CN111484534A - Process for producing 14-bromoanthracyclines - Google Patents
Process for producing 14-bromoanthracyclines Download PDFInfo
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- CN111484534A CN111484534A CN202010073940.9A CN202010073940A CN111484534A CN 111484534 A CN111484534 A CN 111484534A CN 202010073940 A CN202010073940 A CN 202010073940A CN 111484534 A CN111484534 A CN 111484534A
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- 238000000034 method Methods 0.000 title claims abstract description 27
- 150000001875 compounds Chemical class 0.000 claims description 59
- 239000000243 solution Substances 0.000 claims description 31
- 238000004519 manufacturing process Methods 0.000 claims description 29
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 22
- -1 alkali metal salt Chemical class 0.000 claims description 16
- 239000011541 reaction mixture Substances 0.000 claims description 16
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 15
- 238000002156 mixing Methods 0.000 claims description 13
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 12
- 239000012044 organic layer Substances 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 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 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- HHBCEKAWSILOOP-UHFFFAOYSA-N 1,3-dibromo-1,3,5-triazinane-2,4,6-trione Chemical compound BrN1C(=O)NC(=O)N(Br)C1=O HHBCEKAWSILOOP-UHFFFAOYSA-N 0.000 claims description 6
- DXVYLFHTJZWTRF-UHFFFAOYSA-N Ethyl isobutyl ketone Chemical compound CCC(=O)CC(C)C DXVYLFHTJZWTRF-UHFFFAOYSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- VBTQNRFWXBXZQR-UHFFFAOYSA-N n-bromoacetamide Chemical compound CC(=O)NBr VBTQNRFWXBXZQR-UHFFFAOYSA-N 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 150000001409 amidines Chemical class 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- 150000001448 anilines Chemical class 0.000 claims description 4
- 150000002357 guanidines Chemical class 0.000 claims description 4
- 150000003222 pyridines Chemical class 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 3
- QQZOPKMRPOGIEB-UHFFFAOYSA-N 2-Oxohexane Chemical compound CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 claims description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 3
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 claims description 3
- NGAZZOYFWWSOGK-UHFFFAOYSA-N heptan-3-one Chemical compound CCCCC(=O)CC NGAZZOYFWWSOGK-UHFFFAOYSA-N 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 230000003472 neutralizing effect Effects 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 239000003495 polar organic solvent Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- BXBUVIPNRGDTNE-UHFFFAOYSA-N sodium;hydrobromide Chemical compound [Na].Br BXBUVIPNRGDTNE-UHFFFAOYSA-N 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 34
- 229940045799 anthracyclines and related substance Drugs 0.000 abstract description 7
- 238000005580 one pot reaction Methods 0.000 abstract description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 13
- 229910052794 bromium Inorganic materials 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000005893 bromination reaction Methods 0.000 description 9
- 125000000217 alkyl group Chemical group 0.000 description 8
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 8
- 239000010410 layer Substances 0.000 description 7
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 230000031709 bromination Effects 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 150000002905 orthoesters Chemical class 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000005755 formation reaction Methods 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- NAALWFYYHHJEFQ-ZASNTINBSA-N (2s,5r,6r)-6-[[(2r)-2-[[6-[4-[bis(2-hydroxyethyl)sulfamoyl]phenyl]-2-oxo-1h-pyridine-3-carbonyl]amino]-2-(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC(O)=CC=1)C(=O)C(C(N1)=O)=CC=C1C1=CC=C(S(=O)(=O)N(CCO)CCO)C=C1 NAALWFYYHHJEFQ-ZASNTINBSA-N 0.000 description 2
- KQRWYZDETCDVGB-TZSSRYMLSA-N (7s,9s)-7-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-9-(2-bromoacetyl)-6,9,11-trihydroxy-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical compound 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)CBr)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 KQRWYZDETCDVGB-TZSSRYMLSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound 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 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229960003109 daunorubicin hydrochloride Drugs 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound 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-VTZDEGQISA-N 0.000 description 1
- 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 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)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]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 description 1
- WBJRCFQWEOAKLV-UHFFFAOYSA-N [K].Br Chemical compound [K].Br WBJRCFQWEOAKLV-UHFFFAOYSA-N 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- YSRWGQHKNODHTJ-UHFFFAOYSA-N butan-2-one;hydrobromide Chemical compound Br.CCC(C)=O YSRWGQHKNODHTJ-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound 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 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 238000005907 ketalization reaction Methods 0.000 description 1
- 230000007886 mutagenicity Effects 0.000 description 1
- 231100000299 mutagenicity Toxicity 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229960001221 pirarubicin Drugs 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
Abstract
The invention provides a method for preparing 14-bromo anthracycline, which is safe to operate and efficient. The process for producing 14-bromoanthracyclines comprises the steps of ketalizing a 13-carbonyl group, brominating the 14-position by an N-bromo compound, and deketalizing, which are carried out by a one-pot method, according to the following reaction scheme.
Description
Technical Field
The present invention relates to a method for producing 14-bromoanthracyclines from 13-methylanthracene, and more particularly to a method for producing 14-bromoanthracyclines through bromination of the methyl group of 13-ketal-13-methylanthracene.
Background
The 14-bromoanthracyclines are represented by formula (1):
[ CHEM 1 ]
A compound represented generally by the formula (wherein R is1～R21As will be described later. Hereinafter, also referred to as "compound (1)" (corresponding to the compound of formula I in the present invention)) is a synthetic intermediate of 14-hydroxyanthracene such as doxorubicin, pirarubicin and epirubicin, which are anthracycline anticancer agents. For example, typical examples of such compounds include 14-bromodaunorubicin represented by formula (2) (hereinafter, also referred to as "compound (2)"), 14-bromopirarubicin represented by formula (3), and 14-bromoepirubicin.
Further, 14-bromoanthracyclines are also used as important intermediates for synthesizing conjugates composed of anthracyclines and biopolymers such as peptides and proteins (see patent document 1).
A method for producing a specific compound of the compound (1) (non-patent document 1 and patent document 2) has been reported from ume and the like, and for example, the compound (2) is produced in two stages from a hydrochloride of daunorubicin (hereinafter also referred to as "compound (5)") through 14-bromodaunorubicin-13-dimethylacetal (hereinafter also referred to as "compound (6)") as shown in the following reaction scheme 1.
Scheme 1: synthesis of 14-bromoanthracyclines
[ CHEM 3 ]
First, the hydrochloride of compound (5) was dissolved in anhydrous methanol, and trimethyl orthoformate and dioxane were added. Next, a solution of bromine in methylene chloride was added and the reaction was carried out at 25 ℃. The reaction solution was poured into anhydrous ether, the resulting precipitate was compressed by a centrifugal separator, and the supernatant was discarded. The precipitate was washed twice with dry ether, further acetone was added and stirred at 25 ℃ for 1 hour. The reaction solution was again subjected to centrifugal precipitation treatment, and the precipitate was washed twice with diethyl ether and then dried to obtain a hydrochloride of the compound (2).
Documents of the prior art
Patent document
Patent document 1: japanese Kokai publication Hei-2006-504657
Patent document 2: japanese laid-open patent publication No. 56-156300
Non-patent document
Non-patent document 1: bulletin of the Chemical Society of Japan,59(1986), p423-431
Disclosure of Invention
Problems to be solved by the invention
The above-mentioned method for producing 14-bromoanthracyclines is not necessarily satisfactory mainly in the following aspects (a) and (B). (A) Bromine which requires attention in operation is used. (B) Since the anthracycline compound having mutagenicity or the possibility thereof is purified by filtration, it is necessary to handle the compound as powder. Accordingly, an object of the present invention is to produce 14-bromoanthracyclines without using bromine which requires attention in terms of handling and without going through a powder handling step.
Means for solving the problems
In order to solve the above problems, the present inventors have studied various ways on a conventional method for producing 14-bromoanthracyclines. As a result, it has been found that the compound represented by the formula I as the final target compound can be obtained from the compound represented by the formula II as the starting material in a high yield by using N-bromosuccinimide (NBS) instead of bromine in the above-described conventional production method and by changing the reaction treatment conditions to a certain extent, and the target product in each step can be operated in a solution state. In addition, it has been found that NBS can be replaced by N-bromo compounds known to have the same bromination effect.
Therefore, the present specification discloses the following main technical features or embodiments of the invention.
Mode 1: a process for producing a compound represented by the formula I, or a pharmacologically acceptable salt or solvate thereof,
[ CHEM 4 ]
The method comprises the following steps:
(a) reacting a compound represented by formula II with a compound represented by formula CR23(OR22)3Ortho ester represented by the formula R22A step of mixing an alkanol represented by OH to produce a ketal represented by the formula III;
[ CHEM 5 ]
[ CHEM 6 ]
(b) A step of mixing a reaction mixture containing the ketal of the formula III produced in the step (a) with an N-bromo compound selected from N-bromosuccinimide (NBS), N-bromoacetamide (NBA), 1, 3-dibromo-5, 5-Dimethylhydantoin (DBH), and dibromoisocyanuric acid (DBI), thereby producing a bromoketal represented by the formula IV;
[ CHEM 7 ]
(c) A step of converting the compound represented by the formula IV into the compound represented by the formula I by mixing the reaction mixture containing the compound represented by the formula IV generated in the step (b) with an acid and water;
(d) separating an organic layer containing the compound represented by formula I from a mixture obtained by mixing the ketal formation reaction mixture of step (c) with an extraction organic solvent capable of dissolving the compound represented by formula I; and
(e) a step of obtaining the compound represented by the formula I in the state of an organic solution from the organic layer separated in the step (d).
Variable R in the above formulae1～R23The radicals are defined below.
[ TABLE 1 ]
In the above-mentioned table, it is shown,
r as a substituent14～R19May be a cycloalkyl group having 3 to 6 carbon atoms,
the CH group of the cycloalkyl group may be substituted with N,
the secondary carbon may be substituted by NH, O, S,
1 of the hydrogens of the cycloalkyl group may be substituted with a methoxy group,
in addition, the substituent R16Or R17And is selected from the substituents R18And R19Any of which may be bonded via 1 or 2 carbons.
Mode 2: the production method according to mode 1, wherein the N-bromo compound is NBS.
Mode 3: the production method according to mode 1 or 2, wherein the alkanol-containing solvent in the step (a) further contains an organic sulfonic acid.
Mode 4: the production process according to mode 3, wherein the organic sulfonic acid is selected from the group consisting of p-toluenesulfonic acid, camphorsulfonic acid, methanesulfonic acid and trimethylsilyl trifluoromethanesulfonate.
Mode 5: the production method according to mode 3 or 4, further comprising a step of neutralizing the reaction mixture from the step (a) with an organic base before the step (b) is performed.
Mode 6: the production process according to mode 5, wherein the organic base is selected from the group consisting of tri-C1～C3Alkylamines, amidines, guanidines, anilines and pyridines.
Mode 7: the production method according to any one of embodiments 1 to 6, wherein the step (b) is performed in a solvent containing an aprotic polar organic solvent.
Mode 8: the production method according to mode 7, wherein the aprotic organic solvent is selected from tetrahydrofuran, dioxane, and dimethoxyethane.
Mode 9: the production method according to any one of embodiments 1 to 7, wherein the acid in the step (c) is hydrobromic acid.
Mode 10: the production process according to embodiment 9, wherein the hydrobromic acid is added as a solution contained in an aqueous solution containing an alkali metal salt of hydrobromic acid.
Mode 11: the production method according to claim 10, wherein the alkali metal salt is potassium hydrobromate or sodium hydrobromate.
Mode 12: the production method according to any one of embodiments 1 to 10, further comprising adding a base to the reaction mixture from the step (c) before the step (d) is performed.
Mode 13: the production method according to claim 12, wherein the base is selected from the group consisting of sodium hydrogencarbonate, potassium hydrogencarbonate and tri-C1～C3Alkyl-amines, amidines, guanidines, anilines and pyridines.
Mode 14: the production method according to any one of aspects 1 to 10, wherein the organic solvent for extraction in the step (d) is C4～C6-an alkyl ketone.
Mode 15: the method according to claim 14, wherein C is4～C6-the alkyl ketone is selected from the group consisting of methyl ethyl ketone, methyl butyl ketone, ethyl butyl ketone, methyl isobutyl ketone and ethyl isobutyl ketone.
Mode 16: the production method according to any one of aspects 1 to 14, wherein C is4～C6-an alkyl ketone in solution to provide a compound represented by formula I.
Detailed Description
Technical terms and the like used in the present specification are used as terms having meanings customary in the technical field unless otherwise defined.
Variable R in the above formulae1～R23In the definition of the radicals, the substituents are OH, NH, by themselves or as part thereof2NH, H, O and N represent a hydroxyl group, an amino group, an imino group, a hydrogen atom, an oxygen atom and a nitrogen atom, and the substituent itself or C constituting a part of the groupnH2n+1And n ═ 1 to 5 following these groups represent, for example, an alkyl group having 1 to 5 carbon atoms. Examples of such an alkyl group include a linear or branched alkyl group, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, an n-heptyl group, a 4-methylbutyl group, a 3-methylbutyl group, and a 2-ethylpropyl group. n is a group having 1 to 3 carbon atoms in the above specific group. Among these groups, those having 1 or 2 carbon atoms and being a chain alkyl group are preferably used in the production method disclosed in the present specification, though not limited thereto. Further, C constituting a part of the compound used in the present production method1～C3Alkyl radical, C4～C6-C as in alkyl ketonesn(n represents a positive number) each of the above-mentioned alkyl groups having n carbon atoms may be used. tri-C having these groups in part1～C3Alkyl radical, C4～C6The alkyl groups in the alkyl ketones may be identical or different. Furthermore, OCH2C6H5Represents a benzyloxy group.
The method disclosed in the present specification is not limited, and can be generally represented as shown in the following reaction scheme 2. In the following description, variable R in each formula1～R23The groups are as defined above, unless otherwise defined.
Reaction scheme 2
[ CHEM 8 ]
[ respective steps ]
The treatments (i) and (ii) in the reaction scheme 2 correspond to the step (a) in the embodiment 1, the treatment (iii) corresponds to the step (b) in the embodiment 1, and the treatment (iv) corresponds to the step (c) in the embodiment 1.
In the conventional methods for producing 14-bromoanthracyclines described in patent documents 1 and 2, bromination using bromine and ketalization of the 13-ketone functional group in the anthracyclines occur simultaneously. On the other hand, NBS is well known in the art of general organic synthesis as a safer brominating reagent that generally replaces bromine (e.g., Tetrahedron 70(240) 3949-.
However, in the above-described conventional method, when only NBS is used instead of bromine, although the formation of compound (6) in the above-described reaction scheme 1 can be confirmed, the conversion rate from compound (5) is significantly reduced as compared with the case of using bromine. Thus, as a result of examining and studying the respective reactions in scheme 1, a compound of formula II corresponding to compound (5) is first reacted in alkanol R22With ortho-esters CR in the presence of OH, especially an organic sulphonic acid, especially p-toluenesulphonic acid (or toluenesulphonic acid), in methanol23(OR22)3Particularly trimethyl orthoformate, as a reaction intermediate to produce compound represented by formula (7) (or also represented by formula II) in scheme 2. ) The yield of the compound represented by the formula (IV), particularly the compound (6), can be confirmed to be increased by conducting the bromination reaction in which the N-bromo compound is added after the 13-dimethylketal corresponding to the compound of (1) (see the formula III), particularly daunorubicin-13-dimethylketal. Further, when the acid is neutralized with an organic base, particularly triethylamine, and the bromination reaction is carried out in a mixed solvent containing an aprotic polar solvent such as tetrahydrofuran, dioxane, and dimethoxyethane before the bromination is carried out, it is confirmed that the yield is further improved, and the compound (6) can be obtained in a yield comparable to that of bromine.
In this way, in the method disclosed in the present specification, the step (a) and the step (b) are independent, and the step (b) is performed after the step (a).
The method disclosed in the present specification is not limited to the compounds listed as "particularly" in the above description, and compounds within the ranges described in the above embodiments can be used, and the desired reaction can be carried out by mixing the reactants and/or the solvent. When such mixing and mixing in other steps are performed, the reaction product and/or solvent to be mixed may be performed without limitation to the order of addition unless otherwise specified. In this method, even if a solid or the like is contained in the reaction mixture, the target ketal (represented by formula III) does not need to be isolated as a solid or the like, and the subsequent bromination can be carried out while maintaining the state of a solution. Further, the organic sulfonic acid is not limited, and examples thereof include organic sulfonic acids such as p-toluenesulfonic acid, camphorsulfonic acid, methanesulfonic acid, and trimethylsilyl trifluoromethanesulfonate. The bromination is not limited, and may be carried out by using an N-bromo compound selected from N-bromosuccinimide (NBS), N-bromoacetamide (NBA), 1, 3-dibromo-5, 5-Dimethylhydantoin (DBH) and dibromoisocyanuric acid (DBI), alone or in combination.
In step (a), the compound of formula II is reacted with a compound of formula CR23(OR22)3And ortho esters of formula R22And (3) mixing alkanol represented by OH, wherein the use ratio of the compound shown as the formula II to the orthoester is 1 in terms of molar ratio: 1-1: 8, preferably 1: 2-1: 6, more preferably 1: 3-1: 5, the compound of formula II is used in a molar ratio to the organic sulfonic acid of 1: 0.01-1: 1, preferably 1: 0.05-1: 0.5, more preferably 1: 0.1-1: 0.3, the reaction temperature is 0-30 ℃, preferably 5-15 ℃, more preferably 8-12 ℃, and the reaction time can be selected from 0.5-24 hours, preferably 1-12 hours, more preferably 2-6 hours. The ratio of orthoester, the ratio of organic sulfonic acid and the reaction time are more preferably used, and the yield is advantageously improved.
After the step (a) and before the step (b), the yield of bromide in the step (b) can be improved by neutralizing the organic sulfonic acid in the reaction solution of the step (a) with an alkali. As such a base, there may be mentionedBy way of example of organic bases, e.g. tri-C1～C3Alkylamine (here, tri-C1～C3The alkyl groups may be the same or different, and may be, for example, triethylamine, isopropylamine, etc. ) Pyridine, guanidine, amidine, aniline, and the like, and they may be used alone or in combination of two or more.
In the step (b), the N-bromo compound added to the reaction solution prepared as described above is not limited, and NBS is added, for example. Thus, the target products (compounds of formulae II and III) in each of the steps (a) and (b) can be easily handled in a solution state, and these steps can be easily carried out in a one-pot method (one pot). The molar ratio of the N-bromo compound to the compound of formula II or III is 1: 1-1: 6, preferably 1: 1-1: 4, more preferably 1: 1-1: 2. the solvent used in the step (b) may be a mixed solvent of the alkanol, tetrahydrofuran, dioxane, dimethoxyethane or other solvents used in the step (a). The solvent may be used in a volume ratio of 1: 0.2-1: 4, preferably 1: 0.5-1: 3, more preferably 1: 1-1: 2. further, the N-bromo compound may be added after the addition of these aprotic organic solvents, or the N-bromo compound may be dissolved in these aprotic organic solvents and added as a solution. The reaction temperature is 0-50 ℃, preferably 10-40 ℃, more preferably 20-30 ℃, and the reaction time can be 0.5-24 hours, preferably 1-12 hours, more preferably 2-6 hours. When the reaction is carried out under more preferable conditions with respect to the molar ratio of the N-bromo compound, the reaction temperature and the reaction time, there is an advantage that the yield is improved.
The step (c) is a ketal removal reaction of the compound of the formula IV obtained in the step (b), and in general, the reaction can be carried out by reacting water with a ketal in the presence of an acid catalyst according to a conventional method. However, when acetone and an aqueous hydrobromic acid solution are added to the reaction solution after the reaction in the step (b) to attempt the ketal removal as in patent document 2, 14-bromine of the compound (2) is converted into a 14-chlorine by-product in the addition of the compound (6) to the compound (2) in the reaction scheme 1, and the target compound (2) cannot necessarily be obtained in a high yield. Accordingly, the present inventors have made extensive studies and found that the compound of the formula (I) can be obtained in a high yield by adding hydrobromic acid and a metal hydrobromide salt to the bromination reaction solution obtained in the step (b) and reacting them. Further, it has been found that, when a metal hydrobromide salt is present, the reaction solution can be separated into two layers, i.e., an organic layer containing 14-bromine and an aqueous layer, only by adding an organic solvent after the reaction, and the organic solvent extraction of 14-bromine (step (d)) can be performed, thereby avoiding the powder handling step. As such metal salts, there are alkali metal salts, for example, potassium hydrobromide, sodium hydrobromide, and the like. Therefore, in the method disclosed in the present specification, the ketal formation reaction is preferably carried out using an aqueous sodium bromide solution containing hydrobromic acid as an acid. The step (c) may be carried out by a one-pot method together with the steps (a) and (b).
The molar ratio of the compound of formula II to hydrobromic acid is 1: 0.01-1: 100, preferably 1: 0.1-1: 50, more preferably 1: 1-1: 10, the molar ratio of the compound of formula II to hydrobromic acid metal salt is 1: 20-1: 150, preferably 1: 50-1: 130, more preferably 1: 70-1: 120, the amount of water dissolving the hydrobromic acid metal salt is 0.1m L-10 m L, preferably 0.5m L-5 m L, more preferably 1m L-3 m L, the reaction temperature is-10 ℃ to 50 ℃, preferably 0 ℃ to 40 ℃, more preferably 10 ℃ to 30 ℃, the reaction time is 0.2-48 hours, preferably 0.5-24 hours, more preferably 1-12 hours, the molar ratio of hydrobromic acid metal salt, the reaction temperature and the reaction time are improved, and the reaction yield is improved under more preferred conditions.
In the step (d), the compound of formula I can be dissolved in the reaction mixture finally obtained in the step (c), and if necessary, the mixture obtained by mixing the non-water-miscible extraction organic solvent is cooled to about 10 ℃ or the organic layer containing the compound of formula I is separated from the aqueous layer containing the solid matter as the case may be at room temperature. In general, the salt of 14-brominated anthracycline is hardly soluble in the above-mentioned non-water-miscible organic solvent, but it is found that it is soluble in a mixed solvent with the solvent used in the step (a) and the step (b), and can be subjected to liquid separation extraction, and powder handling can be avoided. In this step, more specifically, an aqueous solution of a base, particularly sodium hydrogencarbonate, is added to the reaction mixture and stirred, the organic solvent is then added thereto and further stirred, and the mixture is allowed to stand to separate the organic layer from the aqueous layer, followed by separation of the organic layer. The aqueous layer may be subjected to the same liquid separation and separation operation several times. The addition of a suitable amount of base has the advantage of increasing the yield of 14-brominated anthracyclines. The ratio of hydrobromic acid to base used is 1: 0.01-1: 10, preferably 1: 0.05-1: 5, more preferably 1: 0.1-1: 2. the organic solvent is not limited as long as the liquid separation can be performed, and may be C4 to C6-alkyl ketones, such as methyl ethyl ketone, methyl butyl ketone, ethyl butyl ketone, methyl isobutyl ketone, and ethyl isobutyl ketone. The amount of the compound to be used may be determined in consideration of the solubility of the compound of formula I, the amount of water in the reaction mixture, and the like. This step may be carried out by a one-pot method together with the steps (a), (b) and (c), but the reaction mixture may be transferred to a treatment layer dedicated to liquid separation if necessary.
In step (e), the organic layer containing the compound of formula I separated in step (d) is separated or obtained. This extraction operation can be carried out using a decanter or a suitable solution suction pump commonly used in the art.
The organic layer thus obtained can, if appropriate, be used as such, or else, if desired, be concentrated and/or further organic solvents added and the compound of the formula I contained in the solution be subjected to the next reaction. After the above procedure, the compound of formula I was obtained as a hydrobromide salt.
[ examples ] A method for producing a compound
Example 1, Synthesis of 14-Bromadjuomycin
7.9g (14.0mmol) of daunorubicin hydrochloride was dissolved in 63m L of methanol at room temperature, 6.2m L (56.7mmol) of trimethyl orthoformate was added to the solution at 10 ℃, 599mg of p-toluenesulfonic acid monohydrate was added, the solution was stirred for 3 hours, and a mixture of 0.44m L of triethylamine and 4m L of dioxane was added to the reaction solution, which was then heated to 22 ℃.
Next, an NBS-dioxane solution obtained by dissolving 3g (16.9mmol) of NBS in 108m L of dioxane was added and stirred for 90 minutes, and then the temperature of the solution was cooled to 10 ℃.
To an aqueous solution obtained by dissolving 72.3g of sodium bromide in 112m of L m of water was added 7.2m of L hydrobromic acid and stirred, and the mixture was mixed with the reaction solution and stirred for about 16 hours.
After the reaction, an aqueous solution obtained by dissolving 5.8g of sodium bicarbonate in 90m of L m of water was mixed with the reaction mixture, the temperature was raised to 25 ℃, and then the organic layer and the aqueous layer were separated by 800m of L m of methyl ethyl ketone to obtain a solution of 14-bromodaunorubicin hydrobromide methyl ethyl ketone (10.1mmol, yield 72%).
Comparative example:
examples of using NBS in place of bromine under well-known conditions
To 0.79g (1.40mmol) of daunorubicin hydrochloride were added 6.3m L of methanol and 11m L of dioxane and stirred, after confirming dissolution, the solution was cooled to 9 ℃. after addition of 0.4m L of trimethyl orthoformate, 299mg of NBS was added, and after stirring the solution at 9 ℃, the conversion of 14-bromodaunorubicin-13-dimethylketal was 4.6% after 105 minutes.
Claims (16)
1. A process for producing a compound represented by the formula I, or a pharmacologically acceptable salt or solvate thereof,
the method comprises the following steps:
(a) reacting a compound represented by formula II with a compound represented by formula CR23(OR22)3Ortho ester represented by the formula R22A step of mixing an alkanol represented by OH to produce a ketal represented by the formula III;
(b) a step of obtaining a bromoketal represented by the formula IV by mixing a reaction mixture containing the ketal represented by the formula III produced in the step (a) with an N-bromo compound selected from N-bromosuccinimide (NBS), N-bromoacetamide (NBA), 1, 3-dibromo-5, 5-Dimethylhydantoin (DBH), and dibromoisocyanuric acid (DBI);
(c) a step of converting the compound represented by the formula IV into the compound represented by the formula I by mixing a reaction mixture containing the bromoketal represented by the formula IV generated in the step (b) with an acid and water;
(d) a step of separating an organic layer containing the compound represented by formula I from a mixture obtained by mixing the reaction mixture obtained in the step (c) with an extraction organic solvent capable of dissolving the compound represented by formula I; and
(e) a step of obtaining the compound represented by the formula I in the state of an organic solution from the organic layer separated in the step (d),
variable R in the above formulae1～R23The radicals are defined as follows:
[ TABLE 1 ]
In the above-mentioned table, it is shown,
r as a substituent14～R19May be a cycloalkyl group having 3 to 6 carbon atoms,
the CH group of the cycloalkyl group may be substituted with N,
the secondary carbon may be substituted by NH, O, S,
1 of the hydrogens of the cycloalkyl group may be substituted with a methoxy group,
in addition, substitutionRadical R16Or R17And is selected from the substituents R18And R19Any of which may be bonded via 1 or 2 carbons.
2. The method according to claim 1, wherein the N-bromo compound is NBS.
3. The production process according to claim 1 or 2, wherein the alkanol-containing solvent in the step (a) further contains an organic sulfonic acid.
4. The process according to claim 3, wherein the organic sulfonic acid is selected from the group consisting of p-toluenesulfonic acid, camphorsulfonic acid, methanesulfonic acid and trimethylsilyl trifluoromethanesulfonate.
5. The production method according to claim 3 or 4, further comprising a step of neutralizing the reaction mixture from the step (a) with an organic base before the step (b) is performed.
6. The process according to claim 5, wherein the organic base is selected from the group consisting of tri-C1～C3Alkylamines, amidines, guanidines, anilines and pyridines.
7. The production method according to any one of claims 1 to 6, wherein the step (b) is carried out in a solvent containing an aprotic polar organic solvent.
8. The process according to claim 7, wherein the aprotic organic solvent is selected from tetrahydrofuran, dioxane and dimethoxyethane.
9. The production process according to any one of claims 1 to 7, wherein the acid in the step (c) is hydrobromic acid.
10. The production method according to claim 9, characterized in that hydrobromic acid is added as a solution contained in an aqueous solution containing an alkali metal salt of hydrobromic acid.
11. The process according to claim 10, wherein the alkali metal salt is potassium or sodium hydrobromide.
12. The process according to any one of claims 1 to 10, further comprising adding a base to the reaction mixture from step (c) before performing step (d).
13. The method according to claim 12, wherein the base is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, tri-C1～C3Alkyl-amines, amidines, guanidines, anilines and pyridines.
14. The production method according to any one of claims 1 to 10, wherein the organic solvent for extraction in the step (d) is C4～C6-an alkyl ketone.
15. The method of manufacturing of claim 14, wherein C is4～C6-the alkyl ketone is selected from the group consisting of methyl ethyl ketone, methyl butyl ketone, ethyl butyl ketone, methyl isobutyl ketone and ethyl isobutyl ketone.
16. The method according to any one of claims 1 to 14, wherein C is4～C6-an alkyl ketone in solution to provide a compound represented by formula I.
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