound is obtained in the form of a white solid. This intermediate is then subjected to the action of a reducing reaction according to preceding routes 1 or 2. This isolated compound is new and forms part of the present invention
- Yield: 73% MASS:(FAB) M+1100; MNa+: 1122 NMR: Threonine: 8.51 (1H), 4.72 (1H), 4.38 (1H), 1.20 (3H); γHydroxyproline: 4.37 (1H), 1.90-2.22 (2H), 4.42 (1H), 3.88-3.66 (2H); βHydroxy homo tyrosine 7.46 (1H), 4.17 (1H), 4.17 (1H), 2.46 (2H), 6.96 (2H), 6.65 (2H), Serine: 7.47 (1H), 4.84 (1H), 3,65-3.60 (2H), βHydroxy γmethyl proline: 4.22 (1H), 3.93 (1H), 2.29 (1H), 0.95 (3H), 3.22-3.90 (2H), <<ornithine >>: 7.45 (1H), 2.72-3.51 (2H), 9.55 (1H), 4.28 (1H), 1.63-2.12 (2H); Imidazolidine: 2.63-2.94 (2H); 2.78-3.02 (2H); Aromatic and octyloxy chain: 7.87-7.72 (2H, 2H), 7.66 (2H), 7.03 (2H), 4.02 (2H), 1.72 (2H), 1.27 1.32 1.43 (4.times.2H), 1.29 (2H), 0.88 (3H).
- IV)°: Fourth stage: Purification by chromatography of the compound of formula (Ia) obtained previously (according to route 1, 2 or 3) and separation of the two isomers A and B (A or B corresponding to stereoisomers R or S in position 4) Di-trifluoroacetate of 1-[4-[(2-aminoyl)amino]-N2-[[4′-(octyloxy)[1,1′-biphenyl]-4-yl]carbonyl]-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandin B
- A Prochrom LC 200 column is conditioned with 2.5 g of merck 11763 silica using a methylene chloride (43)-acetonitrile (50)-methanol (7)-water (5)-trifluoroacetic acid (1) mixture as mobile phase. 24 g of the compound obtained above (Stage III, route 1) is dissolved in 126 ml of a mixture composed of acetonitrile (50)-methanol (7)-water (5)-TFA (1). The solution is filtered and 86 ml of methylene chloride is added. This solution is injected into the column. Elution is carried out a flow rate of 76 1/h and a pressure of 14 bars. Detection is carried out at 280 nm, followed by distilling the collected fractions under vacuum at an external temperature of less than 40° C. 36.75 g of product is obtained in the form of the solid di-salt of TFA. Isomeric ratio A/B=99.3/0.7
- V): Fifth Stage: Purification by Chromatography of the Di-trifluoroacetate (Elimination of the Other Salts)
- A Prochrom LC 50 column is conditioned with 300 g of reversed-phase Daisogel SP 120 n° 5/1502 silica, using a water (90)-acetonitrile (10)-trifluoroacetic acid (0.1) mixture as mobile phase. 36.75 g of the salt obtained above in the first chromatography is dissolved in a mixture comprising 57.3 ml of water (90)-acetonitrile (10)-trifluoroacetic acid (0.1) and 26.8 ml of pure acetonitrile. The solution is filtered and this solution is injected into the column. Elution is carried out with water (90)-acetonitrile (10)-trifluoroacetic acid (0.1) in the first instance to remove the mineral salts, then with water (50)-acetonitrile (50)-trifluoroacetic acid (0.1) to remove the product. The fractions collected are distilled under vacuum at an external temperature of less than 40° C. The resultant limpid aqueous solution is lyophilized. 15.59 g of expected product is obtained in the form of a cotonny white solid di-salt of TFA.
- Isomeric ratio A/B=99.4/0.6 Cumulative yield of the two chromatographies: 53.8% Yield of the amino reduction: 28.7%
- VI): Sixth stage: Return to the Base
- 14.37 g of the compound obtained above, in the form the lyophilized di-trifluoroacetate salt, is dissolved in 143.7 ml of water. Agitation is carried out for 15 minutes under nitrogen and 57.5 ml of a saturated aqueous solution of sodium bicarbonate is added over 15 minutes at ambient temperature. Agitation is carried out for 17 hours. 430 ml of an ethyl acetate/methanol mixture 8/2 is added and agitation is carried out for 15 minutes. The upper organic phase is decanted and the aqueous phase is reextracted with 288 ml of an ethyl acetate (8)-methanol (2) mixture. The organic phases are combined, decanted carefully, and distilled to dryness under vacuum without exceeding 35° C. 143.7 ml of water is added to the dry extract and the suspension is agitated for 30 minutes, followed by filtering and washing with water until there are no more fluorides. After drying the solid under vacuum at 40° C., 10.91 g of expected product is obtained in the form of a white powder.
- Yield: 91.6% MICROANALYSIS: (water: 8.8%)
% theory found C 61.020 55.3-55.1 H 07.224 7.5-7.4 N 11.437 10.3-10.3 F 0 not detected
VII): Seventh Stage: Salification (Hydrochloric Acid) Dihydrochloride of 1-[4-[(2-aminoyl)amino]-N2-[[4′-(octyloxy)[1,1 ′-biphenyl]-4-yl]carbonyl]-L-ornithine]-4-[4-(4-5 hydroxyphenyl)-L-threonine]-5-L-serine echinocandin B - 10.53 g of compound obtained in the preceding stage is dissolved in 263 ml of methanol whilst agitating for 30 minutes at ambient temperature, followed by filtering and rinsing with twice 31.6 ml of methanol. 2.1 ml of 36% hydrochloric acid is added agitation and under nitrogen at ambient temperature. Agitation is carried out for 30 minutes, followed by distilling to dryness under vacuum without exceeding 35° C. The dry extract is taken up in 105.3 ml of diisopropyl oxide. The suspension obtained is agitated for 2 hours, followed by filtering and washing with twice 21.1 ml of diisopropyl oxide. After drying the solid in an oven under vacuum at 40.° C., 10.52 g of expected product is obtained in the form of a white powder.
- Yield: 93.7% MICROANALYSIS: (water 5.75%)
% theory found C 57.2 54.3 H 6.95 7.4 N 10.73 9.8 C1 6.03 5.95 F 0 not detected
VIII: Eighth Stage: Crystallization of the Hydrochloric Acid Salt - 2.75 g of the compound obtained according to Stage VII is dissolved in a mixture of 235.4 ml of acetonitrile and 14.8 ml of demineralized water, while heating under reflux (77.4° C.). Agitation is carried out for 15 minutes at 77° C. then the reaction medium is cooled down to +50° C. over 45 minutes. Initiation is carried out with 41.25 mg of crystallized compound, followed by cooling down regularly to 20° C. over 30 minutes and agitating for 2 hours 15 minutes, to allow crystallization to develop. The suspension is concentrated under vacuum to a residual volume of 55 ml whilst allowing the temperature to rise from 5° C. to 20° C. Normal pressure of nitrogen is re-established, followed by cooling down to 0° C. over 20 minutes, agitating at 0° C. for 17 hours, filtering under nitrogen pressure and rinsing with 11 ml of acetonitrile. After drying the crystallized solid in an oven under vacuum and at 40° C. for 24 hours, 2.29 g of expected product is obtained in the form of a white crystalline solid.
- Yield 83.3% HPLC: Rt=5.8 (isomer A); Rt=7.1 (isomer B) Kromasil C18, 15 cm, 4.6 mm, 5 .mu.m Mobile phase: acetonitrile-water-TFA 50/50/0.1 210 nm, 35° C., 1 ml/mn. NMR: CDCl3 9.07 (m) 1H; 8.48 (d, j=8) 1H; 8.00 (d, j=8) 2H; 7.96 (d, j=8.5) 2H; 7.71 (d, j=8.5) 2H; 7.64 (d, j=8.5) 2H; 7.60 (d, j=9) 1H; 7.37 (d, j=9.5) 1H; 7.02 (d, j=8.5) 2H; 6.97 (d, j=8.5) 2H; 6.65 (d, j=8.5) 2H; 4.90 (m) 1H; 4.77 (m) 1H; 4.66 (m) 1H; 4.45 (m) 1H; 4.42 (m) 1H; 4.39 (m) 1H; 4.34 (s) 1H; 4.26 (m) 1H; 4.22 (m) 1H; 4.08 (m) 1H; 4.01 (t, j=6.5) 2H; 3.88 (m) 3H; 3.70 (m) 21H; 3.51 (m) 2H; 3.48 (m) 1H; 3.31 (m) 2H; 3.28 (m) 1H; 3.16 (m) 2H; 2.53 (dd, j=6 and 13.5) 1H; 2.44 (dd, j=7.5 and 13.5) 1H; 2.27 (m) 1H; 2.25 (m) 1H; 2.15 (m) 2H; 1.94 (m, 1H; 1.74 (m) 2H; 1.44 (m) 2H; 1.22 to 1.40 (m) 8H; 1.13 (d, j=6) 3H; 0.99 (d, j=6.5) 3H; 0.88 (t, j=7) 3H.
- Tablets were Prepared Containing
product of Example 1 150 mg Excipient s.q.f 1 g - Detail of excipient: starch, talc, magnesium stearate
Claims (4)
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US11/591,898 US20070105760A1 (en) | 2001-12-14 | 2002-12-12 | Process for the preparation of echinocandin derivatives |
US12/830,941 US20100273977A1 (en) | 2001-12-14 | 2010-07-06 | Process for the preparation of echinocandin derivatives |
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FR0116230A FR2833596B1 (en) | 2001-12-14 | 2001-12-14 | PROCESS FOR THE PREPARATION OF ECHINOCANDIN DERIVATIVES |
FR0116230 | 2001-12-14 | ||
PCT/FR2002/004308 WO2003054001A2 (en) | 2001-12-14 | 2002-12-12 | Method for preparing echinocandin derivatives and their compositions |
US11/591,898 US20070105760A1 (en) | 2001-12-14 | 2002-12-12 | Process for the preparation of echinocandin derivatives |
US10/867,070 US7148322B2 (en) | 2001-12-14 | 2004-06-14 | Process for the preparation of echinocandin derivatives |
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US10/867,070 Expired - Fee Related US7148322B2 (en) | 2001-12-14 | 2004-06-14 | Process for the preparation of echinocandin derivatives |
US12/830,941 Abandoned US20100273977A1 (en) | 2001-12-14 | 2010-07-06 | Process for the preparation of echinocandin derivatives |
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US12/830,941 Abandoned US20100273977A1 (en) | 2001-12-14 | 2010-07-06 | Process for the preparation of echinocandin derivatives |
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US20100197928A1 (en) * | 2007-09-14 | 2010-08-05 | Novexel | Method for preparing disubstituted piperidine and intermediates |
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FR2833596B1 (en) * | 2001-12-14 | 2005-02-18 | Aventis Pharma Sa | PROCESS FOR THE PREPARATION OF ECHINOCANDIN DERIVATIVES |
TW200826957A (en) * | 2006-10-16 | 2008-07-01 | Teva Gyogyszergyar Zartkoruen Mukodo Reszvenytarsasag | Purification processes for echinocandin-type compounds |
FR2936798B1 (en) * | 2008-10-03 | 2012-09-28 | Novexel | NOVEL HETEROCYCLIC NITROGEN COMPOUNDS, THEIR PREPARATION AND THEIR USE AS ANTIBACTERIAL MEDICINES. |
FR2936951B1 (en) * | 2008-10-10 | 2010-12-03 | Novexel | NOVEL COMBINATIONS OF ANTIBACTERIAL NITROGENIC HETEROCYCLIC COMPOUNDS WITH OTHER ANTIBACTERIAL COMPOUNDS AND THEIR USE AS MEDICAMENTS |
FR2937034B1 (en) * | 2008-10-10 | 2012-11-23 | Novexel | NOVEL HETEROCYCLIC NITROGEN COMPOUNDS, THEIR PREPARATION AND THEIR USE AS ANTIBACTERIAL MEDICINES |
CN101928670B (en) * | 2009-09-24 | 2012-02-22 | 上海天伟生物制药有限公司 | High-yield bacterial strain of antibiotic, preparation method and usage thereof |
CN102627688B (en) * | 2012-03-30 | 2014-12-31 | 上海天伟生物制药有限公司 | High purity cyclic peptide compound and preparation method and application thereof |
CN102627689B (en) * | 2012-03-30 | 2014-08-06 | 上海天伟生物制药有限公司 | Hydrate of cyclopeptide compound as well as preparation method and application thereof |
CN102659930B (en) * | 2012-03-30 | 2014-04-23 | 上海天伟生物制药有限公司 | High-purity cyclopeptide crystal and its preparation method and use |
WO2016056022A2 (en) * | 2014-10-07 | 2016-04-14 | Alaparthi Lakshmi Prasad | Intermediates and processes to prepare anidulafungin |
CN112646854B (en) * | 2020-12-11 | 2022-10-11 | 浙江工业大学 | Echinocandin B synthetic medium and application |
CN115785226A (en) * | 2021-09-09 | 2023-03-14 | 上海天伟生物制药有限公司 | Echinocandin medicine impurity, and preparation, purification method and application thereof |
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