CN106380508A - Industrialized production method for antibody coupling medicine connexon - Google Patents
Industrialized production method for antibody coupling medicine connexon Download PDFInfo
- Publication number
- CN106380508A CN106380508A CN201510451473.8A CN201510451473A CN106380508A CN 106380508 A CN106380508 A CN 106380508A CN 201510451473 A CN201510451473 A CN 201510451473A CN 106380508 A CN106380508 A CN 106380508A
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- compounds
- raw material
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003814 drug Substances 0.000 title claims abstract description 24
- 230000008878 coupling Effects 0.000 title claims abstract description 8
- 238000010168 coupling process Methods 0.000 title claims abstract description 8
- 238000005859 coupling reaction Methods 0.000 title claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 title abstract description 3
- 239000002994 raw material Substances 0.000 claims abstract description 37
- 238000000034 method Methods 0.000 claims abstract description 30
- 238000002360 preparation method Methods 0.000 claims abstract description 29
- 229940079593 drug Drugs 0.000 claims abstract description 6
- 229960000455 brentuximab vedotin Drugs 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 96
- 238000006243 chemical reaction Methods 0.000 claims description 67
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 63
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 47
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 239000012065 filter cake Substances 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 23
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 22
- 239000003513 alkali Substances 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- 239000002585 base Substances 0.000 claims description 19
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- 239000003960 organic solvent Substances 0.000 claims description 16
- 239000000376 reactant Substances 0.000 claims description 16
- 239000003208 petroleum Substances 0.000 claims description 15
- 239000007791 liquid phase Substances 0.000 claims description 14
- 238000001291 vacuum drying Methods 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims description 13
- 230000008569 process Effects 0.000 claims description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 238000010009 beating Methods 0.000 claims description 11
- 238000001556 precipitation Methods 0.000 claims description 11
- 238000006467 substitution reaction Methods 0.000 claims description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims description 9
- 238000001953 recrystallisation Methods 0.000 claims description 9
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 8
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 8
- 238000010511 deprotection reaction Methods 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- -1 tetramethyl fluorine Chemical compound 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 230000003213 activating effect Effects 0.000 claims description 6
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 230000004044 response Effects 0.000 claims description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 5
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical group CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 5
- 235000011056 potassium acetate Nutrition 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- 238000006482 condensation reaction Methods 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 claims description 2
- CPOPXARYEANNSX-UHFFFAOYSA-N 4,6-dimethoxytriazine Chemical compound COC1=CC(OC)=NN=N1 CPOPXARYEANNSX-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 230000008859 change Effects 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 238000004108 freeze drying Methods 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 238000006884 silylation reaction Methods 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 2
- 150000003462 sulfoxides Chemical class 0.000 claims 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims 1
- NDQKGYXNMLOECO-UHFFFAOYSA-N acetic acid;potassium Chemical compound [K].CC(O)=O NDQKGYXNMLOECO-UHFFFAOYSA-N 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- 150000007984 tetrahydrofuranes Chemical group 0.000 claims 1
- 238000012805 post-processing Methods 0.000 abstract description 7
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 abstract description 3
- 238000010521 absorption reaction Methods 0.000 abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 17
- 239000000243 solution Substances 0.000 description 15
- 229940049595 antibody-drug conjugate Drugs 0.000 description 13
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 9
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical class O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-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
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 230000008901 benefit Effects 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 229910004373 HOAc Inorganic materials 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 150000002118 epoxides Chemical class 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 239000002619 cytotoxin Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N fluorene Chemical class C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 description 3
- ALBYIUDWACNRRB-UHFFFAOYSA-N hexanamide Chemical compound CCCCCC(N)=O ALBYIUDWACNRRB-UHFFFAOYSA-N 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- IPWFJLQDVFKJDU-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 description 3
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 3
- GTDKXDWWMOMSFL-UHFFFAOYSA-M tetramethylazanium;fluoride Chemical compound [F-].C[N+](C)(C)C GTDKXDWWMOMSFL-UHFFFAOYSA-M 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 2
- 101710112752 Cytotoxin Proteins 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- JLCNONSENSTYER-UHFFFAOYSA-N [O-][N+](C(C=C1)=CC(CC2=CC=CC=C2)=C1C(C1=CC=CC=C1)=O)=O Chemical compound [O-][N+](C(C=C1)=CC(CC2=CC=CC=C2)=C1C(C1=CC=CC=C1)=O)=O JLCNONSENSTYER-UHFFFAOYSA-N 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 231100000481 chemical toxicant Toxicity 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000009987 spinning Methods 0.000 description 2
- 239000000758 substrate Substances 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
- 239000003440 toxic substance Substances 0.000 description 2
- GPIQOFWTZXXOOV-UHFFFAOYSA-N 2-chloro-4,6-dimethoxy-1,3,5-triazine Chemical class COC1=NC(Cl)=NC(OC)=N1 GPIQOFWTZXXOOV-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- FCZTVEPNOOYYJU-UHFFFAOYSA-N C(O)(O)=O.C(C1=CC=CC=C1)C1=C(C(=O)C2=CC=CC=C2)C=CC(=C1)[N+](=O)[O-] Chemical compound C(O)(O)=O.C(C1=CC=CC=C1)C1=C(C(=O)C2=CC=CC=C2)C=CC(=C1)[N+](=O)[O-] FCZTVEPNOOYYJU-UHFFFAOYSA-N 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 108091092195 Intron Proteins 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 102000029749 Microtubule Human genes 0.000 description 1
- 108091022875 Microtubule Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- IEDXPSOJFSVCKU-HOKPPMCLSA-N [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[6-(2,5-dioxopyrrolidin-1-yl)hexanoylamino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methyl N-[(2S)-1-[[(2S)-1-[[(3R,4S,5S)-1-[(2S)-2-[(1R,2R)-3-[[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-N-methylcarbamate Chemical compound CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccc(NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)CCCCCN2C(=O)CCC2=O)C(C)C)cc1)C(C)C IEDXPSOJFSVCKU-HOKPPMCLSA-N 0.000 description 1
- ZCHPKWUIAASXPV-UHFFFAOYSA-N acetic acid;methanol Chemical compound OC.CC(O)=O ZCHPKWUIAASXPV-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 125000004849 alkoxymethyl group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229940124650 anti-cancer therapies Drugs 0.000 description 1
- 239000000611 antibody drug conjugate Substances 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- VZDYWEUILIUIDF-UHFFFAOYSA-J cerium(4+);disulfate Chemical compound [Ce+4].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O VZDYWEUILIUIDF-UHFFFAOYSA-J 0.000 description 1
- 229910000355 cerium(IV) sulfate Inorganic materials 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 229960003297 gemtuzumab ozogamicin Drugs 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 210000004688 microtubule Anatomy 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229960001612 trastuzumab emtansine Drugs 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- 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
Abstract
The invention relates to an industrialized production method for preparing an antibody coupling medicine Adcetris connexon. Through a method for protecting a hydroxyl group of a compound IV, the moisture absorption performance is improved, the post-processing operation is simplified, and the product meeting requirements of pharmaceutical-grade raw material drugs is obtained. The method is not only suitable for a small amount of preparation in laboratories but also suitable for large-scale industrial production.
Description
Technical field
The present invention relates to a kind of industrialized preparing process preparing antibody coupling medicine Adcetris connexon.This
Bright belong to organic synthesis field.
Background technology
, as a kind of important anti-cancer therapies, the cytotoxic reagent that it is used is due to tumor for chemotherapy
Cell lacks specificity, can lead to serious side effect.And antibody coupling medicine (Antibody-Drug
Conjugate, ADC), as one kind of targeted anticancer medicine, can be by monoclonal antibody and high efficiency cell toxin
Ideally combine, that is, take full advantage of the targeting of monoclonal antibody and the advantage that selectivity is strong；
The advantage that again make use of the High Fragmentation to tumor cell for the cytotoxin well；Simultaneously because cytotoxin with
After antibody coupling, medicine that it the is formed toxicity very little to body, also solve single cell poison well
The element defect big to physical toxicity.
General ADC includes target head antibody, introns, chemical linker (Chemical Linker) and medicine
As cytotoxic compound four part.The structure that it is critical only that connexon of ADC drug development, when medicine exists
It is ensured that the antibody and chemicalses integrity under environment in vivo before entering target cell, and proximal or into
After target cell, chemicalses can accurately discharge again.Realize this process and depend on antibody and toxic chemical
" stability " after being connected by connexon.In addition the chemicalses quantity that in ADC medicine, antibody is loaded
Also depend on connexon.The failure of early stage ADC medicament research and development, is passed through with drug molecule mainly due to antibody
After connexon combines, the medicine that formed stability in vivo is poor, and toxic chemical is not reach tumor thin
Just disconnect with the antibody being connected before born of the same parents, cause the serious toxicity to body.These factors have impact on
ADC Drug safety and effectiveness.
The ADC medicine of the listing of U.S.'s food and Drug Administration (FDA) approval in the market has three
Kind, respectively Mylotarg, Adcetris and Kadcyla.Adcetris be by Seattle Genetice company and
Military field pharmacy joint development, for treating Hodgkin lymphoma and systemic primary cutaneous type.
This medicine is currently the only commercially successful ADC medicine, and it is beautiful that listing the first annual sales amount reaches 1.36 hundred million
Unit.It comprises three parts, most important of which is that one can be by antibody cAC10 and Microtubule disruption agent list
The connexon (VIII) that methyl (MMAE) connects, its structure is as follows, and this connexon passes through disulfide bond and resists
Body combines, and the medicine being connected by this mode is more stable in human body.
Its synthetic route in document Bioconjugate Chem, disclosed in 2002,13,855-869.Compound
Through condensation, deprotection, two step substitution reactions obtain connexon VIII to I.The following institute of route of report in document
Show：
The method literature procedures amount is less, only milligram rank.The yield of final step reaction only 15%, and
And post processing bothers, compound VIII needed column purification.Obviously, the method is not suitable for industry's enlarging production.
Patent US20050238649 reports and obtains compound for initiation material through four-step reaction with compound I
VIII.Although the method post-processing operation is simple, the purity of compound VIII only 94% is it is impossible to reach
The quality standard of pharmaceutical industry API.
The preparation of connexon VIII, patent US20050238649 and document Bioconjugate
Chem, 2002,13,855-869 all do not mention the physical property of intermediate, but in the middle of finding in experimentation
The easy moisture absorption of body compound IV, this undoubtedly increased the difficulty of post-reaction treatment.Based on the fact above, this
Bright hygroscopicity is improved by the method to protection on compound IV hydroxyl, simplify post-processing operation, obtain relatively
Good result.
Compound VIII, as the connexon of currently the only commercially successful ADC medicine, does not but have
Document or patent have a large amount of reports synthesizing to this compound.Therefore design and implement one and can be suitably used for industry
Metaplasia is produced, and the synthetic method that easy and simple to handle and purity can reach the connexon VIII of pharmaceutical industry standard has relatively
High economic worth and social benefit.
Content of the invention
It is an object of the invention to provide a kind of industrialized preparing process of ADC connexon, to solve above-mentioned background
The problem that technology is mentioned.
To achieve these goals, the present invention employs the following technical solutions to realize：
A kind of industrialized preparing process of ADC connexon, process route is as follows：
Wherein, R1Can be silylation protection group, Alkoxyalkyl protecting groups, alkyl protecting groups.Preferably
R1For trimethyl silicon substrate (TMS), t-Butyldimethylsilyl (TBS), alkoxy methyl protection group (MOM),
2- (trimethyl silicon substrate) ethoxyl methyl (SEM), more preferably t-Butyldimethylsilyl.
More specifically, the preparation method of the present invention comprises following process：
Step 5：Under inert gas shielding, compound I is in the presence of carboxylic acid activating reagents and alkali and chemical combination
Thing IX reaction obtains compounds X.
Wherein R1As defined above.
Described condensation reaction method and condition can be the conventional method of the such reaction in this area and condition.Relatively
Good, above-mentioned preparation method comprises the steps of：Under nitrogen protection, compound I and compound IX is added to
In organic solvent, under room temperature, stirring half an hour all dissolves to raw material, adds carboxylic acid activating reagents and alkali,
Deca process temperature controls at -5～15 DEG C.Completion of dropping, is slowly increased to room temperature and continues condensation reaction up to liquid
In phase tracing display reaction system, raw material I disappears, stopped reaction.Through normal pressure precipitation after reaction stopping, washing,
Vacuum drying obtains compounds X.
Described carboxylic acid activating reagents be selected from ethyl chloroformate, isobutyl chlorocarbonate, carbonyl dimidazoles, 4- (4,
6- dimethoxy-triazine -2- base) -4- methyl morpholine hydrochloride (DMTMM), 2- chloro- 4,6- dimethoxy -1,
3,5- triazines (CDMT), preferably ethyl chloroformate.Described carboxylic acid activating reagents and compound I rub
Your rate of charge is 1～4：1.
Described alkali is potassium acetate, pyridine, triethylamine, the organic base such as DIPEA, or potassium phosphate,
Potassium carbonate, sodium hydroxide, cesium fluoride, the inorganic base such as cesium carbonate, preferably triethylamine.Described alkali and change
The molar feed ratio of compound I is 1～6：1.
Described organic solvent is oxolane, dimethyl sulfoxide, DMF, ethyl acetate,
One of dichloromethane, or the combination in any of above-mentioned solvent, preferably ethyl acetate.Described is organic molten
The volume mass of agent and compound I is than for 5～20mL/g.
Described compound IX is commercially available.The molar feed ratio of described compound IX and compound I be 1～
4：1.
Described compound I list of references US20050238649 is obtained.
Step 6：In the basic conditions, polar non-solute is by deprotection method for compounds X
Compound XI.
Wherein R1As defined above.
Described deprotection method and condition can be the conventional method of the such reaction in this area and condition.Preferably
, above-mentioned preparation method comprises the steps of：Under room temperature, compounds X is added in polar non-solute,
Stirring half an hour all dissolves to raw material, adds alkali, carries out deprotection, until the reaction of liquid phase tracing display
In system, raw material X disappears, stopped reaction.After reaction stops, precipitation, recrystallization, washing, it is vacuum dried
To compounds X I.Described alkali is potassium acetate, pyridine, diethylamine, the organic base such as diisopropyl ethyl amine,
It is preferably diethylamine.The molar feed ratio of described alkali and compounds X is 2～5：1.
Described polar non-solute is acetonitrile, acetone, DMF or dimethyl sulfoxide
(DMSO), preferably DMF.Described polar non-solute and the body of compounds X
Long-pending mass ratio is 5～20mL/g.
Step 7：Compounds X I and compound V passes through substitution reaction, then sloughs R1Protection obtains intermediate
VI.
Wherein R1As defined above.
Described replacement and deprotection method and condition can be conventional method and the bar of the such reaction in this area
Part, preferably, above-mentioned preparation method comprises the steps of：Under room temperature, compounds X I and compound V is added to pole
Property aprotic solvent in, under greenhouse stirring half an hour to raw material all dissolve, then heat at 45～50 DEG C
Reaction 4～6 hours, obtains substituent reactant liquor, and it is de- that substituent reactant liquor is cooled to -5～0 DEG C of addition
Protection reagent, completion of dropping, it is warmed to room temperature reaction until raw material disappears in liquid phase tracing display reaction system,
Stopped reaction.After reaction stops, reactant liquor is cooled to -5～0 DEG C of tune pH value 7～8, filters, collect filter
Cake, making beating, vacuum drying obtains compound VI.Described polar non-solute is acetonitrile, acetone, N, N-
Dimethylformamide or dimethyl sulfoxide (DMSO), preferably DMF.Itself and chemical combination
The volume mass of thing XI is than for 5～20mL/g.
Described deprotecting regent can be tetrabutyl ammonium fluoride (TBAF), Methanaminium, N,N,N-trimethyl-, fluoride, cesium fluoride,
Fluohydric acid. pyridine, the fluorination reagent such as Fluohydric acid. triethylamine or p-methyl benzenesulfonic acid, trifluoroacetic acid etc. has
Machine acid, can also be hydrochloric acid, sulphuric acid, the mineral acid such as nitric acid.It is preferably Methanaminium, N,N,N-trimethyl-, fluoride, described fluorine
Changing reagent and the molar feed ratio of compounds X I is 1～3：1.
The molar feed ratio of described compound V and compounds X I is 1～5：1.
The described response time is detecting that reaction completes.
Step 8：Under inert gas shielding, compound VI and compound VII in polar non-solute,
Under alkalescence condition, carry out substitution reaction, obtain compound VIII.
Described substitution technique and condition can be the conventional method of the such reaction in this area and condition.Preferably,
Above-mentioned preparation method comprises the steps of：Under nitrogen protection, compound VI and compound VII is added to polarity
In aprotic solvent, under room temperature, stirring half an hour all dissolves to raw material, adds alkali and carries out substitution reaction,
Response time is 3～5 hours.After the completion of reaction, frequent pressure-off is molten, and organic solvent is pulled an oar and recrystallization,
Lyophilization obtains compound VIII.
Described polar non-solute is acetonitrile, acetone, DMF or dimethyl sulfoxide
(DMSO), preferably DMF.Described organic solvent and the volume mass of compound VI
Than for 5～20mL/g.
Described alkali is potassium acetate, pyridine, diethylamine, triethylamine, the organic base such as diisopropyl ethyl amine,
It is preferably diisopropyl ethyl amine.The molar feed ratio of described alkali and compound VI is 1～2：1.
The molar feed ratio of described compound VII and compound VI is 1～2：1.
Described making beating use solvent be, oxolane, acetone, dichloromethane, ethyl acetate, methanol,
Toluene, the combination in any of the organic solvent such as petroleum ether or above-mentioned solvent.Preferably dichloromethane and petroleum ether is according to 1：
1 volume ratio mixing.Organic solvent that described making beating uses and the volume mass of compound VI than for 4～
5mL/g.
The solvent that described recrystallization uses is dimethyl sulfoxide, oxolane, acetone, dichloromethane, acetic acid,
Trifluoroacetic acid, ethyl acetate, methanol, toluene, the combination in any of the organic solvent such as petroleum ether or above-mentioned solvent.
Preferably acetic acid methanol is according to 1：1 volume ratio mixing.Organic solvent and compound VI that described recrystallization uses
Volume mass than for 5～20mL/g.
Advantages of the present invention essentially consists in：
1) preparation of connexon VIII, patent US20050238649 and document Bioconjugate
Chem, 2002,13,855-869 all do not mention the physical property of intermediate, but in the middle of finding in experimentation
The easy moisture absorption of body compound IV, this undoubtedly increased the difficulty of post processing.Based on the fact above, the present invention is led to
Cross the method to protection on compound IV hydroxyl, improve hygroscopicity, simplify post-processing operation.
2) post-processing operation of the present invention is simple, by making beating, the method such as recrystallization is multiple batches of obtain pure
Degree>99%, de>98%, single miscellaneous<0.1% finished product ADC connexon VIII, meets pharmaceutical grade crude drug
Require.
3) this synthesising method reacting condition is gentle, and operational approach is simple and convenient, is not only suitable for laboratory and prepares on a small quantity,
It also is adapted for industrialization large-scale production.
4) present invention has good reference meaning for developing new antibody coupling medicine connexon.
Specific embodiment：
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are only used for
The bright present invention rather than restriction the scope of the present invention.The experiment side of unreceipted actual conditions in the following example
Method, is generally carried out according to normal condition.
In embodiment, raw material used or reagent are in addition to special instruction, all commercially available.
Room temperature described in embodiment refers both to 20～35 DEG C.Unless otherwise indicated, described reagent is not purified
Directly use.All solvents are purchased from commercialization supplier, such as aldrich (Aldrich), and without place
Reason can use.Reaction is analyzed by TLC and/or is analyzed by LC-MS, by the consumption of parent material
To judge the termination reacted.The thin layer chromatography (TLC) of analysis is in 0.25 millimeter of pre-coated silica gel 60 F254
Carry out on the glass plate (EMD chemical company (EMD Chemicals)) of plate, with UV light (254nm) and/
Or the iodine developing on silica gel, and/or with TLC product dyed thereby such as alcohol phosphomolybdic acid, ninhydrin solution, Gao Meng
Sour potassium solution or ceric sulfate solution heat together.
1H-NMR spectrum is on ten thousand Ruian-Mo Qiuli-VX400 (Varian Mercury-VX400) instrument,
The lower record of 400MHz operation.
Used in the present invention, abbreviation has this area conventional sense, such as：DCM represents dichloromethane, DMF
Represent DMF, PE represents petroleum ether, and EA represents ethyl acetate, and HOAc represents acetic acid,
MeOH represents methanol.
Embodiment 1：(9H- fluorenes -9- base) methyl ((S) -1- (((S) -1- ((4- (((tert-butyl group diformazan
Base silicyl) epoxide) methyl) phenyl) amino) -1- oxo -5- urea groups-amyl- 2- yl) amino) -3-
Methyl isophthalic acid-oxo butyl- 2- yl) carbamic preparation
Under nitrogen protection, by compound I (1.08kg, 2.18mol, 1.0eq) and compound IX-1 (517.6
G, 2.18mol, 1.0eq) it is added in ethyl acetate (20.0L), under room temperature, stirring half an hour is complete to raw material
Portion dissolves, then by ethyl chloroformate (236.6g, 2.18mol, 1.0eq) and triethylamine (220.6g, 2.18
Mol, 1.0eq) ethyl acetate (1.6L) solution be added in reaction system, Deca process temperature control
At -5～-15 DEG C.Completion of dropping, is slowly increased to room temperature and continues reaction up in liquid phase tracing display reaction system
Raw material I disappears, stopped reaction.After reaction stops, frequent pressure-off is molten, and remaining solid is with petroleum ether (1L × 3)
Washing, vacuum drying obtains white solid X-1 (1258.7g, yield：80%, purity：99.2%, de：
99.4%).
1H NMR(400MHz,DMSO-d6) δ 9.98 (s, 1H), 8.07 (d, J=7.2,1H), 7.83 (d, J=7.6,
2H),7.71-7.67(m,2H),7.53-7.51(m,2H),7.43-7.40(m,1H),7.37-7.33(m,2H),
7.28-7.25 (m, 2H), 7.18-7.16 (m, 2H), 6.01 (t, J=5.2,1H), 5.44-5.40 (m, 2H), 4.64 (s,
2H),4.44-4.43(m,1H),4.31-4.23(m,3H),3.96-3.92(m,1H),3.05-2.94(m,2H),
2.01-1.98(m,1H),1.75-1.55(m,2H),1.46-1.37(m,2H),0.88-0.85(m,15H),0.06(s,
6H).LC/MS:[M+H]+=716.
Embodiment 2：(S) -2- ((S) -2- amino -3- methybutane amide groups)-N- (4- (((tertiary fourth
Base dimetylsilyl) epoxide) methyl) phenyl) -5- urea groups pentanamide preparation
Under room temperature, compounds X -1 (3.44kg, 4.8mol, 1.0eq) is added to DMF (17.2
L, in), stirring half an hour all dissolves to raw material, adds diethylamine (700.8g, 9.6mol, 2.0eq),
Until raw material X-1 disappears in liquid phase tracing display reaction system, stopped reaction.After reaction stops, normal pressure precipitation
(spinning off the 3/4 of overall solution volume), then residue is added in ethyl acetate (5L), after stirring to clarify
To in system, Deca petroleum ether occurs to white opacity liquid, more anti-Deca ethyl acetate is to just molten clear, and room temperature opens
Mouth standing 16～48 hours, has solid to separate out, filters, and collects filter cake and is washed with petroleum ether (3L × 2),
Vacuum drying, obtains white solid XI-1 (2045.0g, yield：85%, purity：98.5%, de：98.7%).
1H-NMR(400MHz,DMSO-d6)δ10.08(s,1H),8.14-8.12(m,1H),7.58-7.55(m,
2H),7.24-7.22(m,2H),5.99(s,1H),5.43(s,2H),4.64(s,2H),4.49-4.47(m,1H),
3.02-2.92(m,3H),1.73-1.70(m,1H),1.57-1.59(m,4H),1.41-1.37(m,2H),
0.89-0.88 (m, 12H), 0.78 (d, J=6.8,3H), 0.06 (s, 6H) .LC/MS:[M+H]+=494.
Embodiment 3：6- (2,5- dioxo -2,5- dihydro -1H- pyrroles's -1- base)-N- ((S) -1- (((S)
- 1- ((4- (methylol) phenyl) amino) the amyl- 2- yl of -1- oxo -5- urea groups) amino) -3- methyl isophthalic acid -
Oxo butyl- 2- yl) caproamide preparation
Under room temperature by compounds X I-1 (269g, 0.55mol, 1.0eq) and compound V (168.1g, 0.55
Mol, 1.0eq) it is added to DMF (1L), under room temperature, stirring half an hour all dissolves to raw material,
Then heat to react 4～6 hours at 45～50 DEG C, obtain substituent reactant liquor, reactant liquor is cooled to -5～
0 DEG C of DMF (350mL) adding Methanaminium, N,N,N-trimethyl-, fluoride (50.7g, 0.55mol, 1.0eq)
In solution, completion of dropping, it is warmed to room temperature reaction until raw material disappears in liquid phase tracing display reaction system, stop
Only react.After reaction stops, adding water to separate out to no solid again toward in reactant liquor, filter, collect filter cake.
Filter cake is pulled an oar half an hour with water (400mL) and ethyl acetate (800mL), filters, and collects filter cake, very
Sky is dried to obtain off-white powder VI (292.7g, yield：92%, purity：99.0%, de：98.2%).
1H-NMR(400MHz,DMSO-d6) δ 9.87 (s, 1H), 8.03 (d, J=7.2,1H), 7.78 (d, J=8.8,
1H), 7.49 (d, J=8.8,2H), 7.17 (d, J=8.0,1H), 6.95 (s, 2H), 5.96 (s, 1H), 5.38 (s, 2H),
5.05 (t, J=5.6,1H), 4.37-4.33 (m, 3H), 4.13 (m, 1H), 3.40-3.21 (m, 2H), 2.95-2.89 (m,
2H),2.11-2.07(m,2H),1.92-1.90(m,1H),1.63-1.42(m,9H),1.14-1.12(m,2H),
0.80-0.75(m,6H).LC/MS:[M+H]+=573.
Embodiment 4：4- ((S) -2- ((S) -2- (6- (2,5- dioxo -2,5- dihydro -1H- pyrroles
- 1- base) hexanoyl amido) -3- methylbutyryl ammonia) -5- urea groups amyl group) benzyl (4- nitrobenzophenone) carbonic ester
Preparation
Under nitrogen protection, by compound VI (198.0g, 345.9mmol, 1.0eq) and compound VII (105.2
G, 345.9mmol, 1.0eq) it is added in DMF (990mL), stir under room temperature
Half an hour all dissolves to raw material, adds diisopropyl ethyl amine (44.7g, 345.9mmol, 1.0eq)
Carry out substitution reaction, the response time is 3～5 hours.After the completion of reaction, normal pressure precipitation (spins off overall solution
Long-pending 3/4), residue DCM：PE=1：1 (v/v) (792mL) pulls an oar, and making beating finishes, and filters,
Collect filter cake, then use HOAc：MeOH=1：1 (v/v) (990mL) dissolving filter cake, adds toward in filtrate
Entering water until no longer there being solid to separate out, filtering, collect filter cake and washed with water (500mL × 3), vacuum drying
Obtain white solid VIII (226.2g, yield：88%, purity：99.2%, de：99.3%, single miscellaneous<0.1%).
1H-NMR(400MHz,CDCl3) 8.23 (d, J=8.8,2H), 7.65 (d, J=8.8,2H), 7.42-7.39 (m,
4H), 6.66 (s, 2H), 5.26 (s, 2H), 4.59-4.55 (m, 1H), 4.20-4.16 (m, 1H), 3.48 (t, J=7.2,2H),
3.33-3.17 (m, 2H), 2.29-2.25 (t, J=7.2,2H), 2.01-1.89 (m, 2H), 1.74-1.31 (m, 9H),
0.95-0.90(m,6H).LC/MS:[M+H]+=738.
Embodiment 5：(9H- fluorenes -9- base) methyl ((S) -1- (((S) -1- ((4- (((tert-butyl group diformazan
Base silicyl) epoxide) methyl) phenyl) amino) -1- oxo -5- urea groups-amyl- 2- yl) amino) -3-
Methyl isophthalic acid-oxo butyl- 2- yl) carbamic preparation
Nitrogen protection under, by compound I (540g, 1.09mol, 1.0eq) and compound IX-1 (258.8g,
1.09mol, 1.0eq), it is added in DMF (10.0L), under room temperature, stirring half an hour is all molten to raw material
Solution, then by ethyl chloroformate (470.88g, 4.36mol, 4.0eq) and triethylamine (660.54g, 6.54mol,
DMF (0.8L) solution 6.0eq) is added in reaction system, and Deca process temperature controls at -5～-15 DEG C.
Completion of dropping, is slowly increased to room temperature and continues reaction until raw material I disappears in liquid phase tracing display reaction system, stop
Only react.Reaction adds the water of 4L to separate out to solid after stopping toward in reaction system, filters, collects filter cake,
With water (1L × 2), petroleum ether (1L × 3) washs, drying obtain off-white powder X-1 (550.7g,
Yield：70%, purity：99.2%, de：99.0%).
1H NMR(400MHz,DMSO-d6) δ 9.98 (s, 1H), 8.07 (d, J=7.2,1H), 7.83 (d, J=7.6,
2H),7.71-7.67(m,2H),7.53-7.51(m,2H),7.43-7.40(m,1H),7.37-7.33(m,2H),
7.28-7.25 (m, 2H), 7.18-7.16 (m, 2H), 6.01 (t, J=5.2,1H), 5.44-5.40 (m, 2H), 4.64 (s,
2H),4.44-4.43(m,1H),4.31-4.23(m,3H),3.96-3.92(m,1H),3.05-2.94(m,2H),
2.01-1.98(m,1H),1.75-1.55(m,2H),1.46-1.37(m,2H),0.88-0.85(m,15H),0.06(s,
6H).LC/MS:[M+H]+=716.
Embodiment 6：(S) -2- ((S) -2- amino -3- methybutane amide groups)-N- (4- (((tertiary fourth
Base dimetylsilyl) epoxide) methyl) phenyl) -5- urea groups pentanamide preparation
Under room temperature, compounds X -1 (344g, 0.48mol, 1.0eq) is added to DMF (6.9
L, in), stirring half an hour all dissolves to raw material, adds triethylamine (242.9g, 2.4mol, 5.0eq),
Until raw material X-1 disappears in liquid phase tracing display reaction system, stopped reaction.After reaction stops, normal pressure precipitation
(spinning off the 3/4 of overall solution volume), then residue is added in ethyl acetate (500mL), stirs to clear
In backward clearly system, Deca petroleum ether occurs to white opacity liquid, more anti-Deca ethyl acetate is to just molten clear, room
The uncovered standing of temperature 16～48 hours, has solid to separate out, filters, and collects filter cake with petroleum ether (300mL × 2)
Washing, vacuum drying, obtain white solid XI-1.(172.4g, yield：71%, purity：97.6%, de：
98.0%).
1H-NMR(400MHz,DMSO-d6)δ10.08(s,1H),8.14-8.12(m,1H),7.58-7.55(m,
2H),7.24-7.22(m,2H),5.99(s,1H),5.43(s,2H),4.64(s,2H),4.49-4.47(m,1H),
3.02-2.92(m,3H),1.73-1.70(m,1H),1.57-1.59(m,4H),1.41-1.37(m,2H),
0.89-0.88 (m, 12H), 0.78 (d, J=6.8,3H), 0.06 (s, 6H) .LC/MS:[M+H]+=494.
Embodiment 7：6- (2,5- dioxo -2,5- dihydro -1H- pyrroles's -1- base)-N- ((S) -1- (((S)
- 1- ((4- (methylol) phenyl) amino) the amyl- 2- yl of -1- oxo -5- urea groups) amino) -3- methyl isophthalic acid -
Oxo butyl- 2- yl) caproamide preparation
Under room temperature by compounds X I-1 (538g, 1.09mol, 1.0eq) and compound V (1680.18g, 5.45
Mol, 5.0eq) it is added in acetonitrile (10.7L), under room temperature, stirring half an hour all dissolves to raw material, then
It is warming up to and reacts 4～6 hours at 45～50 DEG C, obtain substituent reactant liquor, reactant liquor is cooled to -5～0 DEG C
Add hydrochloric acid (2M, 1.6L, 3.27mol, 3.0eq) completion of dropping, be warmed to room temperature reaction until liquid phase with
In track display reaction system, raw material disappears, stopped reaction.After reaction stops, reactant liquor is cooled to -5～0 DEG C,
Deca saturated sodium bicarbonate aqueous solution is to pH value 7～8.Completion of dropping, filters, and collects filter cake.Filter cake is used
Water (800mL) and ethyl acetate (1.6L) making beating half an hour, filter, collect filter cake, be vacuum dried
To off-white powder VI (466.1g, yield：74%, purity：99.1%, de：99.6%).
1H-NMR(400MHz,DMSO-d6) δ 9.87 (s, 1H), 8.03 (d, J=7.2,1H), 7.78 (d, J=8.8,
1H), 7.49 (d, J=8.8,2H), 7.17 (d, J=8.0,1H), 6.95 (s, 2H), 5.96 (s, 1H), 5.38 (s, 2H),
5.05 (t, J=5.6,1H), 4.37-4.33 (m, 3H), 4.13 (m, 1H), 3.21-3.40 (m, 2H), 2.95-2.89 (m,
2H),2.11-2.07(m,2H),1.92-1.90(m,1H),1.63-1.42(m,9H),1.14-1.12(m,2H),
0.80-0.75(m,6H).LC/MS:[M+H]+=573.
Embodiment 8：4- ((S) -2- ((S) -2- (6- (2,5- dioxo -2,5- dihydro -1H- pyrroles
- 1- base) hexanoyl amido) -3- methylbutyryl ammonia) -5- urea groups amyl group) benzyl (4- nitrobenzophenone) carbonic ester
Preparation
Under nitrogen protection, by compound VI (1.98Kg, 3.46mol, 1.0eq) and compound VII (1.05
Kg, 3.46mol, 1.0eq) it is added in DMF (39.6L), stirring half under room temperature
Hour all dissolves to raw material, adds diisopropyl ethyl amine (89.4g, 6.92mol, 2.0eq) and carries out
Substitution reaction, the response time is 3～5 hours.After the completion of reaction, normal pressure precipitation (spins off overall solution volume
3/4), residue is pulled an oar with DCM (8L), and making beating finishes, and filters, and collects filter cake, then uses HOAc：
MeOH=1：1 (v/v) (39.6L) dissolving filter cake, adds water until no longer there being solid to separate out toward in filtrate,
Filter, collect filter cake and washed with water (5L × 3), vacuum drying obtains white solid VIII, and (2.14Kg receives
Rate：83%, purity：99.2%, de：99.4%, single miscellaneous<0.1%).
1H-NMR(400MHz,CDCl3) 8.23 (d, J=8.8,2H), 7.65 (d, J=8.8,2H), 7.42-7.39 (m,
4H), 6.66 (s, 2H), 5.26 (s, 2H), 4.59-4.55 (m, 1H), 4.20-4.16 (m, 1H), 3.48 (t, J=7.2,2H),
3.33-3.17 (m, 2H), 2.29-2.25 (t, J=7.2,2H), 2.01-1.89 (m, 2H), 1.74-1.31 (m, 9H),
0.95-0.90(m,6H).LC/MS:[M+H]+=738.
Embodiment 9：(9H- fluorenes -9- base) methyl ((S) -1- (((S) -1- ((4- ((methoxyl group methoxy
Base) methyl) phenyl) amino) the amyl- 2- yl of -1- oxo -5- urea groups) amino) -3- methyl isophthalic acid-oxo butyl- 2-
Base) carbamic preparation
Under nitrogen protection, by compound I (2.7kg, 5.44mol, 1.0eq) and compound IX-2 (3638.4
G, 21.76mol, 4.0eq) it is added in ethyl acetate (13L), under room temperature, stirring half an hour is whole to raw material
Dissolving.Again by DMTMM (6413.5g, 21.76mol, 4.0eq) and potassium carbonate (751.9g, 5.44mol,
Ethyl acetate (0.5L) solution 1.0eq) is added in reactant liquor, and Deca process temperature controls -5～
-15℃.Completion of dropping, is slowly increased to room temperature and continues to react up to raw material I in liquid phase tracing display reaction system
Disappear, stopped reaction.Reaction is washed with petroleum ether (3L × 3) through normal pressure precipitation, remaining solid after stopping,
Vacuum drying obtains off-white powder X-1 (2880.9g, yield：81.6%, purity：99.5%, de：99.2%).
1H NMR (400MHz, DMSO-d6) δ 9.98 (s, 1H), 8.07 (d, J=7.2,1H), 7.83 (d, J=7.6,
2H),7.71-7.67(m,2H),7.53-7.51(m,2H),7.43-7.40(m,1H),7.37-7.33(m,2H),
7.28-7.25 (m, 2H), 7.18-7.16 (m, 2H), 6.01 (t, J=5.2,1H), 5.44-5.40 (m, 2H), 4.64 (s,
2H),4.44-4.43(m,3H),4.31-4.23(m,3H),3.96-3.92(m,1H),3.31(s,3H),
3.05-2.94(m,2H),2.01-1.98(m,1H),1.75-1.55(m,2H),1.46-1.37(m,2H),0.85(d,
J=6.8,6H) .LC/MS:[M+H]+=646.
Embodiment 10：(S) -2- ((S) -2- amino -3- methylbutyrylamino)-N- (4- ((methoxyl group
Methoxyl group) methyl) phenyl) and -5- urea groups pentanamide preparation
Under room temperature, compounds X -2 (310.0g, 0.48mol, 1.0eq) is added in acetonitrile (1.6L),
Stirring half an hour all dissolves to raw material, adds diethylamine (70.1g, 0.96mol, 2.0eq), until
In liquid phase tracing display reaction system, raw material X-2 disappears, stopped reaction.After reaction stops, (the rotation of normal pressure precipitation
Fall the 3/4 of overall solution volume), then residue is added in ethyl acetate (500mL), after stirring to clarify
To in system, Deca petroleum ether occurs to white opacity liquid, more anti-Deca ethyl acetate is to just molten clear, and room temperature opens
Mouth standing 16～48 hours, has solid to separate out, filters, and collects filter cake petroleum ether (300mL × 2) and washes
Wash, vacuum drying, obtain white solid XI-2 (173.9g, yield：84%, purity：98.2%, de：
98.1%).
1H-NMR(400MHz,DMSO-d6)δ10.08(s,1H),8.14-8.12(m,1H),7.58-7.55(m,
2H),7.24-7.22(m,2H),5.99(s,1H),5.23(s,2H),4.64(s,2H),4.49-4.47(m,3H),
3.31(s,3H),3.02-2.92(m,3H),1.73-1.70(m,1H),1.57-1.59(m,4H),1.41-1.37(m,
2H), 0.88 (d, J=6.8,3H), 0.78 (d, J=6.8,3H) .LC/MS:[M+H]+=424.
Embodiment 11：6- (2,5- dioxo -2,5- dihydro -1H- pyrroles's -1- base)-N- ((S) -1-
(((S) -1- ((4- (methylol) phenyl) amino) the amyl- 2- yl of -1- oxo -5- urea groups) amino) -3-
Methyl isophthalic acid-oxo butyl- 2- yl) caproamide preparation
Under room temperature by compounds X I-2 (269.0g, 635.2mmol, 1.0eq) and compound V (195.8g,
635.2mmol, 1.0eq) it is dissolved in DMF (5.38L), stir half an hour extremely under room temperature
Raw material all dissolves, and then heats to react 4～6 hours at 45～50 DEG C, obtains substituent reactant liquor, will
Reactant liquor be cooled to -5～0 DEG C add trifluoroacetic acid (217.2g, 1905.6mmol, 3.0eq), completion of dropping,
It is warmed to room temperature reaction until raw material disappears in liquid phase tracing display reaction system, stopped reaction.After reaction stops,
Reactant liquor is cooled to -5～0 DEG C, and Deca saturated sodium bicarbonate aqueous solution is to pH value 7～8.Completion of dropping, mistake
Filter, collects filter cake.Filter cake is pulled an oar half an hour with water (400mL) and ethyl acetate (800mL), filters,
Collect filter cake, vacuum drying obtains off-white powder VI (310.7g, yield：85%, purity：99.5%,
de：99.3%).
1H-NMR(400MHz,DMSO-d6) δ 9.87 (s, 1H), 8.03 (d, J=7.2,1H), 7.78 (d, J=8.8,
1H), 7.49 (d, J=8.8,2H), 7.17 (d, J=8.0,1H), 6.95 (s, 2H), 5.96 (s, 1H), 5.38 (s, 2H),
5.05 (t, J=5.6,1H), 4.37-4.33 (m, 3H), 4.13 (m, 1H), 3.40-3.21 (m, 2H), 2.95-2.89 (m,
2H),2.11-2.07(m,2H),1.92-1.90(m,1H),1.63-1.42(m,9H),1.14-1.12(m,2H),
0.80-0.75(m,6H).LC/MS:[M+H]+=573.
Embodiment 12：4- ((S) -2- ((S) -2- (6- (2,5- dioxo -2,5- dihydro -1H- pyrrole
Cough up -1- base) hexanoyl amido) -3- methylbutyryl ammonia) -5- urea groups amyl group) benzyl (4- nitrobenzophenone) carbonic acid
The preparation of ester
Nitrogen protection under, by compound VI (5g, 8.73mmol, 1.0eq) and compound VII (5.3g,
17.46mmol, 2.0eq) it is added in DMF (100mL), under room temperature, stirring half is little
All dissolve up to raw material, add triethylamine (1.77g, 17.46mmol, 2.0eq) and carry out substitution reaction,
Response time is 3～5 hours.After the completion of reaction, normal pressure precipitation (spins off the 3/4 of overall solution volume), remaining
Thing DCM：PE=1：1 (v/v) (25mL) pulls an oar, and making beating finishes, and filters, and collects filter cake, then uses
HOAc：MeOH=4：1 (v/v) (100mL) dissolving filter cake, adds water until no longer having solid toward in filtrate
Body separates out, and filters, and collects filter cake and is washed with water (15mL × 3), vacuum drying obtains white solid VIII
(4.85g, yield：75%, purity：99.7%, de：99.6%, single miscellaneous<0.1%).
1H-NMR(400MHz,CDCl3) 8.23 (d, J=8.8,2H), 7.65 (d, J=8.8,2H), 7.42-7.39 (m,
4H), 6.66 (s, 2H), 5.26 (s, 2H), 4.59-4.55 (m, 1H), 4.20-4.16 (m, 1H), 3.48 (t, J=7.2,2H),
3.33-3.17 (m, 2H), 2.29-2.25 (t, J=7.2,2H), 2.01-1.89 (m, 2H), 1.74-1.31 (m, 9H),
0.95-0.90(m,6H).LC/MS:[M+H]+=738.
The all documents referring in the present invention are all incorporated as reference in this application, just as each document
It is individually recited as with reference to like that.In addition, it is to be understood that after the above-mentioned teachings having read the present invention,
Those skilled in the art can make various changes or modifications to the present invention, and these equivalent form of values equally fall within this Shen
Please appended claims limited range.
Claims (10)
1. a kind of industrialized preparing process for synthetic antibody coupling drug Adcetris connexon it is characterised in that
Comprise the steps of：
Step 5：Under inert gas shielding, compound I is in the presence of carboxylic acid activating reagents and alkali and compound
IX reaction obtains compounds X；
Step 6：In the basic conditions, polar non-solute obtains chemical combination by deprotection method to compounds X
Thing XI；
Step 7：Compounds X I and compound V passes through substitution reaction, then sloughs R1Protection obtains compound VI；
Step 8：Under inert gas shielding, compound VI and compound VII in polar non-solute, alkali
Under the conditions of property, carry out substitution reaction, obtain compound VIII；
Wherein, R1Can be silylation protection group, Alkoxyalkyl protecting groups, alkyl protecting groups.
2. preparation method as claimed in claim 1 is it is characterised in that described R1For TMS, TBS, MOM,
SEM.
3. preparation method as claimed in claim 1 or 2 is it is characterised in that in step 5, comprise the steps of：
Under nitrogen protection, compound I and compound IX is added in organic solvent, stirs complete to raw material under room temperature
Portion dissolves, and adds carboxylic acid activating reagents and alkali, Deca process temperature controls at -5～15 DEG C.Drip
Finish, be slowly increased to room temperature and continue condensation reaction until raw material I disappears in liquid phase tracing display reaction system, stop
Only react.Through normal pressure precipitation after reaction stopping, washing, vacuum drying obtains compounds X.
4. preparation method as claimed in claim 1 or 2 is it is characterised in that in step 5, described carboxylic acid activated examination
Agent is selected from ethyl chloroformate, isobutyl chlorocarbonate, carbonyl dimidazoles, 4- (4,6- dimethoxy-triazine -2-
Base) -4- methyl morpholine hydrochloride, 2- chlorine-4,6-dimethoxy-1,3,5-triazine, described carboxylic acid is lived
Changing reagent and the molar feed ratio of compound I is 1～4：1；Described alkali is potassium acetate, pyridine, three second
Amine, diisopropyl ethyl amine, potassium phosphate, potassium carbonate, sodium hydroxide, cesium fluoride, cesium carbonate, described
Alkali and compound I molar feed ratio be 1～6：1；Described organic solvent is oxolane, diformazan
Base sulfoxide, DMF, ethyl acetate, one of dichloromethane, or above-mentioned solvent
Combination in any, the volume mass of described organic solvent and compound I is than for 5～20mL/g；Described
The molar feed ratio of compound IX and compound I is 1～4：1.
5. preparation method as claimed in claim 1 or 2 is it is characterised in that in step 6, comprise the steps of：
Under room temperature, compounds X is added in polar non-solute, stirs and all dissolve to raw material, add
Alkali, carries out deprotection, until raw material X disappears in liquid phase tracing display reaction system, stopped reaction, instead
After should stopping, precipitation, recrystallization, washing, vacuum drying obtains compounds X I.
6. preparation method as claimed in claim 1 or 2 is it is characterised in that in step 6, described alkali is acetic acid
Potassium, pyridine, diethylamine, diisopropyl ethyl amine, the molar feed ratio of described alkali and compounds X is
2～5：1；Described polar non-solute is acetonitrile, acetone, DMF or diformazan
Base sulfoxide, its volume mass with compounds X is than for 5～20mL/g.
7. preparation method as claimed in claim 1 or 2 is it is characterised in that in step 7, comprise the steps of：
Under room temperature, compounds X I and compound V is added in polar non-solute, stirs complete to raw material under greenhouse
Portion dissolves, and then heats to react 4～6 hours at 45～50 DEG C, obtains substituent reactant liquor, and will
Substituent reactant liquor be cooled to -5～0 DEG C addition deprotecting regent, completion of dropping, be warmed to room temperature reaction until
In liquid phase tracing display reaction system, raw material disappears, stopped reaction.After reaction stops, reactant liquor is cooled down
To -5～0 DEG C of tune pH value 7～8, filter, collect filter cake, making beating, vacuum drying obtains compound VI.
8. preparation method as claimed in claim 1 or 2 is it is characterised in that in step 7, described compound V
Molar feed ratio with compounds X I is 1～5：1；Described polar non-solute is acetonitrile, acetone,
DMF or dimethyl sulfoxide, its volume mass with compounds X I is than for 5～20
mL/g；The deprotecting regent that described deprotection reaction uses can be tetrabutyl ammonium fluoride, tetramethyl fluorine
Change ammonium, cesium fluoride, Fluohydric acid. pyridine, Fluohydric acid. triethylamine, p-methyl benzenesulfonic acid, trifluoroacetic acid, hydrochloric acid,
Sulphuric acid, nitric acid, the molar feed ratio of described deprotecting regent and compounds X I is 1～3：1.
9. preparation method as claimed in claim 1 or 2 is it is characterised in that in step 8, comprise the steps of：
Under nitrogen protection, compound VI and compound VII is added in polar non-solute, stirs under room temperature
All dissolve to raw material, add alkali and carry out substitution reaction, the response time is 3～5 hours, and reaction completes
Afterwards, frequent pressure-off is molten, and organic solvent is pulled an oar and recrystallization, and lyophilization obtains compound VIII.
10. preparation method as claimed in claim 1 or 2 is it is characterised in that in step 8, described compound VII
Molar feed ratio with compound VI is 1～2：1；Described polar non-solute is acetonitrile, acetone,
DMF or dimethyl sulfoxide, its volume mass with compound VI is than for 5～20
mL/g；Described alkali is potassium acetate, pyridine, diethylamine, triethylamine, and diisopropyl ethyl amine is described
Alkali and compound VI molar feed ratio be 1～2：1；Described making beating use solvent be, tetrahydrochysene furan
Mutter, acetone, dichloromethane, ethyl acetate, methanol, toluene, the organic solvent such as petroleum ether or above-mentioned molten
The combination in any of agent, the organic solvent that described making beating uses and the volume mass of compound VI than for 4～
5mL/g；The solvent that described recrystallization uses is dimethyl sulfoxide, oxolane, acetone, dichloromethane,
Acetic acid, trifluoroacetic acid, ethyl acetate, methanol, toluene, the organic solvent such as petroleum ether or above-mentioned solvent
Combination in any, the organic solvent that described recrystallization uses and the volume mass of compound VI than for 5～
20mL/g.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010493149.3A CN111533778B (en) | 2015-07-28 | 2015-07-28 | Industrial production method of antibody-coupled drug connector |
| CN201510451473.8A CN106380508A (en) | 2015-07-28 | 2015-07-28 | Industrialized production method for antibody coupling medicine connexon |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510451473.8A CN106380508A (en) | 2015-07-28 | 2015-07-28 | Industrialized production method for antibody coupling medicine connexon |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010493149.3A Division CN111533778B (en) | 2015-07-28 | 2015-07-28 | Industrial production method of antibody-coupled drug connector |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106380508A true CN106380508A (en) | 2017-02-08 |
Family
ID=57915906
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510451473.8A Pending CN106380508A (en) | 2015-07-28 | 2015-07-28 | Industrialized production method for antibody coupling medicine connexon |
| CN202010493149.3A Active CN111533778B (en) | 2015-07-28 | 2015-07-28 | Industrial production method of antibody-coupled drug connector |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010493149.3A Active CN111533778B (en) | 2015-07-28 | 2015-07-28 | Industrial production method of antibody-coupled drug connector |
Country Status (1)
| Country | Link |
|---|---|
| CN (2) | CN106380508A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107805274A (en) * | 2017-11-08 | 2018-03-16 | 上海皓元生物医药科技有限公司 | A kind of industrialized preparing process of antibody coupling medicine connexon intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050238649A1 (en) * | 2003-11-06 | 2005-10-27 | Seattle Genetics, Inc. | Monomethylvaline compounds capable of conjugation to ligands |
| WO2015023355A1 (en) * | 2013-08-12 | 2015-02-19 | Genentech, Inc. | 1-(chloromethyl)-2,3-dihydro-1h-benzo[e]indole dimer antibody-drug conjugate compounds, and methods of use and treatment |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9289512B2 (en) * | 2011-06-21 | 2016-03-22 | Immunogen, Inc. | Maytansinoid derivatives with peptide linker and conjugates thereof |
| BR112014028222A2 (en) * | 2012-05-15 | 2017-06-27 | Seattle Genetics Inc | self-stabilizing binding conjugates. |
-
2015
- 2015-07-28 CN CN201510451473.8A patent/CN106380508A/en active Pending
- 2015-07-28 CN CN202010493149.3A patent/CN111533778B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050238649A1 (en) * | 2003-11-06 | 2005-10-27 | Seattle Genetics, Inc. | Monomethylvaline compounds capable of conjugation to ligands |
| WO2015023355A1 (en) * | 2013-08-12 | 2015-02-19 | Genentech, Inc. | 1-(chloromethyl)-2,3-dihydro-1h-benzo[e]indole dimer antibody-drug conjugate compounds, and methods of use and treatment |
Non-Patent Citations (1)
| Title |
|---|
| 陈金龙等: "《精细有机合成原理与工艺》", 30 April 1992, 中国轻工业出版社 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107805274A (en) * | 2017-11-08 | 2018-03-16 | 上海皓元生物医药科技有限公司 | A kind of industrialized preparing process of antibody coupling medicine connexon intermediate |
| CN107805274B (en) * | 2017-11-08 | 2021-02-09 | 上海皓元生物医药科技有限公司 | Industrial production method of antibody-conjugated drug linker intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111533778B (en) | 2023-04-25 |
| CN111533778A (en) | 2020-08-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2343679T3 (en) | COPOLYMERS OF BLOCKS WITH LOW CONTENT OF IMPURITIES; POLYMER VEHICLE; PHARMACEUTICAL PREPARATIONS IN POLYMER FORM AND PROCEDURE FOR THE PREPARATION OF THE SAME | |
| ES2635117T3 (en) | Method for manufacturing a block copolymer | |
| WO2002026867A2 (en) | Dendrimeric support or carrier macromolecule | |
| WO2007140282A1 (en) | Peg linker compounds and biologically active conjugates thereof | |
| CN107915770A (en) | A kind of antibody drug conjugates intermediate and preparation method thereof | |
| ES2704951T3 (en) | Radioactive label precursor compound and method for producing a radioactive fluorinated label compound using the parent compound | |
| CA2334598A1 (en) | Vitamin b12 derivatives and methods for their preparation | |
| KR102522413B1 (en) | Hetero-type monodisperse polyethylene glycol, intermediates for producing hetero-type monodisperse polyethylene glycol, preparation methods thereof, and hetero-type monodisperse polyethylene glycol conjugates | |
| US20230148277A1 (en) | Disulfide bond containing compounds and uses thereof | |
| CN106146325B (en) | A kind of Y type multicondensed ethylene glycol derivative and preparation method thereof | |
| CN109384715A (en) | The preparation method of the micromolecular inhibitor of prostate-specific membrane antigen | |
| CN108863885A (en) | A kind of Ezetimibe and preparation method thereof of mono methoxy polyethylene glycol modification | |
| CN109928908B (en) | Preparation method and intermediate of drug-linker MC-MMAF for antibody drug conjugate | |
| CN106380508A (en) | Industrialized production method for antibody coupling medicine connexon | |
| US8765934B2 (en) | Methods for conjugating nucleic acids with small molecules | |
| US8551447B2 (en) | Bifunctional compound with monosaccharide and N2S2 ligand, and preparation and use thereof | |
| CN110294764A (en) | A kind of podophyllotoxin derivative and preparation method thereof of azo key connection | |
| CN109758587A (en) | A kind of multivalent ligand drug conjugates with weary oxygen targeting | |
| CN103384534B (en) | For the side chain connected body of pharmaceutical grade protein conjugate | |
| CN103232475A (en) | Aspoxicillin trihydrate preparation method | |
| CN113816869A (en) | Preparation method of lacosamide process impurities | |
| CN107216360B (en) | A method of preparing rope Citropten | |
| CN107501378B (en) | A kind of glycocholic acid polyethyleneglycol derivative and preparation method thereof | |
| CN115028552B (en) | Azidation reagent and preparation method and application thereof | |
| US20190262464A1 (en) | Antibody-drug-conjugates comprising novel anthracycline-derivatives for cancer treatment |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| CB02 | Change of applicant information |
Address after: 201203 Shanghai Zhangjiang High Tech Park of Pudong New Area Cailun Road Lane 720 No. 2 Room 601 Applicant after: MEDCHEMEXPRESS CHINA CO.,LTD. Applicant after: SHANGHAI HAOYUAN CHEMEXPRESS CO.,LTD. Address before: 201203 Shanghai Zhangjiang High Tech Park of Pudong New Area Cailun Road Lane 720 No. 2 Room 601 Applicant before: MEDCHEMEXPRESS CHINA CO.,LTD. Applicant before: SHANGHAI HAOYUAN CHEMEXPRESS Co.,Ltd. |
|
| COR | Change of bibliographic data | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information | ||
| CB02 | Change of applicant information |
Address after: 201203 Lane 3, 1999, Zhangheng Road, Pudong New Area, Shanghai Applicant after: MEDCHEMEXPRESS CHINA CO.,LTD. Applicant after: SHANGHAI HAOYUAN CHEMEXPRESS CO.,LTD. Address before: 201203 Room 601, Lane 720, Cailun Road, Zhangjiang High-tech Park, Pudong New Area, Shanghai Applicant before: MEDCHEMEXPRESS CHINA CO.,LTD. Applicant before: SHANGHAI HAOYUAN CHEMEXPRESS CO.,LTD. |
|
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20170208 |