CN108101934B - Process for the preparation of trabectedin and intermediates thereof - Google Patents
Process for the preparation of trabectedin and intermediates thereof Download PDFInfo
- Publication number
- CN108101934B CN108101934B CN201711180265.4A CN201711180265A CN108101934B CN 108101934 B CN108101934 B CN 108101934B CN 201711180265 A CN201711180265 A CN 201711180265A CN 108101934 B CN108101934 B CN 108101934B
- Authority
- CN
- China
- Prior art keywords
- compound
- trabectedin
- preparation
- formula
- acid
- 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.)
- Withdrawn - After Issue
Links
- XXPXYPLPSDPERN-UHFFFAOYSA-N Ecteinascidin 743 Natural products COc1cc2C(NCCc2cc1O)C(=O)OCC3N4C(O)C5Cc6cc(C)c(OC)c(O)c6C(C4C(S)c7c(OC(=O)C)c(C)c8OCOc8c37)N5C XXPXYPLPSDPERN-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 229960000977 trabectedin Drugs 0.000 title claims abstract description 24
- PKVRCIRHQMSYJX-AIFWHQITSA-N trabectedin Chemical compound C([C@@]1(C(OC2)=O)NCCC3=C1C=C(C(=C3)O)OC)S[C@@H]1C3=C(OC(C)=O)C(C)=C4OCOC4=C3[C@H]2N2[C@@H](O)[C@H](CC=3C4=C(O)C(OC)=C(C)C=3)N(C)[C@H]4[C@@H]21 PKVRCIRHQMSYJX-AIFWHQITSA-N 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000000034 method Methods 0.000 title claims abstract description 15
- 239000000543 intermediate Substances 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 31
- 229940043279 diisopropylamine Drugs 0.000 claims description 9
- KIYRSYYOVDHSPG-ZETCQYMHSA-N (2s)-2-amino-2-phenylacetamide Chemical compound NC(=O)[C@@H](N)C1=CC=CC=C1 KIYRSYYOVDHSPG-ZETCQYMHSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- -1 compound salt Chemical class 0.000 abstract description 17
- 125000000217 alkyl group Chemical group 0.000 abstract description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 9
- 125000006239 protecting group Chemical group 0.000 abstract description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical class CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- KIYRSYYOVDHSPG-SSDOTTSWSA-N (2r)-2-amino-2-phenylacetamide Chemical class NC(=O)[C@H](N)C1=CC=CC=C1 KIYRSYYOVDHSPG-SSDOTTSWSA-N 0.000 description 3
- HCKNRHBSGZMOOF-UHFFFAOYSA-N 1-methoxy-2-methylperoxyethane Chemical compound COCCOOC HCKNRHBSGZMOOF-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-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
- 239000003513 alkali Substances 0.000 description 3
- 125000005336 allyloxy group Chemical group 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- NSPJNIDYTSSIIY-UHFFFAOYSA-N methoxy(methoxymethoxy)methane Chemical compound COCOCOC NSPJNIDYTSSIIY-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical class CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000005215 alkyl ethers Chemical class 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940125890 compound Ia Drugs 0.000 description 2
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 2
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 241000798369 Ecteinascidia turbinata Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000005841 biaryl group Chemical group 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003759 ester based solvent Substances 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 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
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- DVFXLNFDWATPMW-IWOKLKJTSA-N tert-butyldiphenylsilyl Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO[Si](C=2C=CC=CC=2)(C=2C=CC=CC=2)C(C)(C)C)[C@@H](OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](CC(O2)N2C3=NC=NC(N)=C3N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)O)C1 DVFXLNFDWATPMW-IWOKLKJTSA-N 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D515/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides processes for the preparation of trabectedin and intermediates thereof. In particular, the invention provides a compound salt of a trabectedin intermediate formula I-1 and a preparation method thereof, wherein P is1、P2Is a hydroxy protecting group, P3Is an amino protecting group, R1Is an alkyl group. Also provided is a process for preparing trabectedin using the compound having the structure of formula I-1.
Description
Technical Field
The present invention relates to a process for the preparation of trabectedin and the corresponding salts of its intermediate S) -3- [ 4-methoxy-3, 5-bis (tert-butyldimethylsilyloxy) ] phenyl-2- (allyloxyacylamino) propionic acid.
Background
Trabectedin (ecteinascidin 743, ET-743) is a very potent marine antineoplastic agent, ema (european Medicines agency) has been approved for marketing in europe in 2007 for the treatment of advanced soft tissue sarcomas. Trabectedin is isolated from marine ecteinascidins (Ecteinascidia turbinata), and the results are small, but the total synthesis is difficult because the trabectedin contains a plurality of chiral centers.
Therefore, it is necessary to develop a synthetic method for producing trabectedin useful as an antitumor agent.
WO2001058905 discloses that (S) -3- [ 4-methoxy-3, 5-bis (tert-butyldimethylsilyloxy) ] phenyl-2- (allyloxyacylamino) propionic acid (Corey 3) compound is a key intermediate for synthesizing trabectedin, but the Corey3 compound is an oily substance, needs complicated column chromatography to achieve the purification effect, is complex to operate, and is difficult to adapt to the requirement of industrial production. To this end, the present invention provides a salt form of (S) -3- [ 4-methoxy-3, 5-di (tert-butyldimethylsilyloxy) ] phenyl-2- (allyloxyacylamino) propionic acid, which is improved in physicochemical properties to be suitable for industrial production and packaging transfer. Meanwhile, the Corey3 salt compound can be crystallized and purified by using a conventional solvent to obtain a high-purity intermediate sample, and the process is simple and convenient.
Wherein TBS is tert-butyl dimethyl silicon base.
Disclosure of Invention
The present invention provides compounds useful as intermediates in the synthesis of trepetidine.
The present invention provides compounds of formula I-1:
wherein, P1、P2Each independently a hydroxyl protecting group which, together with the oxygen atom to which it is bound, is an ester, silyl ether, alkyl ether, arylalkyl ether, and alkoxyalkyl ether; p3Is an amino protecting group; r1Is an alkyl group; m is a base molecule.
The base molecule of the present invention is not particularly limited and known or can be determined by one skilled in the art as an inorganic base or an organic base, the inorganic base forms an inorganic salt with the compound of formula I-1, including but not limited to calcium salt, sodium salt, potassium salt, the corresponding inorganic base selected includes but not limited to calcium hydroxide, sodium hydroxide, potassium hydroxide; the organic base forms an organic salt with the compound of formula I-1, including but not limited to di-n-butylamine salt, tert-butylamine salt, diisopropylamine salt, and D/L-phenylglycinamide salt, with the corresponding organic base selected including but not limited to di-n-butylamine, tert-butylamine, diisopropylamine, and D/L-phenylglycinamide.
Further, the base molecule is an organic base, preferably comprising di-n-butylamine, tert-butylamine, diisopropylamine, D/L-phenylglycinamide, more preferably L-phenylglycinamide, diisopropylamine.
In a particular embodiment of the invention, the compound of formula I-1 may exist as a single stereoisomer, with high stereoisomeric purity, having the formula:
in some embodiments, R is1The alkyl group is selected from, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl, and more preferably methyl.
In a preferred embodiment of the invention, said amino protecting group (P)3) is-CO2An allyl group having the formula:
in some embodiments, the compound of formula I-1 wherein the base molecule is L-phenylglycinamide has the formula:
further, the hydroxyl protecting group P1、P2Each independently preferably tert-butyldimethylsilyl (TBDMS or TBS),
in some embodiments, the compound of formula I-1 wherein the base molecule is diisopropylamine has the formula:
further, the hydroxyl protecting group P1、P2Each independently preferably tert-butyldimethylsilyl (TBDMS or TBS),
the present invention also provides a process for the preparation of trabectedin, which comprises the step of preparing trabectedin from any one of the compounds I-1 to I-7 as described hereinbefore.
In some embodiments, the preparation of trabectedin may be carried out as follows:
in some embodiments, the preparation of trabectedin may be carried out as follows:
in some embodiments, the preparation of trabectedin may be carried out as follows:
further, the compound of formula I-6, after being freed from the acid, is condensed with a Corey 4 compound and subsequently subjected to the step of preparing trabectedin as described in WO2001058905, the contents of which are incorporated in the present description by reference to WO2001058905,
the invention also provides a preparation method of the compound I-1, which comprises the step of preparing the compound of the formula I-1 by salifying the compound I and alkali,
wherein R is1、P1、P2、P3And M is as described in formula I-1.
Further, the compound of formula I may exist as a single stereoisomer, with high stereoisomeric purity, having the formula:
in the preferred embodiment of the present invention, R is1Alkyl is preferably methyl, soThe amino protecting group (P)3) preferably-CO2An allyl group having the formula:
further, the alkali molecules are L-phenylglycinamide and diisopropylamine.
Further, the hydroxyl protecting group P1、P2Each independently preferably tert-butyldimethylsilyl (TBDMS or TBS),
the solvent used for the above salt formation is preferably C1-C4Alcohols of (2), such as methanol, ethanol; ester solvents such as ethyl acetate; ether solvents such as methyl t-butyl ether, ethyl ether, propyl ether; chlorinated hydrocarbon solvent such as dichloromethane or its mixed solvent, acetonitrile, acetone, more preferably methyl tert-butyl ether, diethyl ether, propyl ether, ethanol, acetonitrile, acetone, methanol, and ethyl acetate as precipitation solvent. The equivalent of the corresponding base is preferably 1 to 2 equivalents, and may be 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0 equivalents.
The invention also provides a method for purifying the compound I, which comprises the steps of preparing the compound I-1 by salifying the compound I and a base, and then dissociating the compound I and an acid. The acid of the present invention is known or identifiable to those skilled in the art and is selected from, but not limited to, hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, trifluoroacetic acid.
The invention also provides a method for preparing the trabectedin, which comprises the step of preparing the compound of the formula I-1 by salifying the compound I and a base.
The invention also provides application of any compound of the formulas I-1 to I-7 in preparing the trabectedin compound.
Detailed description of the invention
Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
The "hydroxy-protecting group" according to the present invention is a group known in the art as being suitable for hydroxy-protection, see hydroxy-protecting Groups in the literature ("Protective Groups in Organic Synthesis", 5th.ed.t.w.greene & p.g.m.wuts). Illustratively, the hydroxyl protecting group is taken together with the oxygen atom to which it is bound to form an ester, silyl ether, alkyl ether, arylalkyl ether, or alkoxyalkyl ether. The esters formed are acetyl (Ac), benzoyl (Bz) or pivaloyl (Piv); the silyl group formed is tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), Triisopropylsilyloxymethyl (TOM) or Triisopropylsilyl (TIPS); forming an alkyl, arylalkyl or alkoxyalkyl ether protecting group is benzyl (Bn), Methoxyethoxymethyl Ether (MEM), trityl (Tr), Dimethoxytrityl (DMT), methoxymethyl ether (MOM) or the like, preferably said hydroxy protection is selected from benzyl, methoxyethoxymethyl ether, methoxymethyl ether, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, acetyl, pivaloyl.
The "amino-protecting Groups" according to the invention are suitable Groups known in the art for protecting hydroxyl Groups, see the literature ("Protective Groups in Organic Synthesis", 5Th. ed. T.W.Greene)&P.g.m.wuts). The amino protecting group together with the nitrogen atom to which it is bound forms an amide, alkylamine, alkenylamine or arylamine, preferably, the amino protecting group is-CO2An allyl group.
The number of atoms in the alkyl, alkyl group or aryl group is not particularly limited and should be known to or can be determined by one of ordinary skill in the art. In particular embodiments, the alkyl group is a C1-6An alkyl group. In another embodiment, the aryl group is a C6-14And (4) an aryl group.
"alkyl" refers to a saturated aliphatic hydrocarbon group selected from alkyl groups containing 1 to 6 carbon atoms (which may be described as C)1-6Alkyl groups). Non-limiting examples includeMethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl.
"aryl" refers to an aromatic group having at least one conjugated pi-electron ring and includes carbocyclic aryl, heterocyclic aryl (also referred to as heteroaryl groups), and biaryl groups, all of which may be optionally substituted. The aryl group may include 6 to 14 carbon atoms, non-limiting examples include phenyl, pyridyl, or naphthyl.
The agents for use in the present invention are commercially available.
The HPLC conditions used in the present invention are: the chromatography column Agilent Eclipse XDB-C184.6 x 150mm 5 μm, the mobile phase acetonitrile/water 50:50(V/V), the detection wavelength 254 nm.
Detailed Description
The present invention will be explained in detail with reference to specific examples below, so that those skilled in the art can more fully understand the specific examples of the present invention to illustrate the technical solutions of the present invention, and not to limit the present invention in any way.
Example 1:
the compound Corey 3(1.2kg, obtained according to the method of patent WO 2001058905) was dissolved in methyl tert-butyl ether (MTBE, 20L), L-phenylglycinamide (0.35kg) was added, stirred at 50 ℃ for 0.5 h, part of the solvent (10L) was removed under reduced pressure and filtered, yielding 1.4kg of compound Ia, 91% yield and 99% HPLC purity.
1HNMR(BRUKER-400MHz,DMSO-d6):δ7.64(s,1H),7.50-7.10(m,7H),6.43(s,2H),6.0-5.7(m,1H),5.3-5.1(m,3H),4.6-4.3(m,4H),4.1-3.9(m,1H),3.64(s,3H),3.0-2.9(m,1H),2.8-2.6(m,1H),2.11(s,1H),1.00(s,18H),0.17(s,12H).
Example 2: screening of salt-forming conditions
The salt formation conditions were screened in the above salt formation mode with reference to example 1: dissolving the compound Corey3 in a proper organic solvent, adding alkali molecules dissolved in the organic solvent, stirring for 0.5 hour at the temperature of 50 ℃, removing part of the solvent by decompression and filtering to obtain the product.
From the data of the above experimental examples, it was readily found that dicyclohexylamine and triethylamine were not able to form salts with the compound Corey3 and formed solids, whereas in several bases able to form salts with the compound Corey3, L-phenylglycinamide showed good salt-forming efficiency and the obtained salts were of high purity.
Example 3:
in a 250mL reaction flask, compound Ia (10g) was dissolved in toluene (100mL), an aqueous hydrochloric acid solution (60mL containing 0.51g of hydrogen chloride) was added dropwise, the mixture was stirred vigorously for 1 hour, a little insoluble matter was removed by filtration, and the mixture was separated, dried, and concentrated under reduced pressure to give compound Corey3(8 g).
Dissolving a compound Corey3 and a compound Corey 4(3.8g, 1eq., prepared according to the methods of the documents J.Am.chem.Soc.1996,118, 9202-9203) in dichloromethane (100mL) in 250mL, adding 1-hydroxy-7-azobenzotriazol (HOAT, 3g, 1.5eq.) and 2-chloro-1, 3-dimethylimidazolium hexafluorophosphate (CIP, 6g, 1.5eq.), stirring at room temperature for 4-5 hours, adding water for quenching reaction, separating, extracting with dichloromethane, washing with water, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, and purifying by column chromatography to obtain the target compound Corey6(9.6g, 84% of total yield in two steps).
Example 4: preparation of diisopropylammonium (S) -2- (((allyloxy) formyl) amino) -3- (3, 5-di ((tert-butyldimethylsilyl) oxy) -4-methoxyphenyl) propionate compound
A100 mL reaction flask was charged with Corey 3(3.20g, 5.93mmol, 90.96% pure in HPLC) and acetonitrile (16.0mL), dissolved with stirring, and a solution of diisopropylamine (0.66g, 6.52mmol) in acetonitrile (16.0mL) was added dropwise, whereupon a solid precipitated. The reaction system is heated to reflux, stirred, crystallized, filtered and dried to obtain a target product of 3.25g, 98.76% pure in HPLC, and the yield is 85.6%.
MS m/z(ESI):540.2781[M+H]+
1H NMR(400Hz,CDCl3):δ6.34(s,2H),5.95-5.83(m,1H),5.49-5.46(m,1H),5.27(d,J=17.2Hz,1H),5.17(d,J=10.0Hz,1H),4.52(d,J=5.6Hz,2H),4.23(brs,1H),3.65(s,3H),3.23-3.19(m,2H),3.06-3.02(m,1H),2.92-2.87(m,1H),1.27-1.13(m,12H),0.97(s,18H),0.13(s,12H).
Example 5: preparation of diisopropylammonium (S) -2- (((allyloxy) formyl) amino) -3- (3, 5-di ((tert-butyldimethylsilyl) oxy) -4-methoxyphenyl) propionate compound
A100 mL reaction flask was charged with Corey 3(0.80g,1.48mmol, 90.96% pure in HPLC) compound and acetone (4.0mL), dissolved with stirring, and a solution of diisopropylamine (0.17g,1.63mmol) in acetone (4.0mL) was added dropwise, whereupon a solid precipitated. The reaction system is heated to reflux, stirred, crystallized, filtered and dried to obtain 0.76g of a target product, 98.31% pure in HPLC and 79.6% of yield.
Example 6: preparation of diisopropylammonium (S) -2- (((allyloxy) formyl) amino) -3- (3, 5-di ((tert-butyldimethylsilyl) oxy) -4-methoxyphenyl) propionate compound
A100 mL reaction flask was charged with Corey 3(0.80g,1.48mmol, 90.96% pure in HPLC) and ethyl acetate (4.0mL), the mixture was dissolved under stirring, a solution of diisopropylamine (0.17g,1.63mmol) in ethyl acetate (4.0mL) was added dropwise at 15-25 ℃ and a solid precipitated after completion of the addition. The reaction system is heated to reflux, stirred, crystallized, filtered and dried to obtain 0.60g of a target product, 98.44% pure in HPLC and 63.5% of yield.
Claims (6)
3. A method for purifying compound I, which comprises the step of obtaining a compound of formula I-1 by the preparation method of claim 2, and then dissociating the compound with an acid.
4. The method of claim 3, wherein the acid is selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, and trifluoroacetic acid.
5. A method of preparing trabectedin comprising the step of synthesizing trabectedin from the compound of claim 1.
6. A process for the preparation of trabectedin comprising the preparation process as claimed in claim 2 or the purification process as claimed in claim 3 or 4.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201611042329 | 2016-11-24 | ||
CN201611042329X | 2016-11-24 | ||
CN2017102885126 | 2017-04-27 | ||
CN201710288512 | 2017-04-27 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN108101934A CN108101934A (en) | 2018-06-01 |
CN108101934B true CN108101934B (en) | 2022-02-08 |
Family
ID=62207289
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201711180265.4A Withdrawn - After Issue CN108101934B (en) | 2016-11-24 | 2017-11-23 | Process for the preparation of trabectedin and intermediates thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN108101934B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110092802B (en) * | 2019-06-21 | 2022-01-07 | 爱斯特(成都)生物制药股份有限公司 | Method for preparing trepetidine intermediate |
CN114621245A (en) * | 2020-12-11 | 2022-06-14 | 江苏恒瑞医药股份有限公司 | Crystal form of aspergillin intermediate and preparation method thereof |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1425017A (en) * | 2000-02-11 | 2003-06-18 | 哈佛大学的校长及成员们 | Synthetic process for intermediate for ecteinascidin and phthalascidin compounds |
-
2017
- 2017-11-23 CN CN201711180265.4A patent/CN108101934B/en not_active Withdrawn - After Issue
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1425017A (en) * | 2000-02-11 | 2003-06-18 | 哈佛大学的校长及成员们 | Synthetic process for intermediate for ecteinascidin and phthalascidin compounds |
Non-Patent Citations (1)
Title |
---|
A New, More Efficient, and Effective Process for the Synthesis of a Key Pentacyclic Intermediate for Production of Ecteinascidin and Phthalascidin Antitumor Agents;Eduardo J. Martinez等;《Org. Lett.》;20000315;第2卷(第7期);第993-996页 * |
Also Published As
Publication number | Publication date |
---|---|
CN108101934A (en) | 2018-06-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9550735B2 (en) | Process for the preparation of ivacaftor and solvates thereof | |
CN113874359B (en) | Process for preparing 1-deoxy-1-methylamino-D-glucitol 2- (3, 5-dichlorophenyl) -6-benzoxazole carboxylate | |
JP7339946B2 (en) | Method for producing 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole and hydrogen sulfate thereof | |
CA3030551A1 (en) | Processes for the preparation of 4-alkoxy-3-(acyl or alkyl)oxypicolinamides | |
CN106831737A (en) | The preparation of Wei Patawei and its derivative | |
CN108101934B (en) | Process for the preparation of trabectedin and intermediates thereof | |
EP3013848B1 (en) | Process for the preparation of abiraterone and intermediates thereof | |
US9834561B2 (en) | Process for preparing ibrutinib and its intermediates | |
WO2013177713A1 (en) | Process for preparation of an antifolate agent | |
CN107814757B (en) | Method for synthesizing polysubstituted pyrrole derivative | |
EP3986400B1 (en) | Processes and intermediates for producing diazaspiro lactam compounds | |
CN113666860B (en) | Preparation method of 7-ethyl tryptol | |
EP3911660B1 (en) | Process for preparation of 2-amino-5-hydroxy propiophenone | |
CN109180564B (en) | Preparation method of piperidine and derivatives thereof | |
CN108101881B (en) | Process for the preparation of trabectedin and intermediates thereof | |
CN107778271B (en) | Synthesis method of anticancer compound CX1409 | |
CN117105996B (en) | Preparation method of deoxyribose derivative | |
CN113845530A (en) | Convenient Michal addition reaction of 2-phenylbenzimidazole [2,1-b ] thiazole | |
JP5192807B2 (en) | Stable crystals of protected pseudouridine | |
JP6660393B2 (en) | Method for preparing 4-cyanopiperidine hydrochloride | |
WO2013054273A2 (en) | Process for the preparation of agomelatine | |
CN110551114A (en) | Preparation method of raltitrexed | |
US20220194953A1 (en) | Method for preparing naldemedine | |
CN114957331A (en) | Preparation method of phosphate substituted cyclopropyl amide derived quinazoline compound | |
WO2005021571A1 (en) | Method for producing n4-benzoylcytidine derivative |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
AV01 | Patent right actively abandoned |
Granted publication date: 20220208 Effective date of abandoning: 20240327 |
|
AV01 | Patent right actively abandoned |
Granted publication date: 20220208 Effective date of abandoning: 20240327 |
|
AV01 | Patent right actively abandoned | ||
AV01 | Patent right actively abandoned |