JP2022502463A - 官能化シクロオクテンを調製するためのプロセス - Google Patents
官能化シクロオクテンを調製するためのプロセス Download PDFInfo
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- JP2022502463A JP2022502463A JP2021519581A JP2021519581A JP2022502463A JP 2022502463 A JP2022502463 A JP 2022502463A JP 2021519581 A JP2021519581 A JP 2021519581A JP 2021519581 A JP2021519581 A JP 2021519581A JP 2022502463 A JP2022502463 A JP 2022502463A
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- formula
- compound
- salt
- alkyl
- hydrogen
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 30
- 239000004913 cyclooctene Substances 0.000 title abstract description 6
- URYYVOIYTNXXBN-UPHRSURJSA-N cyclooctene Chemical compound C1CCC\C=C/CC1 URYYVOIYTNXXBN-UPHRSURJSA-N 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 205
- 239000000203 mixture Substances 0.000 claims description 167
- 150000003839 salts Chemical class 0.000 claims description 144
- 238000000034 method Methods 0.000 claims description 129
- 125000000217 alkyl group Chemical group 0.000 claims description 114
- 230000008569 process Effects 0.000 claims description 108
- 229910052739 hydrogen Inorganic materials 0.000 claims description 64
- 239000001257 hydrogen Substances 0.000 claims description 64
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 63
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 58
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 44
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 43
- 239000007787 solid Substances 0.000 claims description 42
- 150000001413 amino acids Chemical group 0.000 claims description 41
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 37
- 229910052757 nitrogen Inorganic materials 0.000 claims description 36
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical group O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 31
- KFZMGEQAYNKOFK-UHFFFAOYSA-N isopropyl alcohol Natural products CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 30
- 239000003960 organic solvent Substances 0.000 claims description 28
- 125000003545 alkoxy group Chemical group 0.000 claims description 24
- 125000000623 heterocyclic group Chemical group 0.000 claims description 23
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 20
- 229960004679 doxorubicin Drugs 0.000 claims description 19
- 235000001014 amino acid Nutrition 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 15
- 238000001816 cooling Methods 0.000 claims description 13
- 238000001914 filtration Methods 0.000 claims description 12
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 10
- 230000003301 hydrolyzing effect Effects 0.000 claims description 9
- GYTMUNSNMBRSEW-UHFFFAOYSA-N hydrogen carbonate;1h-imidazol-1-ium Chemical compound OC(O)=O.C1=CNC=N1 GYTMUNSNMBRSEW-UHFFFAOYSA-N 0.000 claims description 8
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical group C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 claims description 6
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 claims description 6
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical group O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 230000003115 biocidal effect Effects 0.000 claims description 5
- SIOVKLKJSOKLIF-HJWRWDBZSA-N trimethylsilyl (1z)-n-trimethylsilylethanimidate Chemical compound C[Si](C)(C)OC(/C)=N\[Si](C)(C)C SIOVKLKJSOKLIF-HJWRWDBZSA-N 0.000 claims description 5
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 claims description 5
- HXKKHQJGJAFBHI-GSVOUGTGSA-N (2R)-1-aminopropan-2-ol Chemical group C[C@@H](O)CN HXKKHQJGJAFBHI-GSVOUGTGSA-N 0.000 claims description 4
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 claims description 4
- 229960000975 daunorubicin Drugs 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 108010059993 Vancomycin Proteins 0.000 claims description 3
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 claims description 3
- 229940045799 anthracyclines and related substance Drugs 0.000 claims description 3
- 108010044540 auristatin Proteins 0.000 claims description 3
- PFYXSUNOLOJMDX-UHFFFAOYSA-N bis(2,5-dioxopyrrolidin-1-yl) carbonate Chemical compound O=C1CCC(=O)N1OC(=O)ON1C(=O)CCC1=O PFYXSUNOLOJMDX-UHFFFAOYSA-N 0.000 claims description 3
- 230000000593 degrading effect Effects 0.000 claims description 3
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims description 3
- 238000002955 isolation Methods 0.000 claims description 3
- 229960003165 vancomycin Drugs 0.000 claims description 3
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 claims description 3
- IJXJGQCXFSSHNL-MRVPVSSYSA-N (2s)-2-amino-2-phenylethanol Chemical compound OC[C@@H](N)C1=CC=CC=C1 IJXJGQCXFSSHNL-MRVPVSSYSA-N 0.000 claims description 2
- STVVMTBJNDTZBF-VIFPVBQESA-N L-phenylalaninol Chemical compound OC[C@@H](N)CC1=CC=CC=C1 STVVMTBJNDTZBF-VIFPVBQESA-N 0.000 claims description 2
- 108010028921 Lipopeptides Proteins 0.000 claims description 2
- JQIVECLQPHOSDY-QGZVFWFLSA-N [(2s)-1,2-diphenylpyrrolidin-2-yl]methanol Chemical compound C([C@@]1(CO)C=2C=CC=CC=2)CCN1C1=CC=CC=C1 JQIVECLQPHOSDY-QGZVFWFLSA-N 0.000 claims description 2
- DOAKLVKFURWEDJ-QCMAZARJSA-N daptomycin Chemical group C([C@H]1C(=O)O[C@H](C)[C@@H](C(NCC(=O)N[C@@H](CCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@H](CO)C(=O)N[C@H](C(=O)N1)[C@H](C)CC(O)=O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CCCCCCCCC)C(=O)C1=CC=CC=C1N DOAKLVKFURWEDJ-QCMAZARJSA-N 0.000 claims description 2
- SWXVUIWOUIDPGS-UHFFFAOYSA-N diacetone alcohol Natural products CC(=O)CC(C)(C)O SWXVUIWOUIDPGS-UHFFFAOYSA-N 0.000 claims description 2
- 238000000227 grinding Methods 0.000 claims description 2
- 238000006317 isomerization reaction Methods 0.000 claims description 2
- 125000005270 trialkylamine group Chemical group 0.000 claims description 2
- 239000003910 polypeptide antibiotic agent Substances 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 6
- -1 n-octyl Chemical group 0.000 description 66
- 239000002585 base Substances 0.000 description 59
- 239000000243 solution Substances 0.000 description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- 239000000047 product Substances 0.000 description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 25
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 21
- 125000004432 carbon atom Chemical group C* 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 18
- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 description 18
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 17
- 229960002110 vincristine sulfate Drugs 0.000 description 17
- 125000003118 aryl group Chemical group 0.000 description 16
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- 238000001953 recrystallisation Methods 0.000 description 16
- 229940024606 amino acid Drugs 0.000 description 15
- URYYVOIYTNXXBN-OWOJBTEDSA-N trans-cyclooctene Chemical class C1CCC\C=C\CC1 URYYVOIYTNXXBN-OWOJBTEDSA-N 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 13
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 13
- 239000004471 Glycine Substances 0.000 description 12
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
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- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 11
- 125000005842 heteroatom Chemical group 0.000 description 11
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- 239000011734 sodium Substances 0.000 description 11
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- 239000000725 suspension Substances 0.000 description 11
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- RGLRXNKKBLIBQS-XNHQSDQCSA-N leuprolide acetate Chemical compound CC(O)=O.CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 RGLRXNKKBLIBQS-XNHQSDQCSA-N 0.000 description 10
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 229910052717 sulfur Inorganic materials 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 125000002619 bicyclic group Chemical group 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
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- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 7
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- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 7
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- 125000004429 atom Chemical group 0.000 description 6
- SIOVKLKJSOKLIF-UHFFFAOYSA-N bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)OC(C)=N[Si](C)(C)C SIOVKLKJSOKLIF-UHFFFAOYSA-N 0.000 description 6
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- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 229940124597 therapeutic agent Drugs 0.000 description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- C07—ORGANIC CHEMISTRY
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
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- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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Abstract
Description
本出願は、米国特許法第119条(e)の下で、2018年10月10日に提出された米国仮特許出願第62/744,041号に対する利益を主張するものであり、その全体は参照により本明細書に組み込まれる。
R1は、−OR4、任意選択的に置換されたヘテロシクリル、およびアミノ酸部分からなる群から選択され、
nは、0、1、2、3または4であり、
各R2は、独立して、C1−4アルキル、C1−4ハロアルキル、およびC1−4アルコキシであり、
Dはペイロード部分であり、
R4は水素またはC1−4アルキルである)またはその塩を調製するプロセスであって、
式IIの化合物を、
R1は、−OR4、任意選択的に置換されたヘテロシクリル、およびアミノ酸部分からなる群から選択され、
nは、0、1、2、3または4であり、
各R2は、独立して、C1−4アルキル、C1−4ハロアルキル、およびC1−4アルコキシであり、
R4は水素またはC1−4アルキルである)またはその塩を調製するプロセスであって、
式IVの化合物を、
R1は、−OR4、任意選択的に置換されたヘテロシクリル、およびアミノ酸部分からなる群から選択され、
nは、0、1、2、3または4であり、
各R2は、独立して、C1−4アルキル、C1−4ハロアルキル、およびC1−4アルコキシであり、
Dはペイロード部分であり、
R4は水素またはC1−4アルキルである)またはその塩を調製するプロセスであって、
式Xの化合物
nは、0、1、2、3、または4であり、
各R2は、独立して、水素またはC1−4アルキルである)またはその塩を含む組成物を調製するプロセスであって、
1当量の式Vの化合物
nは、0、1、2、3、または4であり、
各R2は、独立して、C1−4アルキル、C1−4ハロアルキル、およびC1−4アルコキシである)またはその塩の1つ以上の立体異性体を含む組成物を分解するためのプロセスであって、
(a)式VIの1つ以上の立体異性体を含む組成物をキラル塩基と接触させて、式VIの化合物のキラル塩を提供するステップと、
(b)ステップ(a)の組成物を冷却するステップと、
(c)式VIの化合物のキラル塩を単離するステップと、
(d)式VIの化合物のキラル塩を加水分解して、式VIの化合物またはその塩を含む鏡像異性的に濃縮された組成物を提供するステップと、を含む、プロセスも提供される。
nは、0、1、2、3または4であり、
各R2は、独立して、C1−4アルキル、C1−4ハロアルキル、およびC1−4アルコキシであり、
R4は、独立して、水素またはC1−4アルキルである)またはその塩を含む鏡像異性的に濃縮された組成物を調製するためのプロセスであって、
式VIの化合物
R5は、水素またはC1−4アルキルである)またはその塩の1つ以上の立体異性体を含む組成物を分解するためのプロセスであって、
(a)式VIIAの1つ以上の立体異性体を含む組成物をキラル塩基と接触させて、式VIIAの化合物のキラル塩を提供するステップと、
(b)ステップ(a)の組成物を冷却するステップと、
(c)式VIIAの化合物のキラル塩を単離するステップと、
(d)式VIIAの化合物のキラル塩を加水分解して、式VIIAの化合物またはその塩を含む鏡像異性的に濃縮された組成物を提供するステップと、を含む、プロセスも提供される。
R4は水素またはC1−4アルキルであり、
R5は水素またはC1−4アルキルである)またはその塩を含む鏡像異性的に濃縮された組成物を調製するためのプロセスであって、
式VIIBの化合物
別段の定義がない限り、本明細書で使用される全ての技術用語および科学用語は、当業者によって一般に理解されるのと同じ意味を有する。矛盾がある場合、定義を含む本明細書が支配する。本明細書に記載されているものと同様または同等の方法および材料を本発明の実施または試験に使用することができるが、好ましい方法および材料を以下に記載する。本明細書で言及される全ての刊行物、特許出願、特許および他の参考文献は、それらの全体が参照により組み込まれる。本明細書に開示される材料、方法、および実施例は、例示のみであり、限定することを意図するものではない。
本明細書に記載のプロセスは、非置換シクロオクテンに連結されたペイロードと比較して改善された水溶性を有する官能化ペイロードを提供する。官能化ペイロードは、生体直交結合またはクリック反応における試薬として使用することができ、化学、化学生物学、分子診断学、および医学の分野において様々な用途で使用されており、分子、細胞、粒子、および表面の選択的操作、ならびにインビトロおよびインビボでの生体分子のタグ付けおよび追跡を容易にするために使用することができる。本明細書に記載のプロセスは、好適な反応条件と、必要に応じて、任意選択的に1つ以上の保護基を使用して実施される。
R1は、−OR4、任意選択的に置換されたヘテロシクリル、およびアミノ酸部分からなる群から選択され、
nは、0、1、2、3または4であり、
各R2は、独立して、C1−4アルキル、C1−4ハロアルキル、およびC1−4アルコキシであり、
Dはペイロード部分であり、
R4は水素またはC1−4アルキルである)またはその塩を調製するためのプロセスであって、
式IIの化合物を、
R1はアミノ酸部分であり、
nは、0、1、2、3または4であり、
各R2は、独立して、C1−4アルキル、C1−4ハロアルキル、およびC1−4アルコキシであり、
Dはペイロード部分である)またはその塩を調製するためのプロセスであって、
式IIの化合物を、
R1は、G1、OH、−NR1c−C1−4アルキレン−G1、−NR1c−C1−4アルキレン−N(R1d)2、−N(R1c)CHR1eCO2H、−N(R1c)−C1−6アルキレン−CO2H、−N(R1f)−C2−4アルキレン−(N(C1−4アルキレン−CO2H)−C2−4アルキレン)m−N(C1−4アルキレン−CO2H)2、−N(R1c)CHR1eC(O)OC1−6アルキル、−N(R1c)−C1−6アルキレン−C(O)OC1−6アルキル、および−N(R1f)−C2−4アルキレン−(N(C1−4アルキレン−C(O)OC1−6アルキル)−C2−4アルキレン)m−N(C1−4アルキレン−C(O)OC1−6アルキル)2からなる群から選択され、
R1cおよびR1dは、各出現において、独立して、水素またはC1−4アルキルであり、
R1eは、−C1−4アルキレン−CO2H、−C1−4アルキレン−CONH2、または−C1−4アルキレン−OHであり、
R1fは、水素、C1−6アルキル、またはC1−4アルキレン−CO2Hであり、
G1は、任意選択的に置換されたヘテロシクリルであり、
各R2は、独立して、C1−4アルキル、C1−4ハロアルキル、およびC1−4アルコキシであり、
Dはペイロード部分であり、
nは、0、1、2、3または4であり、
mは、0、1、2、または3である)またはその塩を調製するためのプロセスであって、
式IIの化合物を、
R1eは、−C1−4アルキレン−CO2Hであり、
R1fは、水素または−C1−4アルキレン−CO2Hであり、
G1は、第1の窒素と、任意選択的に、窒素、酸素、および硫黄から選択される1つの追加のヘテロ原子とを含む4〜8員の単環式ヘテロシクリルであり、G1は、第1の窒素で結合し、任意選択的に、C1−4アルキル、C1−4ハロアルキル、ハロ、シアノ、OH、−OC1−4アルキル、およびオキソからなる基から独立して選択される1〜4個の置換基で置換され、
mは、0、1、または2である。
R1は、−OR4、任意選択的に置換されたヘテロシクリル、およびアミノ酸部分からなる群から選択され、
R4は水素またはC1−4アルキルであり、
R5は水素またはC1−4アルキルであり、
Dはペイロード部分である)によって表され、
式IIの化合物は、式IIA
R1はアミノ酸部分であり、
R5は水素またはC1−4アルキルであり、
Dはペイロード部分である)によって表され、
式IIの化合物は、式IIA
R1は、−OR4、任意選択的に置換されたヘテロシクリル、およびアミノ酸部分からなる群から選択され、
nは、0、1、2、3または4であり、
各R2は、独立して、C1−4アルキル、C1−4ハロアルキル、およびC1−4アルコキシであり、
R4は水素またはC1−4アルキルである)またはその塩を調製するプロセスであって、
式IVの化合物を
R1はアミノ酸部分であり、
nは、0、1、2、3または4であり、
各R2は、独立して、C1−4アルキル、C1−4ハロアルキル、およびC1−4アルコキシである)またはその塩を調製するプロセスであって、
式IVの化合物を
R1は、−OR4、任意選択的に置換されたヘテロシクリル、およびアミノ酸部分からなる群から選択され、
nは、0、1、2、3または4であり、
各R2は、独立して、C1−4アルキル、C1−4ハロアルキル、およびC1−4アルコキシであり、
Dはペイロード部分であり、
R4は、水素またはC1−4アルキルである)またはその塩を調製するプロセスであって、
式Xの化合物
R1はアミノ酸部分であり、
nは、0、1、2、3または4であり、
各R2は、独立して、C1−4アルキル、C1−4ハロアルキル、およびC1−4アルコキシであり、
Dはペイロード部分である)またはその塩を調製するプロセスであって、
式Xの化合物
nは、0、1、2、3、または4であり、
各R2は、独立して、水素またはC1−4アルキルである)またはその塩を含む組成物を調製するプロセスであって、
1当量の式Vの化合物
式Vの化合物は、式VA
nは、0、1、2、3、または4であり、
各R2は、独立して、C1−4アルキル、C1−4ハロアルキル、およびC1−4アルコキシである)またはその塩の1つ以上の立体異性体を含む組成物を分解するためのプロセスであって、
(a)式VIの1つ以上の立体異性体を含む組成物をキラル塩基と接触させて、式VIの化合物のキラル塩を提供するステップと、
(b)ステップ(a)の組成物を冷却するステップと、
(c)式VIの化合物のキラル塩を単離するステップと、
(d)式VIの化合物のキラル塩を加水分解して、式VIの化合物またはその塩を含む鏡像異性的に濃縮された組成物を提供するステップと、を含む、プロセスも本明細書に提供される。
nは、0、1、2、3または4であり、
各R2は、独立して、C1−4アルキル、C1−4ハロアルキル、およびC1−4アルコキシであり、
R4は、独立して、水素またはC1−4アルキルである)またはその塩を含む鏡像異性的に濃縮された組成物を調製するためのプロセスであって、
式VIの化合物
R5は、水素またはC1−4アルキルである)またはその塩の1つ以上の立体異性体を含む組成物を分解するためのプロセスであって、
(a)式VIIAの1つ以上の立体異性体を含む組成物をキラル塩基と接触させて、式VIIAの化合物のキラル塩を提供するステップと、
(b)ステップ(a)の組成物を冷却するステップと、
(c)式VIIAの化合物のキラル塩を単離するステップと、
(d)式VIIAの化合物のキラル塩を加水分解して、式VIIAの化合物またはその塩を含む鏡像異性的に濃縮された組成物を提供するステップと、を含む、プロセスも本明細書に提供される。
R4は水素またはC1−4アルキルであり、
R5は水素またはC1−4アルキルである)またはその塩を含む鏡像異性的に濃縮された組成物を調製するためのプロセスであって、
(a)式VIBの化合物またはその塩の鏡像異性的に濃縮された組成物を、
R4は水素またはC1−4アルキルであり、
R5は水素またはC1−4アルキルである)またはその塩を含む鏡像異性的に濃縮された組成物を調製するためのプロセスであって、
式VIIBの化合物
「アミノ酸」という用語は、天然アミノ酸および非天然アミノ酸の両方を指す。特定の実施形態において、アミノ酸部分は天然アミノ酸である。天然アミノ酸は、遺伝暗号のトリプレットコドンによって直接コードされる20のタンパク質構成アミノ酸を含み、アラニン(ala、A)、アルギニン(arg、R)、アスパラギン(asn、N)、アスパラギン酸(asp、D)、システイン(cys、C)グルタミン(gln、Q)グルタミン酸(glu、E)グリシン(gly、G)ヒスチジン(his、H)イソロイシン(ile、I)ロイシン(leu、L)リジン(lys、K)メチオニン(met、M)フェニルアラニン(phe、F)プロリン(pro、P)セリン(ser、S)スレオニン(thr、T)トリプトファン(trp、W)チロシン(tyr、Y)およびバリン(val、V)を含む。
R1cおよびR1dは、各々独立して、水素またはC1−4アルキルであり、
R1eは、−C1−4アルキレン−CO2H、−C1−4アルキレン−CONH2、または−C1−4アルキレン−OHであり、
R1fは、水素、−C1−6アルキル、または−C1−4アルキレン−CO2Hであり、
mは、0、1、2、または3である。
本明細書で使用される場合、「ペイロード部分」は、ペイロードDから、リンカーに結合するNH、NC1−4アルキル、O、もしくはS等の求核基を差し引いたもの、またはリンカーに結合するC(O)等の求電子基を差し引いたもの、すなわち、ペイロードの残りの部分を指す。「ペイロード」という用語は、一般に、対象の標的部位に送達させるための薬剤を指し、治療薬、診断薬、標的薬等を含むが、これらに限定されない。
evalin(イブリツモマブチウキセタン)、Zinecard(デクスラゾキサン塩酸塩)、Ziv−アフリベルセプト、Zoladex(ゴセレリン酢酸塩)、ゾレドロン酸、Zolinza(ボリノスタット)、Zometa(ゾレドロン酸)およびZytiga(酢酸アビラテロン)が挙げられる。
特定の実施形態において、本開示は、本明細書に記載されるプロセスにおいて有用である中間化合物を提供する。したがって、一実施形態において、表1から選択される化合物またはその塩が提供される。別の実施形態において、表1から選択される化合物またはその塩を含む鏡像異性的に濃縮された組成物が提供される。
以前の報告では、小規模でのみラセミ体として化合物IVが形成されるのに対し、次の手順では、ラセミ出発物質からキログラムスケールで≧97%eeの化合物IVの単一鏡像異性体が生成される(Rossin,R.et al.Bioconjugate Chem.2016,1697−1706)。
−HClの添加により(Z)−1−メチルシクロオクタ−4−エン−1−カルボン酸の遊離酸に変換された塩
−(Z)−1−メチルシクロオクタ−4−エン−1−カルボン酸を溶解し、所望の立体異性体の種を添加して結晶化を誘導する
−沈殿が観察されるが、分析により、固体と上清の間に%eeの差がないことが示される
−ラセミ体が固溶体として存在する可能性があることが示唆され、酸形態の濃縮が実行不可能となる
−47%の低純度のラセミ体を、純粋な、濃縮された(Z)−1−メチルシクロオクタ−4−エン−1−カルボン酸(33%ee)にスパイクした。
−不純物のスパイクは、所望および非所望の鏡像異性体の相対的な溶解度に影響を与えなかった
−したがって、分割プロセスのために、不純な(Z)−1−メチルシクロオクタ−4−エン−1−カルボン酸と比較して純粋な(Z)−1−メチルシクロオクタ−4−エン−1−カルボン酸を使用した場合、有意な%eeの改善は観察されなかった
−所望および非所望の鏡像異性体の溶解度は、0〜88%eeの範囲の様々な程度のエナンチオ濃縮の試料で測定された
−ラセミ物質の場合、非所望の鏡像異性体の溶解度が、所望の鏡像異性体の溶解度を超える
−しかしながら、46%eeに達すると、溶解度の傾向が逆転し、所望の鏡像異性体塩の溶解度が非所望の鏡像異性体塩の溶解度を超える
−この切り替わりは、ラセミ体から出発して≧97%eeに達する高収率のキラル分割プロセスの開発を複雑にする
ラセミ出発物質からキログラムスケールで単一鏡像異性体(≧97%ee)シス−(Z)−6−ヒドロキシ−1−メチルシクロオクタ−4−エン−1−カルボン酸を製造するためのプロセス。文献は、17.5gのラセミシス−(Z)−6−ヒドロキシ−1−メチルシクロオクタ−4−エン−1−カルボン酸の合成を報告する。(Rossin,R. et al.Bioconjugate Chem.2016,1697−1706).
クロマトグラフィーを使用せずに、TCO出発物質シス−(E)−6−ヒドロキシ−1−メチルシクロオクタ−4−エン−1−カルボン酸から、高純度2,5−ジオキソピロリジン−1−イルシス−(E)−6−((((2,5−ジオキソピロリジン−1−イル)オキシ)カルボニル)オキシ)−1−メチルシクロオクタ−4−エン−1−カルボキシレートを100グラムスケールで75%の収率でロバストに合成するためのプロセス。参考文献は、シリカゲルクロマトグラフィーによる精製を必要とする、400mgの2,5−ジオキソピロリジン−1−イルシス−(E)−6−((((2,5−ジオキソピロリジン−1−イル)オキシ)カルボニル)オキシ)−1−メチルシクロオクタ−4−エン−1−カルボキシレートの収率46%での合成を報告している(Rossin,R.et al.Bioconjugate Chem.2016,1697−1706)。
以下の例は、(R)−2−アミノ−2−フェニルエタン−1−オールを使用して(Z)−6−ヒドロキシ−1−メチルシクロオクタ−4−エン−1−カルボン酸のキラル分割を示しており、これにより、実施例2で提供されたものとは反対の鏡像異性体が得られる。(−)記号は、両方の鏡像異性体を区別するために%eeに割り当てられており、旋光度を表すものではない。
化合物11の手順:
TCO出発物質10からトランス−シクロオクテン(TCO)−ドキソルビシンコンジュゲート11を単一グラムスケールで98%の収率で合成するためのプロセス。参考文献は、収率68%での134mgの11の合成を報告する。(Rossin,R.et al.Bioconjugate Chem.2016,1697−1706).
i)1mLのDCM中のグリシン(64.7mg、0.86mmol、10当量)の懸濁液に、窒素下、室温でBSA(0.105mL、5当量)およびDIPEA(0.30mL、20当量)を加えた。混合物を2時間還流し、次いで室温まで冷却した。これに11の反応混合物(0.5mL)を加えた。得られた混合物を40℃で5時間加熱し、HPLCにより監視した。次いで、反応混合物を室温まで冷却し、セライトのパッドを通して濾過し、DCMで洗浄した。濾液を濃縮して残渣(0.64g)を得、これを0.2N NaOH(0.5mL)と混合し、混合物をMTBE(2×1mL)で抽出した。次いで、水層を1N HCl(0.2mL)でpH=4〜5に酸性化した。ガム状の沈殿物が形成され、収集したところ、12で88.7%のLCAPを示した。水溶液は主に水とDMFの混合物である。
ii)1mLのDCM中のグリシン(64.7mg、0.862mmol、10当量の懸濁液に、窒素下、室温でBSA(0.105mL、10当量)およびDIPEA(0.30mL、40当量)を加えた。混合物を室温で5分間撹拌し、次いで反応混合物[24−R174](0.5mL)を加えた。得られた混合物を室温で22時間撹拌した。HPLCは12では90.4%のLCAPを示し、>5%LCAPのピークは他になかった。反応混合物をセライトのパッドを通して濾過し、DCMで洗浄した。濾液を濃縮して残渣を得、これを逆相ISCO精製に供した。収集した画分を凍結乾燥した。
2000mLフラスコは、オーバーヘッドスターラー、温度プローブ、および窒素入口/出口を備えていた。アセトン(5体積、128mL)をフラスコに入れ、窒素下、20〜25℃で撹拌した。粗化合物12(25.6g、0.0315モル、1当量、量は重量アッセイ%から)を一部のアセトン(7体積、179mL)でスラリー化し、フラスコに入れた。残りのアセトンを使用して、フラスコ中の化合物12遊離酸をすすぎ、2000mLフラスコに入れた。混合物を窒素で短時間パージし、次いで窒素下でブランケットした。
TLC:DCM/メタノール/酢酸(20:1:0.2);
Rf(化合物11)=0.35;
LC−MS:851.2[M+H]+;
12−Alaの一般的な手順:DCM(0.5mL)中のL−アラニン(52.6mg、0.59mmol、10当量)、BSA(60mg、0.294mmol、5.0当量)、DIPEA(152mg、1.18mmol、20.0当量)の混合物を30分間撹拌し、DMF(0.2mL)中の化合物11(50.0mg、0.059mmol、1.0当量)の溶液に加えた。反応混合物を、窒素およびアルミホイル保護下、32℃で一晩加熱した。反応混合物を濃縮乾固し、残渣をアセトニトリル(2mL)で希釈した。得られた粗反応混合物を分取HPLC(30分で5%〜100%のCH3CN、中性、pH7)により精製し、所望の質量を有する画分を凍結乾燥した後に12−Ala(2.3mg)を得た。LC−MS:846.8[M+H]+,822.5[M−H]−;1H NMR(300MHz,CD3OD):δ7.85(m,1H),7.78(m,1H),7.52(m,1H),5.64(m,1H),5.40(m,2H),5.07(m,2H),4.74(s,1H),4.24(m,2H),3.82(s,3H),3.82(m,1H),3.61(m,2H),2.98(m,2H),2.90(m,2H),2.38−1.74(m,10H),1.33(d,J=6.3Hz,3H),1.26(d,J=6.3Hz,3H),1.09(s,3H)。
トランス−シクロオクテン(TCO)−ドキソルビシンコンジュゲート(Dox−TCO−Gly)への代替合成アプローチの評価。
PNP−53%
本実施例は、本明細書に記載されるもの(例えば、化合物10)等のTCO出発物質をペキシダルチニブに結合させるための方法を提供する。アミノ酸部分(例えば、グリシン)による化合物15のさらなる修飾が企図される。
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Claims (48)
- 式Iの化合物
R1は、−OR4、任意選択的に置換されたヘテロシクリル、およびアミノ酸部分からなる群から選択され、
nは、0、1、2、3または4であり、
各R2は、独立して、C1−4アルキル、C1−4ハロアルキル、およびC1−4アルコキシであり、
Dはペイロード部分であり、
R4は水素またはC1−4アルキルである)またはその塩を調製するプロセスであって、
式IIの化合物を、
- 前記ペイロード部分は、アントラサイクリン部分、オーリスタチン部分、糖ペプチド抗生物質部分、またはリポペプチド抗生物質部分である、請求項1に記載のプロセス。
- 前記ペイロード部分は、ドキソルビシン部分、ダウノルビシン部分、モノメチルオーリスタチンE部分、バンコマイシン部分またはダプトマイシン部分である、請求項2に記載のプロセス。
- R1は、アミノ酸部分、アラニン部分またはグリシン部分である、請求項1〜3のいずれかに記載のプロセス。
- 前記式IIIの化合物はN,O−ビス(トリメチルシリル)アセトアミドである、請求項1〜4のいずれかに記載のプロセス。
- 式IVの化合物を含む前記組成物を、室温で40〜60体積の水に添加して水性生成物混合物を形成することをさらに含む、請求項15に記載のプロセス。
- 前記水性生成物混合物中に形成された固体を単離することをさらに含む、請求項16に記載のプロセス。
- 約30〜約50℃の温度で、アセトニトリル中で固体を粉砕して、粉砕された固体を形成することをさらに含む、請求項17に記載のプロセス。
- 前記粉砕された固体を単離することをさらに含む、請求項18に記載のプロセス。
- 前記無水有機溶媒は無水アセトニトリルである、請求項15に記載のプロセス。
- 前記塩基はトリアルキルアミン塩基である、請求項15〜20のいずれかに記載のプロセス。
- 前記塩基はジイソプロピルエチルアミンである、請求項21に記載のプロセス。
- 式VIの化合物
nは、0、1、2、3、または4であり、
各R2は、独立して、C1−4アルキル、C1−4ハロアルキル、およびC1−4アルコキシである)またはその塩の1つ以上の立体異性体を含む組成物を分解するためのプロセスであって、
(a)式VIの1つ以上の立体異性体を含む組成物をキラル塩基と接触させて、前記式VIの化合物のキラル塩を提供するステップと、
(b)ステップ(a)の前記組成物を冷却するステップと、
(c)前記式VIの化合物の前記キラル塩を単離するステップと、
(d)前記式VIの化合物の前記キラル塩を加水分解して、式VIの化合物またはその塩を含む鏡像異性的に濃縮された組成物を提供するステップと、を含む、プロセス。 - 前記キラル塩基はシンコニジンである、請求項24に記載のプロセス。
- ステップ(a)の前記接触は、アセトン/水またはアセトン/イソプロピルアルコールから選択される溶媒中で行われる、請求項24に記載のプロセス。
- ステップ(b)の前記冷却は、約15℃以下の温度で行われる、請求項24に記載のプロセス。
- ステップ(b)の前記冷却は、約10〜約15℃の温度にある、請求項24に記載のプロセス。
- ステップ(b)の前記冷却は、少なくとも約8時間維持される、請求項24に記載のプロセス。
- ステップ(c)の前記単離は、濾過によるものである、請求項24に記載のプロセス。
- ステップ(c)から得られた前記式VIの化合物の前記キラル塩を好適な溶媒に溶解することと、ステップ(d)の前にステップ(b)および(c)を繰り返すことと、をさらに含む、請求項24に記載のプロセス。
- ステップ(c)から得られた前記式VIの化合物の前記キラル塩を好適な溶媒に溶解するステップと、ステップ(d)の前にステップ(b)および(c)を2、3、4、5または6回繰り返すステップと、をさらに含む、請求項30に記載のプロセス。
- 前記キラル塩基は、(R)−1−アミノ−2−プロパノール、L−フェニルアラニノール、(S)−フェニルグリシノール、(S)−ジフェニル−2−ピロリジンメタノールである、請求項37に記載のプロセス。
- 式VIIBの化合物
R4は水素またはC1−4アルキルであり、
R5は水素またはC1−4アルキルである)またはその塩を含む鏡像異性的に濃縮された組成物を調製するためのプロセスであって、
(a)式VIBの化合物またはその塩の鏡像異性的に濃縮された組成物を、
- 前記異性化は、前記式VAの化合物をUV光に曝露することを含む、請求項42に記載のプロセス。
- R4がC1−4アルキルである場合、前記プロセスは、R4を水素に変換するための加水分解ステップをさらに含む、請求項42または43に記載のプロセス。
- R2またはR5はメチルである、請求項1〜45のいずれかに記載のプロセス。
- 前記鏡像異性的に濃縮された組成物は、約25%超、または約50%、または約70%、または約80%、または約90%、または約95%、または約98%、または約99%または約100%の%eeを有する、請求項1〜47のいずれかに記載のプロセス。
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US20210346502A1 (en) | 2021-11-11 |
WO2020077140A1 (en) | 2020-04-16 |
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