TWI432416B - 截短側耳素類(pleuromutilins)的製備方法 - Google Patents
截短側耳素類(pleuromutilins)的製備方法 Download PDFInfo
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- TWI432416B TWI432416B TW096137112A TW96137112A TWI432416B TW I432416 B TWI432416 B TW I432416B TW 096137112 A TW096137112 A TW 096137112A TW 96137112 A TW96137112 A TW 96137112A TW I432416 B TWI432416 B TW I432416B
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- Prior art keywords
- compound
- formula
- piperidine
- configuration
- methyl
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 14
- 125000003386 piperidinyl group Chemical group 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 47
- -1 2-amino-3-methyl-butanyl group Chemical group 0.000 claims description 25
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 14
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000004434 sulfur atom Chemical group 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 229930186147 Cephalosporin Natural products 0.000 claims description 7
- 229940124587 cephalosporin Drugs 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- 239000000725 suspension Substances 0.000 claims description 7
- 125000004744 butyloxycarbonyl group Chemical group 0.000 claims description 6
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 150000002081 enamines Chemical group 0.000 claims description 5
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 5
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 150000008064 anhydrides Chemical class 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- 229930182821 L-proline Natural products 0.000 claims description 3
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 claims description 3
- 239000012736 aqueous medium Substances 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 235000017807 phytochemicals Nutrition 0.000 claims description 2
- 229930000223 plant secondary metabolite Natural products 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- DMEOKDAEMWZLCN-KVVVOXFISA-N (z)-octadec-9-enoic acid;hydrochloride Chemical compound Cl.CCCCCCCC\C=C/CCCCCCCC(O)=O DMEOKDAEMWZLCN-KVVVOXFISA-N 0.000 claims 1
- 238000002441 X-ray diffraction Methods 0.000 claims 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 125000005490 tosylate group Chemical class 0.000 claims 1
- 125000003396 thiol group Chemical group [H]S* 0.000 abstract description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 abstract 2
- OBUUFWIMEGVAQS-UHFFFAOYSA-N Pleuromutenol Natural products CC1C(O)C(C)(C=C)CC(O)C2(C)C(C)CCC31C2C(=O)CC3 OBUUFWIMEGVAQS-UHFFFAOYSA-N 0.000 abstract 1
- 125000004432 carbon atom Chemical group C* 0.000 abstract 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- STZYTFJPGGDRJD-NHUWBDDWSA-N retapamulin Chemical compound C([C@H]([C@@]1(C)[C@@H](C[C@@](C)(C=C)[C@@H](O)[C@@H]2C)OC(=O)CS[C@@H]3C[C@H]4CC[C@H](N4C)C3)C)C[C@]32[C@H]1C(=O)CC3 STZYTFJPGGDRJD-NHUWBDDWSA-N 0.000 abstract 1
- 229960002771 retapamulin Drugs 0.000 abstract 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 28
- 229910001868 water Inorganic materials 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000000203 mixture Substances 0.000 description 14
- 238000002425 crystallisation Methods 0.000 description 11
- 230000008025 crystallization Effects 0.000 description 10
- 239000008346 aqueous phase Substances 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- ZRZNJUXESFHSIO-VYTKZBNOSA-N pleuromutilin Chemical compound C([C@H]([C@]1(C)[C@@H](C[C@@](C)(C=C)[C@@H](O)[C@@H]2C)OC(=O)CO)C)C[C@]32[C@H]1C(=O)CC3 ZRZNJUXESFHSIO-VYTKZBNOSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- ZRZNJUXESFHSIO-UHFFFAOYSA-N Pleuromutilin Natural products CC1C(O)C(C)(C=C)CC(OC(=O)CO)C2(C)C(C)CCC31C2C(=O)CC3 ZRZNJUXESFHSIO-UHFFFAOYSA-N 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 3
- YRALAIOMGQZKOW-HYAOXDFASA-N ceruletide Chemical compound C([C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)[C@@H](C)O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(OS(O)(=O)=O)C=C1 YRALAIOMGQZKOW-HYAOXDFASA-N 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- UIJXHKXIOCDSEB-UHFFFAOYSA-N tert-butyl 3-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(O)C1 UIJXHKXIOCDSEB-UHFFFAOYSA-N 0.000 description 3
- WLAZHMYDLUILKR-UHFFFAOYSA-N tert-butyl 3-methylsulfonyloxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1 WLAZHMYDLUILKR-UHFFFAOYSA-N 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- DWHMPBALQYTJFJ-DKWTVANSSA-N (2s)-2-aminobutanedioic acid;hydrochloride Chemical compound Cl.OC(=O)[C@@H](N)CC(O)=O DWHMPBALQYTJFJ-DKWTVANSSA-N 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 108010010737 Ceruletide Proteins 0.000 description 2
- ONIBWKKTOPOVIA-SCSAIBSYSA-N D-Proline Chemical compound OC(=O)[C@H]1CCCN1 ONIBWKKTOPOVIA-SCSAIBSYSA-N 0.000 description 2
- 229930182820 D-proline Natural products 0.000 description 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 241000222350 Pleurotus Species 0.000 description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- 150000001510 aspartic acids Chemical class 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 239000012351 deprotecting agent Substances 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- LKPFBGKZCCBZDK-UHFFFAOYSA-N n-hydroxypiperidine Chemical compound ON1CCCCC1 LKPFBGKZCCBZDK-UHFFFAOYSA-N 0.000 description 2
- QMWWAEFYIXXXQW-UHFFFAOYSA-M potassium;2-[(4-ethoxy-4-oxobut-2-en-2-yl)amino]-2-phenylacetate Chemical compound [K+].CCOC(=O)C=C(C)NC(C([O-])=O)C1=CC=CC=C1 QMWWAEFYIXXXQW-UHFFFAOYSA-M 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- YRALAIOMGQZKOW-UHFFFAOYSA-N sulfated caerulein Natural products C=1C=CC=CC=1CC(C(N)=O)NC(=O)C(CC(O)=O)NC(=O)C(CCSC)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)CNC(=O)C(C(C)O)NC(=O)C(NC(=O)C(CC(O)=O)NC(=O)C(CCC(N)=O)NC(=O)C1NC(=O)CC1)CC1=CC=C(OS(O)(=O)=O)C=C1 YRALAIOMGQZKOW-UHFFFAOYSA-N 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- NVDQWJTWJOLALV-UHFFFAOYSA-N tert-butyl 3-sulfanylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(S)C1 NVDQWJTWJOLALV-UHFFFAOYSA-N 0.000 description 2
- DUYAAUVXQSMXQP-UHFFFAOYSA-M thioacetate Chemical compound CC([S-])=O DUYAAUVXQSMXQP-UHFFFAOYSA-M 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- BIWOSRSKDCZIFM-RXMQYKEDSA-N (3r)-piperidin-3-ol Chemical compound O[C@@H]1CCCNC1 BIWOSRSKDCZIFM-RXMQYKEDSA-N 0.000 description 1
- ZOZNCAMOIPYYIK-UHFFFAOYSA-N 1-aminoethylideneazanium;acetate Chemical compound CC(N)=N.CC(O)=O ZOZNCAMOIPYYIK-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- FLICSJLQAITIQW-UHFFFAOYSA-N 2,2-dimethylpropylazanium;chloride Chemical compound Cl.CC(C)(C)CN FLICSJLQAITIQW-UHFFFAOYSA-N 0.000 description 1
- JYWKEVKEKOTYEX-UHFFFAOYSA-N 2,6-dibromo-4-chloroiminocyclohexa-2,5-dien-1-one Chemical compound ClN=C1C=C(Br)C(=O)C(Br)=C1 JYWKEVKEKOTYEX-UHFFFAOYSA-N 0.000 description 1
- UIZPJCVGVCURNY-UHFFFAOYSA-N 2-piperidin-1-ylethanethioamide Chemical class NC(=S)CN1CCCCC1 UIZPJCVGVCURNY-UHFFFAOYSA-N 0.000 description 1
- ZCIBUCFTEVXKQG-ABLWVSNPSA-N C(=O)(OC(C)(C)C)N1CC(CCC1)C([C@@H](N)CCSCC)=O Chemical compound C(=O)(OC(C)(C)C)N1CC(CCC1)C([C@@H](N)CCSCC)=O ZCIBUCFTEVXKQG-ABLWVSNPSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 241001572230 Clitopilus passeckerianus Species 0.000 description 1
- KZSNJWFQEVHDMF-SCSAIBSYSA-N D-valine Chemical compound CC(C)[C@@H](N)C(O)=O KZSNJWFQEVHDMF-SCSAIBSYSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- DNZHWQKHHVGMAO-UHFFFAOYSA-N [Cl-].C(CCC)[NH+](CCCC)CCCC.C(C1=CC=CC=C1)Cl Chemical compound [Cl-].C(CCC)[NH+](CCCC)CCCC.C(C1=CC=CC=C1)Cl DNZHWQKHHVGMAO-UHFFFAOYSA-N 0.000 description 1
- YJOJVPMOCQHXTM-DDWIOCJRSA-M [K+].COC(C=C(C)N1[C@H](CCC1)C(=O)[O-])=O Chemical compound [K+].COC(C=C(C)N1[C@H](CCC1)C(=O)[O-])=O YJOJVPMOCQHXTM-DDWIOCJRSA-M 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 229960004424 carbon dioxide Drugs 0.000 description 1
- CZTQZXZIADLWOZ-CRAIPNDOSA-N cefaloridine Chemical compound O=C([C@@H](NC(=O)CC=1SC=CC=1)[C@H]1SC2)N1C(C(=O)[O-])=C2C[N+]1=CC=CC=C1 CZTQZXZIADLWOZ-CRAIPNDOSA-N 0.000 description 1
- SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical group C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000011210 chromatographic step Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- BIWOSRSKDCZIFM-UHFFFAOYSA-N piperidin-3-ol Chemical compound OC1CCCNC1 BIWOSRSKDCZIFM-UHFFFAOYSA-N 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- XDLNRRRJZOJTRW-UHFFFAOYSA-N thiohypochlorous acid Chemical compound ClS XDLNRRRJZOJTRW-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
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Description
本發明係關於一種製備14-O-[(N-(3-甲基-2-胺基-丁醯基-哌啶基)硫基)乙醯基]側耳菌素類之新方法。
截短側耳素(pleuromutilin)),一種具有下式之化合物:
係-種天然抗生素,例如由擔子菌綱(basidomycetes)的截短側耳菌(Pleurotus mutilus)及帕氏側耳菌(P.passeckerianus)所產生者;參閱例如The Merck Index,第12版第7694條項下。
許多其他截短側耳素類業經開發出,彼等具有截短側耳素的主要環結構且於羥基上含取代基;例如作為抗微生物劑者。由於彼等顯著的抗微生物活性,一組截短側耳素衍生物、經纈胺醯基(vaiyl)-取代的哌啶基硫基乙醯基側耳菌素,如於WO 02/22580中所揭示者,業經發現為特別令人感興趣者。對於此組化合物的實質純異構物之製造,有需要開發出一種方法,其便於工業規模上所用且避免
使用昂貴的起始材料,對環境有害的藥劑及溶劑,以及耗時又費力的純化步驟等。
於本發明一方面提供一種製備式I化合物之方法
其中接於硫原子之哌啶環的碳原子係呈(S)-構型或呈(R)-構型,且接於哌啶環的2-胺基-3-甲基-丁醯基係呈(S)-構型或呈(R)-構型,該方法包括下列步驟:a)將式II的N-被保護哌啶基硫基乙醯基側耳菌素脫除保護
及分離出游離形式或酸加成鹽形式的式III化合物
其中接於硫原子的哌啶環碳原子係呈(S)-構型或(R)-構型,b)用保護成烯胺形式並經活化成為碳酸混合酐之(R)-或(S)-纈胺酸將該式III化合物醯化而形成式IV化合物
其中R1
及R2
係C1-4
烷基,且R3
係氫或C1-4
烷基,c)將式IV化合物脫保護基並分離出式I化合物。
於一較佳實施態樣中,式I化合物係經分離成藥學上可接受的鹽之形式。於一更佳實施態樣中,式I化合物係
經分離為鹽酸鹽形式。
於式I化合物中,哌啶環碳原子係鍵結到硫原子。此鍵可在哌啶環的任何位置上,例如於α、β或γ位置,較佳地係在相對於哌啶環氮原子的β位置。
式II N-被保護化合物之脫保護係經由將保護基酸性切開形成酸加成鹽,成為針對式II化合物中接於硫原子上的哌啶環碳原子所具構型之異構物混合物而完成。較佳地,式II化合物的側耳菌素環中之構型係與自然產生的側耳菌素相同。該異構物混合物宜於經由結晶化以可得到實質純的異構物之方式分離,其中接於硫原子的哌啶環碳原子係呈(S)-構型或(R)-構型。結晶化步驟導致高純化效應且呈結晶形式的式III化合物因此非常適於作為中間體,尤其是同樣在工業規模上用於製造哌啶基硫基乙醯基側耳菌素的程序中。此外,使用結晶形式的式III化合物具有下述優點:可以免除其他純化步驟,諸如層析術,因為結晶形式的式III化合物之純度完全足以用於製造經纈胺醯基-取代的哌啶基硫基乙醞基側耳菌素類。
礦酸或有機酸都可用以促成式II化合物的脫保護。於一較佳實施態樣中,使用甲烷磺酸來形成呈酸加成鹽形式的個別甲烷磺酸鹽。有關式II化合物中名為Prot的保護基,可用習用的N-保護基。較佳者,使用第三丁氧羰基。
業經顯示者,經由選擇適當的脫護劑,(S)-構型或(R)-構型任一者的溶解性可選擇地增進使得異構(S)-
構型可與(R)-構型分離。例如,通過使用甲烷磺酸作為脫護劑,結晶化產物係純的(S)-異構物,而(R)-異構物則留於溶液中(參閱實施例1F)。
在隨後的步驟中,纈胺醯基部份導到實質純的式III化合物異構物之步驟係經由用經保護成為烯胺形式的(R)-或(S)-纈胺酸將該化合物醯化以形成式IV化合物而完成。此經保護的纈胺酸係經由使(R)-或(S)-纈胺酸與式R1
-CO-CH(R3
)-COOR2
之β-酮基酯的反應所產生,其中R1
、R2
及R3
都為上面所定義者。較佳者為使用乙醯乙酸甲酯。較佳地,纈胺酸係根據混合碳酸酐程序加以活化。此混合酐係於原位(in situ)產生;例如經由添加三甲基乙醯氯(pivalic acid chloride)。在添加步驟a)中所產生的式III化合物之後,得到經保護的式IV化合物。此等化合物的結晶化性質比具有其他保護基,例如第三丁氧羰基的化合物為優。具有此等優良結晶化性質的化合物在製造和分離上易於操作且提供進一步純化的更好機會;例如關於式I的3-取代哌啶基硫基乙醯基側耳菌素,可以通過結晶化來分離和純化出根據式IV的經烯胺保護之化合物,而對應的經第三丁氧羰基保護的衍生物就必須使用沈長費力的層析術步驟來純化。
式IV化合物的保護基係以酸性切開來移除。於移除乙醯乙酸酯與萃取之後,可以分離出游離形式的式I化合物,或在添加可提供藥學上可接受的鹽之酸且將各別水相冷凍乾燥後,可以得到非晶態的藥學上可接受的鹽之形式
,如鹽酸鹽。
於一較佳實施態樣中,鍵結到硫原子的哌啶環碳原子係在哌啶環氮原子之β-位置上,即式I之3-取代哌啶基硫基乙醯基側耳菌素。更佳者,本發明係關於14-O-[(N-3-甲基-2-(R)-胺基-丁醯基-哌啶-3(S)-基)硫基)乙醯基]側耳菌素 鹽酸鹽。
本發明進一步關於一種14-O-[(N-3-甲基-2-(R)-胺基-丁醯基-哌啶-3(S)-基)硫基)乙醯基]側耳菌素 鹽酸鹽之新穎結晶形式。經由上述反應程序所得經凍乾的非晶態化合物14-O-[(N-3-甲基-2-(R)-胺基-丁醯基-哌啶-3(S)-基)硫基)乙醯基]側耳菌素 鹽酸鹽係於含水介質中使用結晶化法予以轉變為結晶形式。該結晶化法可利用晶種來增強及加速。經由再結晶化,可以將結晶型14-O-[(N-3-甲基-2-(R)-胺基-丁醯基-哌啶-3(S)-基)硫基)乙醞基]側耳菌素 鹽酸鹽調成具有所欲一致性及化學和光學純度之形式。因此得到實質純的具有針對3-(S)-位置≧97%之非鏡像異構過量之異構物。
結晶型14-O-[(N-3-甲基-2-(R)-胺基-丁醯基-哌啶-3(S)-基)硫基)乙醯基]側耳菌素 鹽酸鹽之特徵在於具有峰值2-θ在6.2±0.2、10.9±0.2、12.3±0.2、13.4±0.2、14.1±0.2、20.8±0.2度(2-θ、CuK-α)之X-射線粉末繞射圖等。其亦可以具有特性譜帶在約2927、1721、1645、1462、1403、1142 cm-1
之紅外線光譜特徵化。
圖1:14-O-[(N-3-甲基-2-(R)-胺基-丁醞基-哌啶-3(S)-基)硫基)乙醯基]側耳菌素 鹽酸鹽之粉末繞射譜
於結晶形式時,14-O-[(N-3-甲基-2-(R)-胺基-丁醯基-哌啶-3(S)-基)硫基)乙醯基]側耳菌素 鹽酸鹽可提供比非晶態凍乾形式更高的純度及更佳的穩定性,此有利於製備含結晶型14-O-[(N-3-甲基-2-(R)-胺基-丁醯基-哌啶-3(S)-基)硫基)乙醯基]側耳菌素 鹽酸鹽作為活性成分的藥學組成物。
式II之N-被保護哌啶基硫基乙醯基側耳菌素可經由使14-O-氫硫基乙醞基-側耳菌素與在哌啶環氮原子的α、β或γ位置上具有脫離基的N-被保護羥基哌啶,例如,於WO 02/22580中所揭示的N-BOC-3(R)-甲基磺醯氧基-哌
啶)反應來製備。
更為便利,且為本發明另一方面者,N-被保護哌啶基硫基乙醯基側耳菌素可經由使截短側耳素-22-O磺酸鹽(例如,甲烷磺酸鹽、苯磺酸鹽或甲苯磺酸鹽)與N-被保護哌啶硫醇反應來製備。保護基包括適當的保護基,例如,習用的保護基。
較佳地,用第三丁氧羰基作為N-保護基且於另一較佳實施態樣中,使用在哌啶環3-位置上具有硫醇基之N-被保護哌啶。可以使用外消旋性或鏡像異構純的在帶有硫醇基的碳原子具有(R)-或(S)-構型之N-被保護哌啶硫醇。
較佳地,使用外消旋物形式的N-被保護哌啶硫醇以避免使用昂貴的手性起始物。N-被保護哌啶硫醇可從使用適當的羥基哌啶起始經由添加N-保護基(例如,第三丁氧羰基)及與磺醯氯或酐(如,甲烷磺醯氯)反應而製備。硫醇基係經由與含硫親核物,例如硫代醋酸鹽反應及將對應的硫酯(例如,N-BOC-3-(R,S)-乙醯硫基-哌啶)鹼性切開而導入。
若羥基哌啶係以單一鏡像異構物(例如,3-(R)-羥基哌啶)的形式使用,則上述包括使用硫代醋酸鹽的親核取代的反應順序係於控制方式進行(Walden反轉)而製造出對應的N-被保護哌啶硫醇,其中接於硫原子的哌啶環碳原子係呈(S)-構型或(R)-構型(例如,3-(S)-哌啶硫醇)。
與截短側耳素-22-O-磺酸鹽的進一步反應提供式II的N-被保護哌啶基硫基乙醯基側耳菌素,其中接於硫原子的哌啶環碳原子係呈(S)-構型或(R)-構型。
於闡述本發明的下面諸實施例中係以攝氏度提及溫度。
使用下面的縮寫:N-BOC=N-丁氧羰基
RT=室溫
MTBE=甲基第三丁基醚
在實施例中提到的側耳菌素環系(cyclus)之編號係於下式中給出
14-O-[(N-3-甲基-2-(R)-胺基-丁醯基-哌啶-3(S)-基)硫基)乙醯基]側耳菌素 鹽酸鹽
A. N-BOC-3-(R,S)-羥基哌啶
將202.4克的3-(R,S)羥基哌碇溶於裝在10-升反應器內之4.5升去離子水中。加入溶解在1.1升水中的336克碳酸氫鈉。於激烈攪拌的該溶液中在室溫下加入534克的二碳酸二-第三丁酯。於整夜攪拌後,用CH2
Cl2
(3次)萃取該混合物,將合併的萃取液用去離子水洗過且蒸餾掉溶劑。將殘餘物再溶解於CH2
Cl2
中且將該溶液蒸發乾。得到423克的N-BOC-3(R,S)-羥基哌啶,其不再純化即可用於下一步驟中。
B. N-BOC-3-(R,S)-甲基磺醯氧基-哌啶
於216克的N-BOC-3(R,S)-羥基哌啶在5升CH2
Cl2
中的溶液內於0-5℃下加入222毫升的三乙胺。於45分鐘內,在維持於0-5℃的溫度下,逐滴添加由137克甲磺醯氯於300毫升CH2
Cl2
中所形成的混合物。於再攪拌70分鐘之後加入2升的去離子水且透過添加約90毫升的2 n HCl將pH值調至5.9。分離出水相且用水將有機相洗過。將此溶液蒸發乾,得到270-280克的油狀殘留物。在以1升的正庚烷處理之後發生結晶化。將晶體分離出來並真空乾燥。得到250克N-BOC-3(R,S)-甲基磺醯氧基-哌啶。熔點:69℃
1
H NMR(CDCl3
):4.71(m,1H,CHOSO2
CH3
),3.2-3.6(m,4H,CHN),3.05(s,3H,CH3
SO2
),1.94(m,2H,H4),1.83,1.54(2xm,2H,H5),1.46(m,9H,第三丁基)
C. N-BOC-3-(R,S)-乙醯硫基-哌啶
將2.7升的二甲基甲醯胺於惰性氣體環境中置於反應器內。於加溫下,添加251.4克的N-BOC-3(R,S)-甲基磺醯氧基-哌啶。於50C的內部溫度下,一次加入256.8克的硫代醋酸鉀。於95℃攪拌90分鐘之後,將反應混合物移入裝有4升水的反應器內。加入4.2升的石油醚。在激烈攪動5分鐘之後,移除水相。在加水後,將pH用氫氧化鈉調至>8。分出有機相,用水洗過,並用活性炭處理。將溶液蒸發乾。在氧化矽(silica)上用石油醚、甲苯及乙酸乙酯進行快速層析術且將含產物的溶液濃縮之後,於冷卻下發生結晶化而得到110克的N-BOC-3(R,S)-乙醯硫基-哌啶。
熔點:46-48℃(正庚烷)
1
H NMR(CDCl3
):3.79(dd,1H,H2),3.5-3.6(m,2H,H3,H6),3.17-3.27(m,2H,H2,H6),2.32(s,3H,CH3
SO2
),1.99(m,1H,H4),1.55-1.72(m,H4,H5),1.47(s,9H第三丁基)
D. N-BOC-哌啶-3-(R,S)-硫醇
將200克的N-BOC-3(R,S)-乙醯硫基-哌啶於惰性氣體環境中與3.4升的甲醇放置於10-升反應器內。於此溶液中,在15分鐘期間內,加入42克甲氧化鈉/甲醇。於再攪拌後,加入170毫升的5 n HCl,並將pH調至2.6-
3。將該溶液在一蒸發器上濃縮。所得二相混合物用1.7升的甲基第三丁基醚(MTBE)和1.7升的水溶取。於搖動之後,分離出水相且洗過,將MTBE相分離出並蒸發,產生170克的油狀物。
1
H NMR(DMSO-d6
):3.92(b,1H,H6),3.69(d,1H,H2),2.7-29(m,3H,H2,H3,H6),2.61(d,1H,SH),200(m,1H,H4),1.64(m,1H,H5),1.45-1.31(m,2H,H4,H5),1.39(s,9H,第三丁基)
E. 14-O-[(N-BOC-哌啶-3-(R,S)-基)-硫基乙醯基]側耳菌素
將359.7克的22-O-截短側耳素甲苯磺酸鹽懸浮於3.2升的MTBE中。加入1350毫升的1 n氫氧化鈉和21.1克的氯化苯甲基-三丁基銨。將該混合物冷卻至15℃且逐滴添加由161.1克N-BOC-哌啶-3(R,S)-硫醇在800毫升MTBE中所形成的溶液。於20℃下攪拌該雙相反應混合物1小時。於反應完成後將各相分開。將有機相乾燥並蒸發而產生521.5克的14-O-[(N-BOC-哌啶-3(R,S)-基)-硫基乙醯基]-側耳菌素,為油狀物,其不再純化即用於下一步驟中。
1
H NMR(CDCl3
):6.48(dd,1H,H19,J=17.4Hz,J=11.2Hz),5.77(d,1H,H14,J=8.4Hz),5.34,5.20(2xdd,2H,H20,J=11.2Hz,J=1.3Hz,J=17.4Hz,J=1.3Hz),4.0,3.75,2.96,2.01(b,6H,哌啶),3.37(dd,1H,
H11,J=10.5Hz,J=6.6Hz),3.19(m,2H,SCH2
),2.85(m,1H,CHS),2.36(dq,1H,H10,J=6.6Hz,J=6.5Hz),2.11(b,1H,H4)1.47(s,12H,(CH3
)3
,(CH3
)15),1.18(s,3H,(CH3
)18),0.89(d,3H(CH3
)17,J=6.9Hz),0.75(d,3H,(CH3
)16J=6.5Hz).
F. 14-O-[(哌碇-3-(S)-硫基乙醯基)-側耳菌素 甲磺鹽酸
將521克14-O-[(N-BOC-哌啶-3(R,S)-基)硫基乙醯基]-側耳菌素溶於4升的2-丙醇中並加熱至55C。於加入165毫升甲烷磺酸後,於此溫度下攪拌該溶液5小時。在BOC-基的切開完成之後,將反應混合物冷卻至0℃並再攪拌2小時。過濾出結晶產物,用2-丙醇洗滌且真空乾燥。得到159.8克的14-O-[(哌啶-3(S)-硫基乙醯基)]-側耳菌素 甲磺鹽酸。
熔點:250-255C
1
H NMR(DMSO-d6
):8.58(m,2H,NH2 +
),6.15(dd,1H,H19,J=17.2Hz,J=11.5Hz),5.57(d,1H,H14,J=8.2Hz),507(m,2H,H20),45(b,1H,OH),3.41(s,2H,SCH2
),2.4(b,1H,H4),2.32(s,3H,CH3
SO3 -
),1.37(s,3H,(CH3
)15),1.07(s,3H,(CH3
)18),0.83(d,3H,(CH3
)17,J=7.0Hz),0.64(d,3H,(CH3
)16,J=6.6Hz).
G. N-(3-甲氧基-1-甲基-3-酮基-1-丙烯基)-R-纈胺酸,鉀鹽(R-纈胺酸Dane鹽)
將36.6克固體KOH溶解於稍微加溫下1250毫升的2-丙醇中。加入65克R-纈胺酸及65.9毫升的乙醯乙酸甲酯。將該混合物攪拌並回流2小時。將回流冷疑器改換上克氏(Claisen)冷疑器和一短管柱且將縮合反應形成的水經由蒸餾掉約1升的2-丙醇而移除。其後,加入500毫升的2-丙醇且再蒸餾掉500毫升。將該溫熱溶液倒到3升的MTBE中並於冰-冷卻下攪拌約3小時,將所得懸浮液於4C下靜置整夜(排除濕氣),過濾、用500毫升MTBE洗過、並乾燥而產生N-(3-甲氧基-1-甲基-3-酮基-1-丙烯基)-R-纈胺酸鉀鹽。
H. 14-O-[(N-(3-甲基-2-(R)-N-(3-甲氧基-1-甲基-3-酮基-1-丙烯基-胺基)-丁醯基)-哌啶-3-(S)-基)-硫基乙酸基]-側耳菌素(Dane化合物)
於88.2克的R-纈胺酸Dane鹽在2175毫升MTBE之懸浮液內加入14.5毫升的水且於室溫下攪拌此混合物10分鐘。將混合物冷卻至0℃且加入3.5毫升4-甲基嗎啉和41毫升三甲基乙醯氯並攪拌1小時。加入2175毫升預冷卻的水(0-4℃)及166.4克14-O-[(哌啶-3(S)-硫乙醯基)]-側耳菌素甲烷磺酸鹽。經由添加約210毫升的2n NaOH將該混合物的pH值保持在7.0。攪拌冷卻混合物(
0℃)30分鐘,藉以發生Dane化合物的結晶化。為了完成反應,將懸浮液加溫至30℃並攪拌1小時。其後,經由添加約85毫升的2n NaOH將pH值調定至9.5。於冷卻至0℃並再攪拌2小時之後,濾出晶體,用冷卻水及MTBE洗滌且真空乾燥。得到195.4克呈MTBE-溶劑合物的Dane化合物。
熔點:136-142℃
1
H NMR(DMSO-d6
,兩種穩定的旋轉異構物之1:1混合物):8.87,8.83(2xd,1H,NH,J=9.3Hz),6.15(m,1H,H19),5.60,5.56(2xd,1H,H14,J=8.3Hz),5.04(m,2H,H20),4.50(m,1H,α-H-Val),437(s,1H,CH-烯胺),3.50,(s,3H,OCH3
),2.42,2.40(2xb,1H,H4),1.87,1.85(2xs,3H,CH3
-烯胺),1.36(2xs,3H,(CH3
)15),1.07(s,3H,(CH3
)18),0.96-0.77(m,9H,(CH3
)17),(CH3
)2
Val),0.64(m,3H,(CH3
)16)。
I. 14-O-[(N-3-甲基-2-(R)-胺基-丁醯基-哌啶-3(S)-基)硫基)-乙醯基]-側耳菌素 鹽酸鹽
將145克的Dane化合物懸浮於1.8升的MTBE與1.8升的水之混合物中。將該混合物加溫至約50C並激烈攪拌。經由逐滴添加2n HCl將pH值保持在1.0。完成烯胺保護基的切開之後繼以HPLC。分離出有機相且用MTBE萃
取水相兩次(每次1.6升)以移除乙醯乙酸甲酯。於攪拌的水相中加入1.6升的MTBE且經由添加10n NaOH將pH調至10。將各相分開且用1.6升份的水對MTBE相萃取二次。於添加1.5升的水之後,經由添加約100毫升的2n HCl將pH調至3.2。該水相在旋轉蒸發器中濃縮。將剩餘溶液冷凍乾燥產生117.4克的標題化合物。
1
H NMR( DMSO-d6
,兩種穩定旋轉異構物之~1:1混合物):7.95(b,3H,NH3 +
),6.15(dd.1H,H19,J=17.6Hz,J=11.2Hz),5.6(d,1H,H14,J=8.2Hz),5.05(m,2H,H20),4.53(m,1H,OH),4.24 4.30(2xd,1H,α-H-Val,J=4.8Hz),4.08(dd,0.5H,H2-哌啶,J=13.7Hz,J=3.3Hz),3.08(dd,0.5Hz,H2-哌啶,J=13.7Hz,J=9.8Hz),3.89(dd,0.5H,H2-哌啶,J=13.1Hz,J=3.2Hz),3.41(m,0.5H,H2-哌啶),AB-系統:A=3.44,B=3.33(2H,SCH2
,J=149Hz),3.42(m,1H,H11),2.83,2.96(2xm,1H,CHS),2.4(b,1H,H4),1.34(s,3H,(CH3
)15),1.05(s,1H,(CH3
)18),0.9,1.0(2xm,6H,(CH3
)2
Val),081(d,3H,(CH3
)17,J=6.9Hz),063(m,3H,(CH3
)16).
14-O-[(N-3-甲基-2-(R)-胺基-丁醯基-哌啶-3-(S)-基)硫基)乙醯基]側耳菌素 鹽酸鹽之結晶形式
將3.0升的水置於反應器中並升溫至40℃。添加1仟克的凍乾14-O-[(N-3-甲基-2-(R)-胺基-丁醯基-哌啶-3(S)-基)硫基)乙醯基]側耳菌素 鹽酸鹽並用1.0升的水沖洗添加裝置。約10分鐘之後,得到淺黃色溶液。於溶液中置入晶種且於40℃緩慢攪拌6小時。隨後停止加熱且在周溫下再攪拌該晶體懸浮液64小時。過濾出產物,用1.5升的冷水洗滌,且不乾燥即再結晶化,或於40℃真空中乾燥濕產物,產生819克的晶型標題化合物。
再結晶:將1.5升的水置於一反應器中並加溫至50℃。加入首次結晶化的濕產物並用1.0升的水沖洗添加裝置。將懸浮物加熱至70-75℃直到該產物溶解為止。將該溶液冷卻,下晶種並於40℃緩慢攪拌6小時。然後,停止加熱且於周溫下,再攪拌晶體懸浮液24小時。過濾出產物,用1.3升的冷水洗滌並於40℃真空中乾燥,產生765克的晶型標題化合物。
熔點:150-155℃
Claims (18)
- 一種製備式I哌啶基硫基乙醯基側耳菌素類(piperidineylsulfanylacetylmutilins)之方法,
- 根據申請專利範圍第1項之方法,其中該式I化合物係經分離成為藥學上可接受的鹽之形式。
- 根據申請專利範圍第2項之方法,其中該式I化合物係經分離為鹽酸鹽。
- 根據申請專利範圍第1項之方法,其中該式III化合物係與甲烷磺酸的加成鹽。
- 根據申請專利範圍第1項之方法,其中該N-保護基係第三丁氧羰基。
- 根據申請專利範圍第1項之方法,其中該N-被保護哌啶基硫基乙醯基側耳菌素係經由將截短側耳素-22-O-磺酸鹽(如,甲烷磺酸鹽、苯磺酸鹽或甲苯磺酸鹽)與N-被保護哌啶硫醇反應而製成。
- 根據申請專利範圍第6項之方法,其中N-被保護哌啶基硫基乙醯基側耳菌素係經由使截短側耳素-22-O-磺酸鹽與N-被保護哌啶硫醇反應而製備,其中接於硫原子的哌啶環碳原子係呈(S)-構型或呈(R)-構型。
- 根據申請專利範圍第1項之方法,其中該分離出的式I化合物係3-取代哌啶基硫基乙醯基側耳菌素。
- 根據申請專利範圍第8項之方法,其中該3-取代哌啶基硫基乙醯基側耳菌素係14-O-[(N-3-甲基-2-(R)-胺基-丁醯基-哌啶-3(S)-基)硫基)乙醯基]側耳菌素鹽酸鹽。
- 一種式IV化合物:
- 根據申請專利範圍第10項之化合物,其中R1 和R2 係甲基且R3 係氫。
- 根據申請專利範圍第11項之化合物,其係呈結晶型。
- 一種呈結晶型酸加成鹽形式之式III化合物 酸
- 一種結晶型的14-O-[(N-3-甲基-2-(R)-胺基-丁醯基-哌啶-3(S)-基)硫基)乙醯基]側耳菌素鹽酸鹽。
- 根據申請專利範圍第14項之化合物,其具有≧97%的3-(S)-非鏡像異構過量。
- 根據申請專利範圍第14項之化合物,其具有下列X-射線繞射(XRD)峰2-θ值:角[2-θ]6.2±0.2 10.9±0.2 12.3±0.2 13.4±0.2 14.1±0.2 20.8±0.2。
- 一種製備申請專利範圍第14項之結晶型化合物之方法,其包括下列步驟:- 將14-O-[(N-3-甲基-2-(R)-胺基-丁醯基-哌啶-3(S)-基)硫基)乙醯基]側耳菌素鹽酸鹽溶解於含水介質中且予以加溫- 隨意地在溶液中加入晶種並於增溫下攪拌- 將所得懸浮液冷卻並於周溫下攪拌- 分離出結晶產物並隨意地重複此程序。
- 一種藥學組成物,包含結晶型14-O-[(N-3-甲基-2-(R)-胺基-丁醯基-哌啶-3(S)-基)硫基)乙醯基]側耳菌素鹽酸鹽。
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