CN110452158B - Method for synthesizing halofuginone with optical activity and intermediate thereof - Google Patents
Method for synthesizing halofuginone with optical activity and intermediate thereof Download PDFInfo
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- CN110452158B CN110452158B CN201910090473.8A CN201910090473A CN110452158B CN 110452158 B CN110452158 B CN 110452158B CN 201910090473 A CN201910090473 A CN 201910090473A CN 110452158 B CN110452158 B CN 110452158B
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- reaction
- compound
- chloropropenyl
- hydroxypiperidine
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- 229950010152 halofuginone Drugs 0.000 title claims abstract description 47
- 238000000034 method Methods 0.000 title claims abstract description 46
- 230000003287 optical effect Effects 0.000 title claims abstract description 38
- LVASCWIMLIKXLA-LSDHHAIUSA-N halofuginone Chemical compound O[C@@H]1CCCN[C@H]1CC(=O)CN1C(=O)C2=CC(Cl)=C(Br)C=C2N=C1 LVASCWIMLIKXLA-LSDHHAIUSA-N 0.000 title claims abstract 17
- 230000002194 synthesizing effect Effects 0.000 title claims description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 150
- 239000003960 organic solvent Substances 0.000 claims abstract description 38
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 239000007864 aqueous solution Substances 0.000 claims abstract description 13
- 239000002244 precipitate Substances 0.000 claims abstract description 10
- 230000003472 neutralizing effect Effects 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 146
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 92
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 90
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 90
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 72
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 58
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 47
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 45
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 40
- -1 methoxy formyl Chemical group 0.000 claims description 37
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 34
- 239000003054 catalyst Substances 0.000 claims description 33
- 229910052757 nitrogen Inorganic materials 0.000 claims description 32
- 230000009471 action Effects 0.000 claims description 28
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 19
- 239000002585 base Substances 0.000 claims description 19
- 239000003153 chemical reaction reagent Substances 0.000 claims description 19
- 239000002253 acid Substances 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 17
- 239000003513 alkali Substances 0.000 claims description 17
- 239000011541 reaction mixture Substances 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
- 238000006114 decarboxylation reaction Methods 0.000 claims description 14
- 230000008569 process Effects 0.000 claims description 14
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 14
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 12
- 238000005804 alkylation reaction Methods 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 238000001953 recrystallisation Methods 0.000 claims description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 11
- 235000011181 potassium carbonates Nutrition 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 10
- 238000006228 Dieckmann condensation reaction Methods 0.000 claims description 8
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 8
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 8
- 238000006555 catalytic reaction Methods 0.000 claims description 8
- 239000003638 chemical reducing agent Substances 0.000 claims description 8
- 238000005886 esterification reaction Methods 0.000 claims description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 8
- 125000003386 piperidinyl group Chemical group 0.000 claims description 8
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 8
- 238000006722 reduction reaction Methods 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- FALCMQXTWHPRIH-UHFFFAOYSA-N 2,3-dichloroprop-1-ene Chemical compound ClCC(Cl)=C FALCMQXTWHPRIH-UHFFFAOYSA-N 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 7
- ISOLMABRZPQKOV-UHFFFAOYSA-N diethyl 2-acetamidopropanedioate Chemical compound CCOC(=O)C(NC(C)=O)C(=O)OCC ISOLMABRZPQKOV-UHFFFAOYSA-N 0.000 claims description 7
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 claims description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 6
- 241001643725 Hydrangea febrifuga Species 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 6
- 235000017550 sodium carbonate Nutrition 0.000 claims description 6
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000012312 sodium hydride Substances 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- 235000002906 tartaric acid Nutrition 0.000 claims description 6
- 239000011975 tartaric acid Substances 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 5
- YONLFQNRGZXBBF-KBPBESRZSA-N (2s,3s)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@H](C(=O)O)[C@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-KBPBESRZSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 150000001336 alkenes Chemical class 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 230000031709 bromination Effects 0.000 claims description 4
- 238000005893 bromination reaction Methods 0.000 claims description 4
- 229960001701 chloroform Drugs 0.000 claims description 4
- IRXSLJNXXZKURP-UHFFFAOYSA-N fluorenylmethyloxycarbonyl chloride Chemical compound C1=CC=C2C(COC(=O)Cl)C3=CC=CC=C3C2=C1 IRXSLJNXXZKURP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 238000006317 isomerization reaction Methods 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 238000006386 neutralization reaction Methods 0.000 claims description 4
- 239000011736 potassium bicarbonate Substances 0.000 claims description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 230000001681 protective effect Effects 0.000 claims description 3
- WMSUFWLPZLCIHP-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 9h-fluoren-9-ylmethyl carbonate Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)ON1C(=O)CCC1=O WMSUFWLPZLCIHP-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- KNSPZTVPSAKHBN-UHFFFAOYSA-N benzotriazol-1-yl 9h-fluoren-9-ylmethyl carbonate Chemical compound N1=NC2=CC=CC=C2N1OC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 KNSPZTVPSAKHBN-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 16
- 238000000746 purification Methods 0.000 abstract description 10
- 238000002360 preparation method Methods 0.000 abstract description 9
- 238000004440 column chromatography Methods 0.000 abstract description 4
- 239000012535 impurity Substances 0.000 abstract description 4
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 70
- 239000012044 organic layer Substances 0.000 description 31
- LVASCWIMLIKXLA-CABCVRRESA-N 7-bromo-6-chloro-3-[3-[(2r,3s)-3-hydroxypiperidin-2-yl]-2-oxopropyl]quinazolin-4-one Chemical compound O[C@H]1CCCN[C@@H]1CC(=O)CN1C(=O)C2=CC(Cl)=C(Br)C=C2N=C1 LVASCWIMLIKXLA-CABCVRRESA-N 0.000 description 30
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 26
- 235000019441 ethanol Nutrition 0.000 description 26
- 238000001914 filtration Methods 0.000 description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- 238000012544 monitoring process Methods 0.000 description 19
- 238000003786 synthesis reaction Methods 0.000 description 19
- 230000015572 biosynthetic process Effects 0.000 description 18
- 238000001816 cooling Methods 0.000 description 17
- 239000000706 filtrate Substances 0.000 description 17
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 15
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 15
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 14
- 239000012043 crude product Substances 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 12
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 12
- 238000001035 drying Methods 0.000 description 11
- 239000010410 layer Substances 0.000 description 10
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 10
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 8
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000012295 chemical reaction liquid Substances 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 238000010511 deprotection reaction Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000012279 sodium borohydride Substances 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 5
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 238000002386 leaching Methods 0.000 description 4
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 4
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 4
- 235000009518 sodium iodide Nutrition 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 3
- XBPOBCXHALHJFP-UHFFFAOYSA-N ethyl 4-bromobutanoate Chemical compound CCOC(=O)CCCBr XBPOBCXHALHJFP-UHFFFAOYSA-N 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 239000003223 protective agent Substances 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
- C07D211/40—Oxygen atoms
- C07D211/42—Oxygen atoms attached in position 3 or 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention relates to a preparation method of cis-2- (2-chloropropenyl) -3-hydroxypiperidine with optical activity and application thereof in preparing halofuginone. The preparation method of cis-2- (2-chloropropenyl) -3-hydroxypiperidine with optical activity comprises the following steps: (1) in a first organic solvent, carrying out salt-forming reaction on racemic cis-2- (2-chloropropenyl) -3-hydroxypiperidine and dibenzoyl tartaric acid or derivatives thereof to generate a precipitate, and recrystallizing the precipitate to obtain chiral double salt; (2) and neutralizing the chiral double salt with an alkaline aqueous solution in a second organic solvent to be alkaline to obtain the cis-2- (2-chloropropenyl) -3-hydroxypiperidine with optical activity. The method has the advantages of cheap and easily-obtained raw materials, simple preparation process, less product impurities, no need of column chromatography purification, and realization of large-scale production and preparation of the halofuginone with high optical purity.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a method for synthesizing halofuginone with optical activity and an intermediate thereof.
Background
The dichrone alkaloids separated from the traditional Chinese medicine dichrone comprise dichroine (Febrifugine), isodichroine (isobifurane) and halogenated derivatives of dichrone (Halofuginone), and have a plurality of pharmacological activities, particularly, the research on dichrone in recent years shows that dichrone has a plurality of important pharmacological effects in the aspect of human diseases besides being used for preventing and treating animal coccidiosis and the like. Dichroa febrifuga ketone specifically inhibits fibroblast to synthesize type I collagen fiber, and is used for preventing diseases characterized by excessive type I collagen synthesis, such as hepatic fibrosis, pulmonary fibrosis, scleroderma, and the like. Since inhibition of collagen synthesis results in decreased cell activity that is critical for tumor growth, which in turn affects blood vessel growth and cell proliferation, and blocks tumor cell growth and metastasis, halofuginone has entered clinical trials approved by the FDA in 2000 for the treatment of malignant tumors.
The dichroine is a natural product separated from dichroa febrifuga, the absolute configuration of the dichroa febrifuga is 2R,3S, and the optical rotation is "+", namely, the dextrorotatory optical activity; the dichroa febrifuga ketone derivative is racemate without optical activity used in veterinary medicines. In recent years, numerous researches on halofuginone show that the pharmacological activity of dextro-2R, 3S-halofuginone with the same absolute configuration as that of a natural product halofuginine is obviously superior to that of levo-2S, 3R-halofuginone. Therefore, the synthesis of halofuginone with high optical activity is of great significance.
The piperidine ring segment of halofuginone and halofuginone alkaloid contains two chiral centers of trans-form 2-position and 3-position, and the reported chiral synthesis method mainly comprises the following methods: (1) constructing 2-position and 3-position chiral centers by Sharpless asymmetric double hydroxylation reaction or Sharpless epoxidation; (2) introducing 3-chiral center hydroxyl by reducing carbonyl through yeast; (3) introducing 3-chiral hydroxyl by acetylase; (4) 3-hydroxyl chirality is constructed through asymmetric aldol condensation reaction catalyzed by a chiral micromolecule compound; (5) carrying out chemical resolution by brucine and the like; (6) a synthetic method using chiral compounds as starting materials, and the like. The methods for asymmetrically synthesizing optically active halofuginone or halofuginine have the defects of complicated synthetic route, harsh reaction conditions, low yield, complicated separation and purification, use of highly toxic and expensive reagents and the like.
Disclosure of Invention
Based on the method, the method for preparing cis-2- (2-chloropropenyl) -3-hydroxypiperidine with optical activity is simple in process, less in product impurities and free of column chromatography purification, and can be applied to preparation of the halofuginone with optical activity, so that large-scale production and preparation of the halofuginone with high optical purity can be realized.
The specific technical scheme is as follows:
a method for preparing cis-2- (2-chloropropenyl) -3-hydroxypiperidine with optical activity, which comprises the following steps:
(1) in a first organic solvent, carrying out salt-forming reaction on racemic cis-2- (2-chloropropenyl) -3-hydroxypiperidine and dibenzoyl tartaric acid or derivatives thereof to generate a precipitate, and recrystallizing the precipitate to obtain chiral double salt;
(2) neutralizing the chiral double salt with an alkaline aqueous solution to be alkaline in a second organic solvent to obtain cis-2- (2-chloropropenyl) -3-hydroxypiperidine with optical activity;
the racemic cis-2- (2-chloropropenyl) -3-hydroxypiperidine has a structure shown by a formula (+/-) -9; the cis-2- (2-chloropropenyl) -3-hydroxypiperidine with optical activity has a structure shown in a formula (+) -9 or (-) -9; the dibenzoyl tartaric acid or the derivative thereof has a structure shown in a formula 15 or a formula 16; the chiral double salt has a structure shown in formula 14 or formula 17; the reaction formula is as follows:
or,
wherein each R is independently selected from: hydrogen or C1-C4An alkoxy group.
In some of these embodiments, the dibenzoyl tartaric acid of formula 15 or its derivative described in step (1) is L- (-) -dibenzoyl tartaric acid or L- (-) -di-p-methoxybenzoyl tartaric acid, and the dibenzoyl tartaric acid of formula 16 or its derivative is D- (+) -dibenzoyl tartaric acid or D- (+) -di-p-methoxybenzoyl tartaric acid.
In some of these embodiments, the molar ratio of racemic cis-2- (2-chloropropenyl) -3-hydroxypiperidine to dibenzoyltartaric acid or a derivative thereof described in step (1) is 1: 1 to 2.
In some embodiments, the recrystallization is carried out at a volume ratio of 1 to 10: 1 in a mixed solvent of a third organic solvent and water; the third organic solvent is selected from any one or more of ethanol, methanol, isopropanol, acetonitrile, 1, 4-dioxane and acetone.
In some embodiments, the recrystallization is carried out at a volume ratio of 3 to 5: 1 in a mixed solvent of a third organic solvent and water; the third organic solvent is acetonitrile.
In some embodiments, the first organic solvent in step (1) is selected from any one or more of ethanol, methanol, isopropanol, acetonitrile, dichloromethane, 1, 4-dioxane, tetrahydrofuran, toluene, acetone, and ethyl acetate; and/or the presence of a catalyst in the reaction mixture,
the second organic solvent in the step (2) is selected from any one or more of ethyl acetate, dichloromethane and trichloromethane.
In some of the embodiments, the temperature of the salt forming reaction is 0 to 100 ℃; and/or the temperature of recrystallization is 0-30 ℃.
In some embodiments, the temperature of the salt forming reaction is 20-40 ℃; and/or the temperature of recrystallization is 15-28 ℃.
In some embodiments, the alkaline aqueous solution in step (2) is any one of an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, an aqueous lithium hydroxide solution, an aqueous potassium carbonate solution and an aqueous sodium carbonate solution, and the neutralization is performed until the alkaline is reached and the pH is 8-14.
In some of these embodiments, the process for synthesizing the racemic cis-2- (2-chloropropenyl) -3-hydroxypiperidine comprises the steps of:
(a) reacting diethyl acetylaminomalonate with 2, 3-dichloropropene under the action of alkali and a catalyst to generate a compound shown in a formula 2;
(b) the compound of the formula 2 undergoes a hydrolysis decarboxylation reaction under the catalysis of acid to generate a compound of a formula 3;
(c) carrying out an esterification reaction on the compound of the formula 3 under the catalysis of acid to generate a compound of a formula 4;
(d) the compound of formula 4 and 4-halobutyrate are subjected to nitrogen alkylation reaction under the action of alkali and a catalyst, and then are subjected to nitrogen protection reaction with an amino protection reagent to generate a compound of formula 5;
(e) carrying out Dieckmann condensation reaction on the compound shown in the formula 5 under the action of alkali to generate a compound shown in a formula 6;
(f) the compound of the formula 6 undergoes decarboxylation under the action of inorganic salt to generate a compound of a formula 7;
(g) the compound of the formula 7 is subjected to a reduction reaction under the action of a reducing agent to generate a compound of a formula 8;
(h) deprotecting nitrogen in the compound of formula 8 to produce a compound of formula 9;
the reaction formula is as follows:
wherein:
R1selected from: methyl, ethyl, n-propyl, isopropyl or tert-butyl, preferably methyl and ethyl;
R2selected from: methyl, ethyl;
R3selected from: methoxycarbonyl, ethoxyformyl, tert-butoxyformyl, benzyloxyformyl, trichloroethoxycarbonyl or benzyl, preferably benzyloxyformyl.
In some of these embodiments, the base of step (a) is selected from at least one of potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium hydride, and potassium hydride.
In some of the embodiments, the catalyst in step (a) is a combination of quaternary ammonium salt and iodide, the quaternary ammonium salt is selected from any one of tetrabutylammonium bromide, tetraethylammonium bromide, tetrabutylammonium iodide and benzyltriethylammonium chloride, and the iodide is selected from any one of sodium iodide, potassium iodide and lithium iodide.
In some of these embodiments, the molar ratio of quaternary ammonium salt to iodide is 1: 2 to 6.
In some of the embodiments, the solvent for the alkylation reaction in step (a) is selected from any one of acetonitrile, methanol, ethanol, N-dimethylacetamide, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1, 4-dioxane, toluene, dichloromethane, and 1, 2-dichloroethane.
In some of the embodiments, the reaction temperature of the alkylation reaction in the step (a) is 20 to 120 ℃.
In some of these embodiments, the molar ratio of the diethyl acetamidomalonate of step (a), the 2, 3-dichloropropene, the catalyst, and the base is from 1: 1 to 2: 0.1 to 0.5: 1 to 3.
In some of the embodiments, the acid in step (b) is an aqueous solution of hydrogen chloride, and the concentration of the aqueous solution of hydrogen chloride is 5-12 mol/L.
In some of these embodiments, the molar ratio of the compound of formula 2 to hydrogen chloride is 1: 5 to 30.
In some of these embodiments, the acid of step (c) is selected from any one of sulfuric acid, phosphoric acid, hydrochloric acid, and p-toluenesulfonic acid.
In some of the embodiments, the solvent for the esterification reaction in step (c) is selected from at least one of ethanol, diethyl carbonate, dimethyl carbonate, methanol, propanol, and benzyl alcohol.
In some of the embodiments, the esterification reaction of step (c) is carried out at a reaction temperature of 0 to 120 ℃.
In some of these embodiments, the base of step (d) is selected from any one of potassium carbonate, potassium bicarbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene.
In some of these embodiments, the 4-halobutyrate of step (d) is selected from any one of 4-bromobutyrate, 4-chlorobutyrate, 4-iodobutyrate.
In some embodiments, the catalyst in step (d) is a quaternary ammonium salt selected from any one of tetrabutylammonium bromide, tetraethylammonium bromide, tetrabutylammonium iodide and benzyltriethylammonium chloride, or a combination of a quaternary ammonium salt and an iodide selected from any one of sodium iodide and potassium iodide.
In some of the embodiments, the solvent for the nitrogen alkylation reaction in step (d) is any one of acetonitrile, methanol, ethanol, N-dimethylacetamide, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1, 4-dioxane, toluene, dichloromethane, and 1, 2-dichloroethane.
In some of the embodiments, the reaction temperature of the nitrogen alkylation reaction in the step (d) is 20 to 100 ℃.
In some embodiments, the molar ratio of the compound of formula 4, 4-halobutyrate, base, and catalyst in step (d) is 1: 1 to 1.5: 1 to 3: 0.01 to 0.2.
In some of these embodiments, the amino protecting reagent of step (d) is selected from any one of benzyl chloroformate, di-tert-butyl dicarbonate, methyl chloroformate, ethyl chloroformate, trichloroethyl chloroformate, benzyl bromide, and benzyl chloride.
In some of these embodiments, the molar ratio of the amino protecting agent of step (d) to the compound of formula 4 is 0.8 to 2: 1.
in some of the embodiments, the reaction temperature of the nitrogen protection reaction in the step (d) is 0 to 100 ℃.
In some of these embodiments, the 4-halobutyrate of step (d) is ethyl 4-bromobutyrate.
In some of the embodiments, the amino protecting reagent of step (d) is benzyl chloroformate, the molar ratio of benzyl chloroformate to the compound of formula 4 is 0.8-1.2: 1, and the reaction temperature of the nitrogen protection reaction is 0-50 ℃.
In some embodiments, the base in step (e) is selected from any one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium diisopropylamide, sodium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, and potassium bis (trimethylsilyl) amide.
In some embodiments, the solvent for the Dieckmann condensation reaction of step (e) is selected from any one or a combination of two of tetrahydrofuran, toluene, xylene, methyl tert-butyl ether, methanol, and ethanol.
In some of these embodiments, the molar ratio of base to compound of formula 5 for the reaction of step (e) is 1-3: 1.
In some embodiments, the Dieckmann condensation reaction of step (e) is carried out at a reaction temperature of-20 to 80 ℃.
In some of the embodiments, the inorganic salt in step (f) is selected from any one of sodium chloride, lithium chloride, sodium bromide and lithium bromide.
In some of these embodiments, the molar ratio of the inorganic salt of step (f) to the compound of formula 6 is 1-3: 1.
In some embodiments, the reaction solvent for the decarboxylation reaction of step (f) is a combination of an organic solvent selected from any one of dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, N-dimethylacetamide and N, N-dimethylformamide and water.
In some embodiments, the volume-to-mass ratio of the organic solvent, water and the compound of formula 6 in step (f) is 3-5: 0.1-1: 1.
In some of the embodiments, the decarboxylation reaction of step (f) is performed at a temperature of 100-150 ℃.
In some of these embodiments, the inorganic salt of step (f) is lithium chloride and the reaction solvent for the decarboxylation reaction is a combination of N, N-dimethylformamide and water.
In some of these embodiments, the reducing agent of step (g) is selected from any one of sodium borohydride, potassium borohydride, lithium aluminum hydride, sodium bis (2-methoxyethoxy) dihydroaluminate, borane, sodium amalgam, lithium tri-tert-butoxyaluminum hydride. Sodium borohydride is preferred.
In some of these embodiments, the solvent for the reduction reaction of step (g) is ethanol.
In some embodiments, the molar ratio of the reducing agent of step (g) to the compound of formula 7 is 1-2: 1.
In some of these embodiments, the temperature of the reduction reaction of step (g) is 0 to 10 ℃.
In some of these embodiments, R3The compound of the formula 8 is subjected to nitrogen deprotection reaction under the action of acid to generate the compound of the formula 9, wherein the acid is at least one selected from hydrochloric acid, hydrobromic acid and sulfuric acid; the solvent of the deprotection reaction in the step (h) is acetic acid, water or a combination of water and alcohol, and the alcohol is any one of methanol, ethanol and isopropanol.
In some of these embodiments, R1Is ethyl; r2Is ethyl; r3Is a benzyloxyformyl group.
The invention also provides a synthetic method of the halofuginone with optical activity.
The specific technical scheme is as follows:
a method for synthesizing halofuginone with optical activity comprises the following steps:
(3) the cis-2- (2-chloropropenyl) -3-hydroxypiperidine with optical activity reacts with an amino protective reagent under the action of alkali to generate a compound with the optical activity of a formula (+) -10 or a formula (-) -10;
(4) reacting an optically active compound of formula (+) -10 or formula (-) -10 with an olefinic brominating agent and water to produce an optically active compound of formula (+) -11 or formula (-) -11;
(5) reacting the optically active compound of the formula (+) -11 or the formula (-) -11 with the compound of the formula 12 under the action of alkali, and then removing the 9-fluorenylmethyloxycarbonyl protecting group on the piperidine ring nitrogen to generate the optically active compound of the formula (+) -13 or the formula (-) -13;
(6) isomerizing the optically active compound of formula (+) -13 or formula (-) -13 to produce optically active halofuginone;
the dichroa febrifuga ketone with optical activity has a structure shown as a formula (+) -1 or (-) -1, and the reaction formula is as follows:
or,
in some embodiments, the base in step (3) is selected from any one of sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.
In some embodiments, the amino protecting reagent of step (3) is selected from any one of chloroformate-9-fluorenylmethyl ester, 9-fluorenylmethyl-1-benzotriazolyl carbonate, and 9-fluorenylmethyl-N-succinimidyl carbonate.
In some embodiments, the solvent for the reaction in step (3) is a combination of an organic solvent and water, and the organic solvent is any one of 1, 4-dioxane and tetrahydrofuran.
In some of these embodiments, the molar ratio of base, amino protecting agent and cis-2- (2-chloropropenyl) -3-hydroxypiperidine in step (3) is from 1 to 5: 1-2: 1.
in some of the embodiments, the temperature of the reaction in the step (3) is 0-20 ℃.
In some of the embodiments, the alkene bromination reagent in step (4) is selected from any one of N-bromosuccinimide and 1, 3-dibromo-5, 5-dimethylhydantoin.
In some embodiments, the solvent for the reaction of step (4) is selected from any one of acetonitrile, tetrahydrofuran, and 1, 4-dioxane.
In some of these embodiments, the molar ratio of alkene bromination reagent described in step (4) to compound of formula (+) -10 or (-) -10 is 0.9-1.2: 1.
in some of the embodiments, the reaction temperature of the reaction in the step (4) is-10 to 35 ℃.
In some of the embodiments, the reaction temperature of the reaction is-10 to 10 ℃.
In some embodiments, the base in step (5) is selected from any one of potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium diisopropylamide, sodium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, and potassium bis (trimethylsilyl) amide.
In some of the embodiments, the solvent for the reaction of step (5) is selected from any one of acetonitrile, methanol, ethanol, N-dimethylacetamide, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, 1, 4-dioxane, toluene, dichloromethane, and 1, 2-dichloroethane.
In some of these embodiments, the molar ratio of the compound of formula (+) -11 or formula (-) -11, the compound of formula 12 and the base of step (5) is 0.8 to 1.2: 1: 1 to 2.
In some embodiments, the reaction temperature of the reaction in the step (5) is-10 to 25 ℃.
In some embodiments, the removal of the 9-fluorenylmethyloxycarbonyl protecting group from the nitrogen of the piperidine ring in step (5) is performed under the action of a secondary organic amine or a tertiary organic amine.
In some embodiments, the reaction temperature for removing the 9-fluorenylmethyloxycarbonyl protecting group of the nitrogen on the piperidine ring in the step (5) is-10 to 25 ℃.
In some of these embodiments, the secondary or tertiary organic amine of step (5) is diethylamine.
In some embodiments, the solvent for the isomerization reaction in step (6) is selected from any one or a combination of two of water, ethanol, methanol, N-butanol, N-propanol, t-butanol, N-dimethylformamide, tetrahydrofuran and 1, 4-dioxane.
In some of the embodiments, the isomerization reaction of step (6) has a reaction temperature of 50 to 80 ℃.
In some embodiments, the method for synthesizing optically active halofuginone further comprises a step of preparing optically active cis-2- (2-chloropropenyl) -3-hydroxypiperidine, which comprises:
(1) in a first organic solvent, carrying out salt-forming reaction on racemic cis-2- (2-chloropropenyl) -3-hydroxypiperidine and dibenzoyl tartaric acid or derivatives thereof to generate a precipitate, and recrystallizing the precipitate to obtain chiral double salt;
(2) neutralizing the chiral double salt with an alkaline aqueous solution to be alkaline in a second organic solvent to obtain cis-2- (2-chloropropenyl) -3-hydroxypiperidine with optical activity;
the racemic cis-2- (2-chloropropenyl) -3-hydroxypiperidine has a structure shown by a formula (+/-) -9; the optically active cis-2- (2-chloropropenyl) -3-hydroxypiperidine has a structure shown by a formula (+) -9 or a formula (-) -9; the dibenzoyl tartaric acid or the derivative thereof has a structure shown in a formula 15 or a formula 16; the chiral double salt has a structure shown in formula 14 or formula 17; the reaction formula is as follows:
or,
wherein each R is independently selected from: hydrogen or C1-C4An alkoxy group.
In some of these embodiments, the dibenzoyl tartaric acid of formula 15 or its derivative described in step (1) is L- (-) -dibenzoyl tartaric acid or L- (-) -di-p-methoxybenzoyl tartaric acid, and the dibenzoyl tartaric acid of formula 16 or its derivative is D- (+) -dibenzoyl tartaric acid or D- (+) -di-p-methoxybenzoyl tartaric acid.
In some of these embodiments, the molar ratio of racemic cis-2- (2-chloropropenyl) -3-hydroxypiperidine to dibenzoyltartaric acid or a derivative thereof described in step (1) is 1: 1 to 2.
In some embodiments, the recrystallization is carried out at a volume ratio of 1 to 10: 1 in a mixed solvent of a third organic solvent and water; the third organic solvent is selected from any one or more of ethanol, methanol, isopropanol, acetonitrile, 1, 4-dioxane and acetone.
In some of these embodiments, the recrystallization is carried out in a volume ratio of 1: 3-5 of a third organic solvent and water; the third organic solvent is acetonitrile.
In some embodiments, the first organic solvent in step (1) is selected from any one or more of ethanol, methanol, isopropanol, acetonitrile, dichloromethane, 1, 4-dioxane, tetrahydrofuran, toluene, acetone, and ethyl acetate; and/or the presence of a catalyst in the reaction mixture,
the second organic solvent in the step (2) is selected from any one or more of ethyl acetate, dichloromethane and trichloromethane.
In some of the embodiments, the temperature of the salt forming reaction is 0 to 100 ℃; and/or the temperature of recrystallization is 0-30 ℃.
In some embodiments, the temperature of the salt forming reaction is 20-40 ℃; and/or the temperature of recrystallization is 15-28 ℃.
In some embodiments, the alkaline aqueous solution in step (2) is any one of an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, an aqueous lithium hydroxide solution, an aqueous potassium carbonate solution and an aqueous sodium carbonate solution, and the neutralization is performed until the alkaline is reached and the pH is 8-14.
In some of these embodiments, the process for synthesizing the racemic cis-2- (2-chloropropenyl) -3-hydroxypiperidine comprises the steps of:
(a) reacting diethyl acetylaminomalonate with 2, 3-dichloropropene under the action of alkali and a catalyst to generate a compound shown in a formula 2;
(b) the compound of the formula 2 undergoes a hydrolysis decarboxylation reaction under the catalysis of acid to generate a compound of a formula 3;
(c) carrying out an esterification reaction on the compound of the formula 3 under the catalysis of acid to generate a compound of a formula 4;
(d) the compound of formula 4 and 4-halobutyrate are subjected to nitrogen alkylation reaction under the action of alkali and a catalyst, and then are subjected to nitrogen protection reaction with an amino protection reagent to generate a compound of formula 5;
(e) carrying out Dieckmann condensation reaction on the compound shown in the formula 5 under the action of alkali to generate a compound shown in a formula 6;
(f) the compound of the formula 6 undergoes decarboxylation under the action of inorganic salt to generate a compound of a formula 7;
(g) the compound of the formula 7 is subjected to a reduction reaction under the action of a reducing agent to generate a compound of a formula 8;
(h) deprotecting nitrogen in the compound of formula 8 to produce a compound of formula 9;
the reaction formula is as follows:
wherein:
R1selected from: methyl, ethyl, n-propyl, isopropyl or tert-butyl, preferably methyl and ethyl;
R2selected from: methyl, ethyl;
R3selected from: methoxycarbonyl, ethoxyformyl, tert-butoxyformyl, benzyloxyformyl, trichloroethoxycarbonyl or benzyl, preferably benzyloxyformyl.
In some of these embodiments, the base of step (a) is selected from at least one of potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium hydride, and potassium hydride.
In some of the embodiments, the catalyst in step (a) is a combination of quaternary ammonium salt and iodide, the quaternary ammonium salt is selected from any one of tetrabutylammonium bromide, tetraethylammonium bromide, tetrabutylammonium iodide and benzyltriethylammonium chloride, and the iodide is selected from any one of sodium iodide, potassium iodide and lithium iodide.
In some of these embodiments, the molar ratio of quaternary ammonium salt to iodide is 1: 2 to 6.
In some of the embodiments, the solvent for the alkylation reaction in step (a) is selected from any one of acetonitrile, methanol, ethanol, N-dimethylacetamide, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1, 4-dioxane, toluene, dichloromethane, and 1, 2-dichloroethane.
In some of the embodiments, the reaction temperature of the alkylation reaction in the step (a) is 20 to 120 ℃.
In some of these embodiments, the molar ratio of the diethyl acetamidomalonate of step (a), the 2, 3-dichloropropene, the catalyst, and the base is from 1: 1 to 2: 0.1 to 0.5: 1 to 3.
In some of the embodiments, the acid in step (b) is an aqueous solution of hydrogen chloride, and the concentration of the aqueous solution of hydrogen chloride is 5-12 mol/L.
In some of these embodiments, the molar ratio of the compound of formula 2 to hydrogen chloride is 1: 5 to 30.
In some of these embodiments, the acid of step (c) is selected from any one of sulfuric acid, phosphoric acid, hydrochloric acid, and p-toluenesulfonic acid.
In some of the embodiments, the solvent for the esterification reaction in step (c) is selected from at least one of ethanol, diethyl carbonate, dimethyl carbonate, methanol, propanol, and benzyl alcohol.
In some of the embodiments, the esterification reaction of step (c) is carried out at a reaction temperature of 0 to 120 ℃.
In some of these embodiments, the base of step (d) is selected from any one of potassium carbonate, potassium bicarbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene.
In some of these embodiments, the 4-halobutyrate of step (d) is selected from any one of 4-bromobutyrate, 4-chlorobutyrate, 4-iodobutyrate.
In some embodiments, the catalyst in step (d) is a quaternary ammonium salt selected from any one of tetrabutylammonium bromide, tetraethylammonium bromide, tetrabutylammonium iodide and benzyltriethylammonium chloride, or a combination of a quaternary ammonium salt and an iodide selected from any one of sodium iodide and potassium iodide.
In some of the embodiments, the solvent for the nitrogen alkylation reaction in step (d) is any one of acetonitrile, methanol, ethanol, N-dimethylacetamide, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1, 4-dioxane, toluene, dichloromethane, and 1, 2-dichloroethane.
In some of the embodiments, the reaction temperature of the nitrogen alkylation reaction in the step (d) is 20 to 100 ℃.
In some embodiments, the molar ratio of the compound of formula 4, 4-halobutyrate, base, and catalyst in step (d) is 1: 1 to 1.5: 1 to 3: 0.01 to 0.2.
In some of these embodiments, the amino protecting reagent of step (d) is selected from any one of benzyl chloroformate, di-tert-butyl dicarbonate, methyl chloroformate, ethyl chloroformate, trichloroethyl chloroformate, benzyl bromide, and benzyl chloride.
In some of these embodiments, the molar ratio of the amino protecting agent of step (d) to the compound of formula 4 is 0.8 to 2: 1.
in some of the embodiments, the reaction temperature of the nitrogen protection reaction in the step (d) is 0 to 100 ℃.
In some of these embodiments, the 4-halobutyrate of step (d) is ethyl 4-bromobutyrate.
In some of the embodiments, the amino protecting reagent of step (d) is benzyl chloroformate, the molar ratio of benzyl chloroformate to the compound of formula 4 is 0.8-1.2: 1, and the reaction temperature of the nitrogen protection reaction is 0-50 ℃.
In some embodiments, the base in step (e) is selected from any one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium diisopropylamide, sodium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, and potassium bis (trimethylsilyl) amide.
In some embodiments, the solvent for the Dieckmann condensation reaction of step (e) is selected from any one or a combination of two of tetrahydrofuran, toluene, xylene, methyl tert-butyl ether, methanol, and ethanol.
In some of these embodiments, the molar ratio of base to compound of formula 5 for the reaction of step (e) is 1-3: 1.
In some embodiments, the Dieckmann condensation reaction of step (e) is carried out at a reaction temperature of-20 to 80 ℃.
In some of the embodiments, the inorganic salt in step (f) is selected from any one of sodium chloride, lithium chloride, sodium bromide and lithium bromide.
In some of these embodiments, the molar ratio of the inorganic salt of step (f) to the compound of formula 6 is 1-3: 1.
In some embodiments, the reaction solvent for the decarboxylation reaction of step (f) is a combination of an organic solvent selected from any one of dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, N-dimethylacetamide and N, N-dimethylformamide and water.
In some embodiments, the volume-to-mass ratio of the organic solvent, water and the compound of formula 6 in step (f) is 3-5: 0.1-1: 1.
In some of the embodiments, the decarboxylation reaction of step (f) is performed at a temperature of 100-150 ℃.
In some of these embodiments, the inorganic salt of step (f) is lithium chloride and the reaction solvent for the decarboxylation reaction is a combination of N, N-dimethylformamide and water.
In some of these embodiments, the reducing agent of step (g) is selected from any one of sodium borohydride, potassium borohydride, lithium aluminum hydride, sodium bis (2-methoxyethoxy) dihydroaluminate, borane, sodium amalgam, lithium tri-tert-butoxyaluminum hydride. Sodium borohydride is preferred.
In some of these embodiments, the solvent for the reduction reaction of step (g) is ethanol.
In some embodiments, the molar ratio of the reducing agent of step (g) to the compound of formula 7 is 1-2: 1.
In some of these embodiments, the temperature of the reduction reaction of step (g) is 0 to 10 ℃.
In some of these embodiments, R3The compound of the formula 8 is subjected to nitrogen deprotection reaction under the action of acid to generate the compound of the formula 9, wherein the acid is at least one selected from hydrochloric acid, hydrobromic acid and sulfuric acid; the solvent of the deprotection reaction in the step (h) is acetic acid, water or a combination of water and alcohol, and the alcohol is any one of methanol, ethanol and isopropanol.
In some of these embodiments, R1Is ethyl; r2Is ethyl; r3Is a benzyloxyformyl group.
It is understood that the above method for synthesizing optically active halofuginone can synthesize optically active halofuginone by directly carrying out the subsequent reaction using the reaction product obtained in any of the steps (a) to (g) and (1) to (6) as a starting material. For example, racemic cis-2- (2-chloropropenyl) -3-hydroxypiperidine may be used as a starting material and subjected to the steps (1) to (6) described above to synthesize optically active halofuginone, or a compound of formula 3 may be used as a starting material and subjected to the steps (c) to (g) and (1) to (6) described above to synthesize optically active halofuginone.
The invention obtains cis-2- (2-chloropropenyl) -3-hydroxypiperidine with optical activity by chiral resolution of racemic cis-2- (2-chloropropenyl) -3-hydroxypiperidine with chiral dibenzoyl tartaric acid, and further prepares the halofuginone with optical activity by using the resolved cis-2- (2-chloropropenyl) -3-hydroxypiperidine with optical activity. The basic nitrogen atom of the cis-2- (2-chloropropenyl) -3-hydroxypiperidine can be salified with chiral dibenzoyl tartaric acid, and the cis-2- (2-chloropropenyl) -3-hydroxypiperidine with optical activity can be obtained by simple crystallization and resolution after salification. The chiral dibenzoyltartaric acid used by the synthetic method has wide sources and low price, the preparation process is simple, the product has few impurities, column chromatography purification is not needed, and the large-scale production and preparation of the halofuginone with high optical purity can be realized. The synthesis method of chiral halofuginone and the intermediate thereof solves the technical defects in the conventional halofuginone synthesis, has the advantages of simple synthesis process, low cost, less by-products in the synthesis process, simple purification process, no need of column chromatography purification, high product yield, less impurities, high purity and controllable product quality, and solves the defects of complicated synthesis route, harsh reaction conditions, low yield, complicated separation and purification or use of virulent and expensive reagents and the like in the conventional process for synthesizing optically active halofuginone or halofuginine.
Further, the inventors of the present invention found that the reasonable selection of the protecting group of the piperidine ring nitrogen atom is very important in the synthesis of halofuginone, and if the protecting group is not properly selected, many byproducts are generated during the deprotection process, which may result in low yield of the product, poor product quality, or difficult purification. The invention selects 9-fluorenylmethyloxycarbonyl (Fmoc) as the protective group of the nitrogen atom of the piperidine ring, the removal is very simple, the removal can be realized only by acting in secondary or tertiary organic amine for several seconds or several minutes, and the generation of byproducts is greatly reduced.
Detailed Description
The process for producing halofuginone according to the present invention will be described in detail with reference to specific examples.
In the present invention, the compounds represented by formula 8, formula 9, formula 10, formula 11, formula 13 and formula 1 are racemic compounds when they are not (+) or (-) or when they are (+ -) labeled, and the steric structure in the formula is a relative configuration, not an absolute configuration; when (+) or (-) is injected into the compounds represented by formula 8, formula 9, formula 10, formula 11, formula 13 and formula 1, they are chiral compounds having optical activity, and the steric structure in the formula is an absolute configuration.
The temperature range of room temperature in the following examples is 18-25 ℃.
Example 1 Synthesis of racemic halofuginone
Intermediate Compound 4 (R)1Et) synthesis
Step (a), adding diethyl acetylaminomalonate (5.00kg, 23.02mol), anhydrous potassium carbonate (6.35kg, 46.04mol), potassium iodide (0.76kg, 4.6mol), tetrabutylammonium bromide (0.37kg, 1.15mol) and acetonitrile (25L) into a 50L reaction kettle at room temperature, stirring for 20 minutes, adding 2, 3-dichloropropene (3.07kg, 27.62mol), heating to 85-90 ℃ for reaction, monitoring the reaction by using HP L C, cooling the reaction liquid to below 25 ℃ after the reaction is finished, slowly dropping diluted hydrochloric acid into the reaction kettle to neutralize the pH to 7-7.5, standing, separating, concentrating the organic layer at 50 ℃, adding ethanol-water (1: 10, 20L) into the concentrated residue, stirring for 1 hour for crystallization, filtering under reduced pressure, and leaching a filter cake by using water to obtain a yellow solid, namely the compound of formula 2 (10.50 kg) without drying, and directly reacting.
1H NMR(500MHz,Chloroform-d)5.28(d,J＝1.2Hz,1H),5.17(d,J＝1.1Hz,1H),4.26(qd,J＝7.1,2.4Hz,4H),3.47(s,2H),2.03(s,3H),1.55–1.51(m,1H),1.27(t,J＝7.1Hz,6H).
13C NMR(126MHz,Chloroform-d)169.3,167.3,136.5,117.8,65.2,63.0,41.6,23.0,14.0.
HRMS(m/z):calc.for C12H19ClNO5[M+H]+＝292.0952；found,292.0954
And (b) adding the compound of the formula 2 (10.5 kg of wet weight, 23.02mol) and a hydrochloric acid solution (6 mol/L, 57.5L, 345.27mol) into a 100L reaction kettle at room temperature, stirring, heating to 100 ℃, carrying out reflux reaction, monitoring the reaction at T L C, adding activated carbon (650g) into the reaction kettle after the reaction is finished, cooling to 50 ℃, carrying out reduced pressure filtration, leaching a filter cake with water, combining the filter liquor, carrying out reduced pressure concentration on the filter liquor at 80-85 ℃ to remove the solvent to obtain a light yellow solid, namely the compound of the formula 3 (4.05kg), wherein the product is not required to be further purified, and is directly put into the next step of reaction.
And (C) adding the compound (4.05kg, 21.77mol) of the formula 3, diethyl carbonate (12L) and absolute ethyl alcohol (4L) into a 50L reaction kettle at room temperature, stirring, dropwise adding concentrated sulfuric acid (1.13kg, 11.51mol), completing dropwise within about 20-30 minutes, heating to 85-95 ℃ for reflux reaction, monitoring the reaction by using HP L C, cooling the reaction liquid to within 50-60 ℃ after the reaction is finished, concentrating the residual liquid under reduced pressure by adding water, cooling to within 10 ℃, dropwise adding 30% sodium hydroxide to adjust the pH to 8-9, transferring to room temperature, extracting by using dichloromethane (10 L× 3) to mix organic layers, adding anhydrous sodium sulfate for drying, filtering under reduced pressure, and concentrating the filtrate at 40 ℃ under reduced pressure to obtain a light brown oily substance, namely the compound 4(3.07kg, wherein the yield of 3 steps is 75%).
1H NMR(500MHz,Chloroform-d)5.30(d,J＝1.3Hz,1H),5.26(q,J＝1.1Hz,1H),4.20(q,J＝7.1Hz,2H),3.78(dd,J＝8.6,4.8Hz,1H),2.81(ddd,J＝14.2,4.8,1.1Hz,1H),2.56(dd,J＝14.2,8.6Hz,1H),1.28(t,J＝7.1Hz,3H).
13C NMR(126MHz,Chloroform-d)174.5,138.5,115.9,61.4,52.3,44.6,14.3.
HRMS(m/z):calc.for C7H13ClNO2[M+H]+＝178.0635；found,178.0628.
Description of the drawings: in step (a), the product is a wet product without drying, and the calculated yield is over the theoretical value, so that the mole number of the compound of formula 2 is 23.02mol based on 100% yield.
Intermediate Compound 6 (R)1＝Et；R2＝Et；R3C — Cbz) synthesis
Step (d), adding the compound of formula 4(3.07kg, 17.26mol), anhydrous sodium carbonate (5.49kg, 51.79mol), tetrabutylammonium iodide (0.64kg, 1.73mol) and toluene (9L) into a 50L reaction kettle at room temperature, stirring for 20 minutes, adding a toluene (6L) solution of 4-bromobutyric acid ethyl ester (3.37kg, 17.26mol), heating to 75-80 ℃, stirring for reaction, monitoring the reaction at HP L C, cooling to 20-25 ℃, adding water (9L), stirring for 10-15 minutes, dropwise adding benzyl chloroformate (2.94kg, 17.26mol), after finishing dropping for about 2-3 hours, continuing stirring for reaction at 20-25 ℃, monitoring the reaction at T L C, adding water (10L) and toluene (10L) after the reaction is finished, stirring for 0.5 hours, separating an organic layer, sequentially adding 5% NaOH (15%), water (465%) and 20-25% carbon (4835.5%) into the organic layer, directly adding hydrochloric acid (5g), stirring for 0.5 g) and filtering to obtain a brown organic layer, and directly adding a purified product at room temperature, wherein the organic layer is prepared by stirring and the organic layer is not subjected to obtain a brown active substance after stirring for 20-5 hours, and filtering, and the organic layer is performed after the organic layer is performed by suction filtration step (5 hours, and the steps of 5.
1H NMR(500MHz,Chloroform-d)7.39–7.27(m,5H),5.19(d,J＝1.3Hz,1H),5.17–5.07(m,2.6H),5.02(s,0.4H),4.27–3.89(m,5H),3.68–3.56(m,1H),3.23–3.10(m,1.6H),3.02–2.90(m,1.4H),2.47–2.26(m,2H),1.99–(m,2H),1.27–1.17(m,4.8H),1.13(t,J＝7.2Hz,1.2H).
13C NMR(126MHz,Chloroform-d)173.3,173.2,170.3,170.2,155.6,138.8,138.4,136.7,136.2,128.7,128.6,128.4,128.2,127.9,116.3,116.0,67.6,67.4,61.7,60.5,59.6,58.7,49.2,48.9,40.5,39.4,31.6,31.4,24.2,23.7,14.4,14.14,14.07.
HRMS(m/z):calc.for C21H29ClNO6[M+H]+＝426.1683；found,426.1678
Adding sodium tert-butoxide (3.31kg, 34.53mol) and anhydrous tetrahydrofuran (38L) into a 100L reaction kettle at room temperature under the protection of nitrogen, stirring, cooling to below-5 ℃, dissolving a compound (8.10kg, 17.26mol) of formula 5 in tetrahydrofuran (15L), dropwise adding into the reaction kettle, controlling the temperature to be less than 0 ℃, completing dropwise adding within 4-5 hours, continuously stirring at 0-5 ℃, monitoring the reaction at HP L C, after the reaction is finished, dropwise adding dilute hydrochloric acid into the kettle, adjusting the pH to 5-6, adding ethyl acetate (10L), stirring at room temperature, separating, washing an organic layer with saturated sodium chloride (20 L× 2), extracting an aqueous layer with ethyl acetate (10L), combining the organic layers, adding activated carbon (500g), stirring at room temperature for 1 hour, performing suction filtration, and concentrating the filtrate under reduced pressure to obtain a light brown oily substance, namely the compound 6(5.44kg, the yield of 83%).
1H NMR(500MHz,Chloroform-d)12.23(s,1H),7.41–7.28(m,5H),5.27–5.05(m,4H),5.01(s,0.4H),4.94–4.82(m,0.6H),4.30(dd,J＝13.6,5.7Hz,0.6H),4.23(q,J＝7.1Hz,2H),4.19–4.12(m,0.4H),3.09–2.66(m,3H),2.46–2.23(m,2H),1.30(t,J＝7.1Hz,3H).
13C NMR(126MHz,Chloroform-d)172.0,171.9,168.8,168.2,155.2,155.1,138.4,138.3,136.7,136.3,128.5,128.2,128.0,115.8,115.6,97.7,97.4,67.7,67.5,61.0,52.7,52.5,41.5,40.7,38.2,37.3,22.8,22.3,14.3.
HRMS(m/z):calc.for C19H23ClNO5[M+H]+＝380.1265；found,380.1266
Description of the drawings: in the step (d), the yield is calculated to exceed the theoretical value, so that the number of moles of the compound of formula 5 is 17.26mol based on 100% yield.
Intermediate Compound 7 (R)3C — Cbz) synthesis
And (f) adding the compound 6(5.44kg, 14.33mol), DMF (16.3L), water (2.7L) and lithium chloride (0.61kg, 14.33mol) into a 50L reaction kettle at room temperature, stirring, heating to 120 ℃, stirring for reaction, monitoring the reaction by using HP L C, cooling the reaction liquid to 20-25 ℃ after the reaction is finished, adding water (25L) and methyl tert-butyl ether (30L), stirring, separating the organic layers, washing the organic layers with water (25 L× 2), separating the organic layers, extracting the produced water layers with methyl tert-butyl ether (25L), combining the organic layers, and concentrating at 45 ℃ under reduced pressure to obtain a brown oily substance, namely the compound 7(4.19kg, the yield is 95%).
1H NMR(500MHz,Chloroform-d)7.40–7.29(m,5H),5.32–5.03(m,4H),4.86(s,1H),4.34–3.98(m,1H),3.23(s,1H),2.94–2.59(m,2H),2.59–2.39(m,2H),2.05(s,1H),2.01–1.92(m,1H).
13C NMR(126MHz,Chloroform-d)206.7,155.5,128.6,128.3,116.1,67.8,61.8,37.1,22.5.
HRMS(m/z):calc.for C16H19ClNO3[M+H]+＝308.1053；found,308.1057
Intermediate Compound 8 (R)3C — Cbz) synthesis
Adding absolute ethyl alcohol (18L) and sodium borohydride (0.51kg, 13.61mol) into a 50L reaction kettle at room temperature, stirring and cooling to 5-10 ℃, dissolving a compound 7(4.19kg, 13.61mol) by absolute ethyl alcohol (9L), then dropwise adding the mixture into the reaction kettle, controlling the temperature in the dropwise adding process to be not more than 10 ℃, after dropwise adding, continuously stirring at 5-10 ℃, monitoring the reaction by HP L C, after the reaction is finished, dropwise adding water (20L) into the reaction kettle, after dropwise adding, adding methyl tert-butyl ether (25L), stirring, separating, washing an organic layer by 10% of NaOH (10L), 5% of hydrochloric acid (10 L× 2) and water (10L), extracting a generated water layer by using methyl tert-butyl ether (25L), combining the organic layers, adding activated carbon (500g), stirring for 1 hour at room temperature, and filtering under reduced pressure to obtain a brown oily substance, namely the compound 8(3.50kg, the yield 83%).
1H NMR(500MHz,Chloroform-d)7.42–7.27(m,5H),5.21–5.06(m,4H),4.76(s,1H),4.05(d,J＝14.0Hz,1H),3.92–3.79(m,1H),2.84–2.60(m,3H),1.87–1.76(m,1H),1.76–1.65(m,1H),1.58–1.42(m,2H).
13C NMR(126MHz,Chloroform-d)155.8,139.8,136.7,128.5,128.2,128.1,114.5,68.7,67.5,54.2,37.9,33.5,27.9,24.3.
HRMS(m/z):calc.for C16H21ClNO3[M+H]+＝310.1210；found,310.1208
Synthesis of intermediate Compound 9
Adding a compound 8(3.55kg, 12.36mol), hydrochloric acid (6 mol/L, 18.83L, 112.98mol) and ethanol (20L) into a 50L reaction kettle at room temperature, stirring and heating to reflux to react, monitoring the reaction by using HP L C, cooling the reaction liquid to 50-55 ℃ after the reaction is finished, concentrating under reduced pressure to remove the ethanol, adding methyl tert-butyl ether (20 L× 2) into the residual liquid, stirring, separating liquid, adjusting the pH of a water layer to be more than 11 by using 40% sodium hydroxide, adding ethyl acetate (20 L× 2) to extract, combining organic layers, adding anhydrous magnesium sulfate to dry, filtering, concentrating the filtrate under reduced pressure to obtain a crude product, adding acetonitrile (5L) into the crude product, stirring and dissolving at 70 ℃, standing at room temperature to crystallize, filtering, and drying in vacuum to obtain a near-white solid, namely the compound 9(1.01kg, the yield of 50.7%).
1H NMR(500MHz,Chloroform-d)5.25(d,J＝1.1Hz,1H),5.23(t,J＝1.0Hz,1H),3.65(S,1H),3.03(ddt,J＝11.5,4.3,2.0Hz,1H),2.88(ddd,J＝7.5,6.3,1.4Hz,1H),2.65(td,J＝11.9,2.9Hz,1H),2.49(d,J＝6.8Hz,2H).,1.91(dtt,J＝13.4,4.0,2.0Hz,1H),1.73(qt,J＝13.1,4.3Hz,1H),1.54(tdd,J＝13.3,4.7,2.5Hz,1H),1.45(ddq,J＝12.9,4.9,2.6Hz,1H).
13C NMR(126MHz,Chloroform-d)139.8,115.2,67.1,57.7,47.2,43.0,32.2,20.4.
HRMS(m/z):calc.for C8H15ClNO[M+H]+＝176.0842；found,176.0837
Synthesis of intermediate Compound 13
Adding the compound 9(1kg, 5.69mol), 1, 4-dioxane (5L), water (5L) and sodium carbonate (0.91kg, 8.54mol) into a 50L reaction kettle at room temperature, stirring and cooling to 5-10 ℃, dissolving chloroformic acid-9-fluorenylmethyl ester (1.47kg, 5.69mol) in 1, 4-dioxane (2L), dropwise adding into the reaction kettle at the temperature of not more than 20 ℃, continuing stirring at room temperature for reaction, monitoring T L C, adding ethyl acetate (20L) and water (20L) after the reaction is finished, stirring, separating, washing an organic layer with saturated sodium chloride (5 L× 2), separating, extracting an aqueous layer with ethyl acetate (10L), combining the organic layers, adding activated carbon (500g), stirring for 1 hour at room temperature, filtering, concentrating the filtrate under reduced pressure to obtain a light yellow thick substance, namely the compound 10(2.81kg), and directly putting the product into the reaction kettle without further purification.
1H NMR(500MHz,Chloroform-d)7.81–7.71(m,2H),7.65–7.53(m,2H),7.40(td,J＝7.5,2.4Hz,2H),7.31(t,J＝7.4Hz,2H),5.17(s,1H),5.14(s,1H),4.93–4.51(m,1H),4.49(dd,J＝10.7,6.7Hz,1H),4.41(dd,J＝10.7,6.5Hz,1H),4.25(t,J＝6.5Hz,1H),3.92(s,1H),3.76(s,1H),2.85–2.54(m,3H),1.87–1.74(m,1H),1.73–1.58(m,1H),1.57–1.33(m,2H).
13C NMR(126MHz,Chloroform-d)155.8,144.1,141.5,141.4,139.8,127.73,127.70,127.15,127.10,125.09,125.06,120.02,119.99,114.4,68.4,67.5,54.3,47.5,37.9,33.3,27.7,24.2.
HRMS(m/z):calc.for C23H25ClNO3[M+H]+＝398.1523；found,398.1530
Adding compound 10(2.81kg, 5.69mol), acetonitrile (10L) and water (5L) into a 50L reaction kettle at room temperature, stirring and cooling to 0-5 ℃, adding N-bromosuccinimide (1.01kg, 5.69mol) into the reaction kettle in batches, controlling the temperature to be not more than 5 ℃, continuing stirring and reacting at 0-5 ℃, monitoring the reaction by HP L C, adding 10% sodium sulfite solution (10L) and stirring for 0.5 hour after the reaction is finished, adding ethyl acetate (10 L× 2) for extraction and liquid separation, respectively washing and liquid separation of an organic layer by using saturated sodium bicarbonate (5L) and saturated sodium chloride (5 L× 2) and adding activated carbon (320g) into the organic layer, stirring for 1 hour at room temperature, adding anhydrous magnesium sulfate and continuing stirring for 0.5 hour, filtering, and concentrating the filtrate under reduced pressure to obtain compound 11(2.85kg), wherein the product does not need to be further purified and is directly put into the reaction.
Description of the drawings: in step (i), the yield is calculated to exceed the theoretical value, and thus the number of moles of the compound of formula 10 is 5.69mol, calculated as a yield of 100%.
And (k) adding the compound 12(1.40kg, 5.41mol), lithium hydroxide (0.15kg, 6.26mol) and N, N-dimethylformamide (28L) into a 100L reaction kettle at room temperature, stirring at room temperature for 1 hour, cooling to 0-5 ℃, dissolving the compound 11(2.85kg, 5.69mol) in N, N-dimethylformamide (2.8L), dropwise adding into the reaction kettle, controlling the temperature to be not more than 5 ℃, completing dropwise addition within 4-5 hours, stirring at 0-5 ℃, monitoring reaction at HP L C, after the reaction is finished, adding diethylamine (1L) into the reaction kettle, stirring at 0-5 ℃, monitoring reaction at HP L C, after the reaction is finished, adding water (25L) and ethyl acetate (30L), stirring, separating, extracting an aqueous layer by using ethyl acetate (20L) to extract, combining organic layers, concentrating at 50 ℃, adding 85% lactic acid solution (1.5% under reduced pressure), stirring for 1.5 hours, adjusting the yield of ethyl acetate (30L), adding ethyl acetate (30) to obtain a crude product, filtering, adding ethyl acetate (4613) to obtain a crude product, and filtering, and concentrating the crude product, and adding white potassium carbonate (30) to obtain a crude product, after filtering, and filtering the filtrate, the filtrate at room temperature, the filtrate is dried at room temperature to obtain a filtrate, the filtrate is dried product after the filtrate is dried.
1H NMR(400MHz,Chloroform-d)8.32(s,1H),8.26(s,1H),7.98(s,1H),4.34(d,J＝13.9Hz,1H),4.16(d,J＝13.9Hz,1H),3.88(t,J＝3.1Hz,1H),3.29(t,J＝3.4Hz,1H),2.97(d,J＝10.9Hz,1H),2.52(t,J＝11.8Hz,1H),2.10(d,J＝15.1Hz,1H),2.03(dd,J＝13.1,3.7Hz,2H),1.83(d,J＝13.2Hz,1H),1.81–1.72(m,1H),1.54(ddt,J＝15.0,12.0,3.4Hz,2H).
13C NMR(126MHz,Chloroform-d)160.1,149.5,147.2,133.4,132.7,129.4,127.9,122.1,105.3,78.0,55.8,50.3,44.67,43.7,26.9,20.2.
HRMS(m/z):calc.for C16H18BrClN3O3[M+H]+＝414.0220/416.0200；found,414.0216/416.0197
Description of the drawings: in both steps (i) and (j), the calculated yield exceeds the theoretical value, so that the number of moles of the compound of formula 11 is 5.69mol based on 100% yield.
Synthesis of racemic halofuginone (Compound 1)
And (l) adding the compound 13(1.84kg, 4.43mol) and absolute ethyl alcohol (20L) into a 50L reaction kettle at room temperature, stirring and heating until reflux reaction is carried out, monitoring the reaction by using HP L C, cooling the reaction liquid to 55-60 ℃ after the reaction is finished, carrying out reduced pressure filtration, eluting the ethanol, and drying a filter cake in vacuum to obtain a white solid, namely the compound 1(1.31kg, the yield is 71.2%, and the purity of the HP L C is 98.6%).
1H NMR(400MHz,DMSO-d6)8.23(s,1H),8.22(s,1H),8.15(s,1H),4.99(d,J＝2.8Hz,2H),4.79(d,J＝5.8Hz,1H),2.98(dt,J＝15.3,4.7Hz,2H),2.78(d,J＝12.3Hz,1H),2.64(td,J＝8.9,3.8Hz,1H),2.44(dd,J＝15.5,8.7Hz,1H),2.36(td,J＝12.1,2.7Hz,1H),1.95–1.83(m,1H),1.56(dt,J＝13.3,3.2Hz,1H),1.34(qt,J＝12.4,3.7Hz,1H),1.28–1.13(m,1H).
13C NMR(126MHz,DMSO-d6)200.7,158.6,149.5,147.2,132.4,131.8,128.4,126.8,121.7,66.7,56.2,54.4,43.0,30.5,20.1.
HRMS(m/z):calc.for C16H18BrClN3O3[M+H]+＝414.0220/416.0200；found,414.0214/416.0195
Example 2
Synthesis of a Compound of formula (+) -9 ([ (+) - (2S,3S) -2- (2-chloropropenyl) -3-hydroxypiperidine ]) optically active on the dextro-rotary side
Step (1), adding a racemic compound (140g, 0.797mol, prepared according to the method of example 1) of formula 9 and acetonitrile (1400ml) into a 5L three-necked flask at room temperature, heating to 60 ℃, stirring and dissolving, dissolving L- (-) -dibenzoyltartaric acid (300g, 0.837mol) of formula 15 in acetonitrile (800ml), dropwise adding into the reaction flask, dripping for about 10 minutes, stirring for 20-30 minutes, moving to room temperature, stirring for 2 hours, filtering, leaching acetonitrile (300ml), pumping to obtain a crude double salt, adding pure water-acetonitrile (1: 4, 2000ml), stirring, heating to 80 ℃, dissolving, filtering while hot, stirring the filtrate at room temperature for 2 hours, crystallizing, filtering, leaching the acetonitrile, and drying to obtain a refined double salt, namely the compound (136g, yield 32%) of formula 14.
Step (2) of adding the compound of formula 14 (136g), pure water (700ml) and ethyl acetate (700ml) to a 5L three-necked flask at room temperature, stirring, adding 1 mol/L NaOH dropwise to adjust the pH to 12-14, separating the liquids, extracting the aqueous layer with ethyl acetate (700ml × 2), combining the organic layers, adding anhydrous MgSO4Drying, filtering and concentrating the filtrate at 50 ℃ under reduced pressure to give compound (+) -9(44g, yield 98%) as a white solid.
[α]D＝+8.43°(c＝0.46,MeOH)
1H NMR(500MHz,Chloroform-d)5.25(d,J＝1.1Hz,1H),5.23(t,J＝1.0Hz,1H),3.65(S,1H),3.03(ddt,J＝11.5,4.3,2.0Hz,1H),2.88(ddd,J＝7.5,6.3,1.4Hz,1H),2.65(td,J＝11.9,2.9Hz,1H),2.49(d,J＝6.8Hz,2H).,1.91(dtt,J＝13.4,4.0,2.0Hz,1H),1.73(qt,J＝13.1,4.3Hz,1H),1.54(tdd,J＝13.3,4.7,2.5Hz,1H),1.45(ddq,J＝12.9,4.9,2.6Hz,1H).
13C NMR(126MHz,Chloroform-d)139.8,115.2,67.1,57.7,47.2,43.0,32.2,20.4.
HRMS(m/z):calc.for C8H15ClNO[M+H]+＝176.0842；found,176.0837
Example 3
Synthesis of compound of formula (-) -9 (levorotatory optically active [ (-) - (2R,3R) -2- (2-chloropropenyl) -3-hydroxypiperidine ])
Step (1) adding racemic compound of formula 9 (14g, 79.7mmol, prepared according to the method of example 1) and acetonitrile (140ml) into a 5L three-necked flask at room temperature, heating to 60 ℃, stirring and dissolving L- (-) -dibenzoyltartaric acid of formula 16 (30g, 83.7mmol) in acetonitrile (80ml), then adding dropwise into the flask, after about 10 minutes of dripping, stirring for 20-30 minutes, moving to room temperature, stirring for 2 hours, filtering, rinsing with acetonitrile (30ml), draining to obtain crude double salt, adding pure water-acetonitrile (1: 4, 200ml), stirring, heating to 80 ℃, dissolving, filtering while hot, stirring the filtrate at room temperature for 2 hours, crystallizing, filtering, rinsing with acetonitrile, drying to obtain refined double salt, namely compound of formula 17 (12.1g, yield 28.4%).
Step (2) of adding the compound of formula 17 (12.1g), pure water (70ml) and ethyl acetate (100ml) to a 5L three-necked flask at room temperature, stirring, adding 1 mol/L NaOH dropwise to adjust pH to 12-14, separating the liquids, extracting the aqueous layer with ethyl acetate (100ml × 2), combining the organic layers, adding anhydrous MgSO4Drying, filtration and concentration of the filtrate at 50 ℃ under reduced pressure gave (-) -9(3.7g, 93.1% yield) as a white solid.
[α]D＝-8.43°(c＝0.46,MeOH)
1H NMR(500MHz,Chloroform-d)5.25(d,J＝1.1Hz,1H),5.23(t,J＝1.0Hz,1H),3.65(S,1H),3.03(ddt,J＝11.5,4.3,2.0Hz,1H),2.88(ddd,J＝7.5,6.3,1.4Hz,1H),2.65(td,J＝11.9,2.9Hz,1H),2.49(d,J＝6.8Hz,2H).,1.91(dtt,J＝13.4,4.0,2.0Hz,1H),1.73(qt,J＝13.1,4.3Hz,1H),1.54(tdd,J＝13.3,4.7,2.5Hz,1H),1.45(ddq,J＝12.9,4.9,2.6Hz,1H).
13C NMR(126MHz,Chloroform-d)139.8,115.2,67.1,57.7,47.2,43.0,32.2,20.4.
HRMS(m/z):calc.for C8H15ClNO[M+H]+＝176.0842；found,176.0837
Example 4 preparation of the Compound (+) -1, i.e., (+) -halofuginone (D-halofuginone)
And (3) adding a compound (+) -9(10g, 56.9mmol), 1, 4-dioxane (50m L), water (50m L) and sodium carbonate (9.1g, 85.4mmol) into a 500m L reaction bottle at room temperature, stirring and cooling to 5-10 ℃, dissolving chloroformic acid-9-fluorenylmethyl ester (14.7g, 56.9mmol) in 1, 4-dioxane (20m L), then dropwise adding into the reaction bottle, controlling the temperature to be not more than 20 ℃, continuing stirring at room temperature for reaction, monitoring by T L C, after the reaction is finished, adding ethyl acetate (200m L) and water (200m L), stirring, separating, washing an organic layer with saturated sodium chloride (50m L× 2), extracting a water layer with ethyl acetate (100m L), combining the organic layers, adding activated carbon (5g), stirring at room temperature for 1 hour, filtering, concentrating the filtrate under reduced pressure to obtain a pale yellow thick substance (+) -10.1 g, directly adding a reaction product, and purifying the product without further adding the product.
[α]D＝+25.42°(c＝0.35,CHCl3)
1H NMR(500MHz,Chloroform-d)7.81–7.71(m,2H),7.65–7.53(m,2H),7.40(td,J＝7.5,2.4Hz,2H),7.31(t,J＝7.4Hz,2H),5.17(s,1H),5.14(s,1H),4.93–4.51(m,1H),4.49(dd,J＝10.7,6.7Hz,1H),4.41(dd,J＝10.7,6.5Hz,1H),4.25(t,J＝6.5Hz,1H),3.92(s,1H),3.76(s,1H),2.85–2.54(m,3H),1.87–1.74(m,1H),1.73–1.58(m,1H),1.57–1.33(m,2H).
13C NMR(126MHz,Chloroform-d)155.8,144.1,141.5,141.4,139.8,127.73,127.70,127.15,127.10,125.09,125.06,120.02,119.99,114.4,68.4,67.5,54.3,47.5,37.9,33.3,27.7,24.2.
HRMS(m/z):calc.for C23H25ClNO3[M+H]+＝398.1523；found,398.1530
Adding a compound (+) -10(28g, 56.9mol), acetonitrile (100m L) and water (50m L) into a 500m L reaction bottle at room temperature, stirring and cooling to 0-5 ℃, adding N-bromosuccinimide (10.1g, 56.9mol) into the reaction bottle in batches, controlling the temperature to be not more than 5 ℃, continuing stirring and reacting at 0-5 ℃, monitoring the reaction by HP L C, adding a 10% sodium sulfite solution (100m L) into the reaction bottle after the reaction is finished, stirring for 0.5 hour, adding ethyl acetate (100m L× 2) into the reaction bottle to extract and separate the organic layer, washing and separating the organic layer by using saturated sodium bicarbonate (50m L) and saturated sodium chloride (50m L× 2), adding activated carbon (5g) into the organic layer, stirring for 1 hour at room temperature, adding anhydrous magnesium sulfate into the mixture, continuing stirring for 0.5 hour, filtering, and concentrating the filtrate under reduced pressure to obtain a thick substance, namely the compound (+) -11[27.5g, [ α ] α]D＝+36.66°(c＝0.30,CHCl3)]And the product is directly put into the next reaction without further purification.
Step (5) adding compound 12(14g, 54.1mol), lithium hydroxide (1.5g, 62.6mol) and N, N-dimethylformamide (280m L) into a 1000m L reaction flask at room temperature, stirring at room temperature for 1 hour, cooling to 0-5 ℃, dissolving compound (+) -11(27.5g, 56.9mol) in N, N-dimethylformamide (30m L), dropwise adding into the reaction kettle, controlling the temperature to be not more than 5 ℃, completing dropwise addition within 4-5 hours, continuing stirring at 0-5 ℃, monitoring reaction at HP L C, after the reaction is finished, adding diethylamine (10m L) into the reaction kettle, continuing stirring at 0-5 ℃, monitoring reaction at HP L C, after the reaction is finished, adding water (250m L) and ethyl acetate (300m 734), stirring, separating, extracting an aqueous layer with ethyl acetate (200m L), combining organic layers, concentrating at 50 ℃, adding 85% of lactic acid solution (15% potassium carbonate), stirring at room temperature, stirring for 85% after stirring, adjusting pH to 1m L, adding ethyl acetate (300 m) into the reaction kettle, extracting a crude product with ethyl acetate (150 m) at room temperature, after drying, adding white tert-butyl ether (30 m) and obtaining a crude product, filtering, extracting a crude product, after obtaining yield, adding white butyl ether (50-30 m) and filtering, and obtaining a crude product, and obtaining yield, wherein the crude product after the crude product is 150 g, the yield is 150m 3-5).
[α]D＝+81.21°(c＝0.52,CHCl3)
1H NMR(400MHz,Chloroform-d)8.32(s,1H),8.26(s,1H),7.98(s,1H),4.34(d,J＝13.9Hz,1H),4.16(d,J＝13.9Hz,1H),3.88(t,J＝3.1Hz,1H),3.29(t,J＝3.4Hz,1H),2.97(d,J＝10.9Hz,1H),2.52(t,J＝11.8Hz,1H),2.10(d,J＝15.1Hz,1H),2.03(dd,J＝13.1,3.7Hz,2H),1.83(d,J＝13.2Hz,1H),1.81–1.72(m,1H),1.54(ddt,J＝15.0,12.0,3.4Hz,2H).
13C NMR(126MHz,Chloroform-d)160.1,149.5,147.2,133.4,132.7,129.4,127.9,122.1,105.3,78.0,55.8,50.3,44.67,43.7,26.9,20.2.
HRMS(m/z):calc.for C16H18BrClN3O3[M+H]+＝414.0220/416.0200；found,414.0216/416.0197
And (6) adding a compound (+) -13(15g, 36.17mmol) and absolute ethyl alcohol (150m L) into a 500m L reaction bottle at room temperature, stirring and heating to reflux reaction, monitoring the reaction by using HP L C, cooling the reaction liquid to 55-60 ℃ after the reaction is finished, filtering under reduced pressure, eluting the ethanol, and drying a filter cake in vacuum to obtain a white solid, namely (+) -halofuginone (12.1g, the yield is 80.6%, the purity of the HP L C is 98.5%, and the ee is 99.6%).
[α]D＝+18.52°(c＝0.53,DMSO)
1H NMR(400MHz,DMSO-d6)8.23(s,1H),8.22(s,1H),8.15(s,1H),4.99(d,J＝2.8Hz,2H),4.79(d,J＝5.8Hz,1H),2.98(dt,J＝15.3,4.7Hz,2H),2.78(d,J＝12.3Hz,1H),2.64(td,J＝8.9,3.8Hz,1H),2.44(dd,J＝15.5,8.7Hz,1H),2.36(td,J＝12.1,2.7Hz,1H),1.95–1.83(m,1H),1.56(dt,J＝13.3,3.2Hz,1H),1.34(qt,J＝12.4,3.7Hz,1H),1.28–1.13(m,1H).
13C NMR(126MHz,DMSO-d6)200.7,158.6,149.5,147.2,132.4,131.8,128.4,126.8,121.7,66.7,56.2,54.4,43.0,30.5,20.1.
HRMS(m/z):calc.for C16H18BrClN3O3[M+H]+＝414.0220/416.0200；found,414.0214/416.0195
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (23)
1. A method for preparing cis-2- (2-chloropropenyl) -3-hydroxypiperidine with optical activity, which is characterized by comprising the following steps:
(1) in a first organic solvent, carrying out salt-forming reaction on racemic cis-2- (2-chloropropenyl) -3-hydroxypiperidine and dibenzoyl tartaric acid or derivatives thereof to generate a precipitate, and recrystallizing the precipitate to obtain chiral double salt;
(2) neutralizing the chiral double salt with an alkaline aqueous solution to be alkaline in a second organic solvent to obtain cis-2- (2-chloropropenyl) -3-hydroxypiperidine with optical activity;
the racemic cis-2- (2-chloropropenyl) -3-hydroxypiperidine has a structure shown by a formula (+/-) -9; the cis-2- (2-chloropropenyl) -3-hydroxypiperidine with optical activity has a structure shown in a formula (+) -9 or (-) -9; the dibenzoyl tartaric acid or the derivative thereof has a structure shown in a formula 15 or a formula 16; the chiral double salt has a structure shown in formula 14 or formula 17; the reaction formula is as follows:
or,
wherein each R is independently selected from: hydrogen or C1-C4An alkoxy group.
2. The method for preparing optically active cis-2- (2-chloropropenyl) -3-hydroxypiperidine according to claim 1, wherein the dibenzoyltartaric acid of formula 15 or a derivative thereof in step (1) is L- (-) -dibenzoyltartaric acid or L- (-) -di-p-methoxybenzyltartaric acid, and the dibenzoyltartaric acid of formula 16 or a derivative thereof is D- (+) -dibenzoyltartaric acid or D- (+) -di-p-methoxybenzyltartaric acid.
3. The process for producing an optically active cis-2- (2-chloropropenyl) -3-hydroxypiperidine according to claim 1, wherein the molar ratio of the racemic cis-2- (2-chloropropenyl) -3-hydroxypiperidine to the dibenzoyltartaric acid or a derivative thereof in the step (1) is 1: 1 to 2.
4. The method for producing an optically active cis-2- (2-chloropropenyl) -3-hydroxypiperidine according to claim 1, wherein the recrystallization is carried out in a volume ratio of 1 to 10: 1 in a mixed solvent of a third organic solvent and water; the third organic solvent is selected from any one or more of ethanol, methanol, isopropanol, acetonitrile, 1, 4-dioxane and acetone.
5. The process for producing an optically active cis-2- (2-chloropropenyl) -3-hydroxypiperidine according to claim 1, wherein the first organic solvent in the step (1) is one or more selected from the group consisting of ethanol, methanol, isopropanol, acetonitrile, dichloromethane, 1, 4-dioxane, tetrahydrofuran, toluene, acetone and ethyl acetate; and/or the presence of a catalyst in the reaction mixture,
the second organic solvent in the step (2) is selected from any one or more of ethyl acetate, dichloromethane and trichloromethane.
6. The method for preparing optically active cis-2- (2-chloropropenyl) -3-hydroxypiperidine according to claim 1, wherein the temperature of the salt-forming reaction is 0 to 100 ℃; and/or the temperature of recrystallization is 0-30 ℃.
7. The method for producing an optically active cis-2- (2-chloropropenyl) -3-hydroxypiperidine according to claim 1, wherein the basic aqueous solution in step (2) is any one of an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, an aqueous lithium hydroxide solution, an aqueous potassium carbonate solution and an aqueous sodium carbonate solution, and the neutralization is performed until the pH is 8 to 14.
8. The process for producing an optically active cis-2- (2-chloropropenyl) -3-hydroxypiperidine according to any one of claims 1 to 7, wherein the process for synthesizing a racemic cis-2- (2-chloropropenyl) -3-hydroxypiperidine comprises the steps of:
(a) reacting diethyl acetylaminomalonate with 2, 3-dichloropropene under the action of alkali and a catalyst to generate a compound shown in a formula 2;
(b) the compound of the formula 2 undergoes a hydrolysis decarboxylation reaction under the catalysis of acid to generate a compound of a formula 3;
(c) carrying out an esterification reaction on the compound of the formula 3 under the catalysis of acid to generate a compound of a formula 4;
(d) the compound of formula 4 and 4-halobutyrate are subjected to nitrogen alkylation reaction under the action of alkali and a catalyst, and then are subjected to nitrogen protection reaction with an amino protection reagent to generate a compound of formula 5;
(e) carrying out Dieckmann condensation reaction on the compound shown in the formula 5 under the action of alkali to generate a compound shown in a formula 6;
(f) the compound of the formula 6 undergoes decarboxylation under the action of inorganic salt to generate a compound of a formula 7;
(g) the compound of the formula 7 is subjected to a reduction reaction under the action of a reducing agent to generate a compound of a formula 8;
(h) deprotecting nitrogen in the compound of formula 8 to produce a compound of formula 9;
the reaction formula is as follows:
wherein:
R1selected from: methyl, ethyl, n-propyl, isopropyl or tert-butyl;
R2selected from: methyl, ethyl;
R3selected from: methoxy formyl, ethoxy formyl, tert-butoxy formyl, benzyloxy formyl, trichloroethoxy formyl or benzyl.
9. The process for producing an optically active cis-2- (2-chloropropenyl) -3-hydroxypiperidine according to claim 8, wherein R is1Selected from: methyl or ethyl.
10. A method for synthesizing halofuginone with optical activity is characterized by comprising the following steps:
(3) the cis-2- (2-chloropropenyl) -3-hydroxypiperidine with optical activity reacts with an amino protective reagent under the action of alkali to generate a compound with the optical activity of a formula (+) -10 or a formula (-) -10;
(4) reacting an optically active compound of formula (+) -10 or formula (-) -10 with an olefinic brominating agent and water to produce an optically active compound of formula (+) -11 or formula (-) -11;
(5) reacting the optically active compound of the formula (+) -11 or the formula (-) -11 with the compound of the formula 12 under the action of alkali, and then removing the 9-fluorenylmethyloxycarbonyl protecting group on the piperidine ring nitrogen to generate the optically active compound of the formula (+) -13 or the formula (-) -13;
(6) isomerizing the optically active compound of formula (+) -13 or formula (-) -13 to produce optically active halofuginone;
the dichroa febrifuga ketone with optical activity has a structure shown as a formula (+) -1 or (-) -1, and the reaction formula is as follows:
or,
a step of preparing an optically active cis-2- (2-chloropropenyl) -3-hydroxypiperidine, which comprises:
(1) in a first organic solvent, carrying out salt-forming reaction on racemic cis-2- (2-chloropropenyl) -3-hydroxypiperidine and dibenzoyl tartaric acid or derivatives thereof to generate a precipitate, and recrystallizing the precipitate to obtain chiral double salt;
(2) neutralizing the chiral double salt with an alkaline aqueous solution to be alkaline in a second organic solvent to obtain cis-2- (2-chloropropenyl) -3-hydroxypiperidine with optical activity;
the racemic cis-2- (2-chloropropenyl) -3-hydroxypiperidine has a structure shown by a formula (+/-) -9; the cis-2- (2-chloropropenyl) -3-hydroxypiperidine with optical activity has a structure shown in a formula (+) -9 or (-) -9; the dibenzoyl tartaric acid or the derivative thereof has a structure shown in a formula 15 or a formula 16; the chiral double salt has a structure shown in formula 14 or formula 17; the reaction formula is as follows:
or,
wherein each R is independently selected from: hydrogen or C1-C4An alkoxy group.
11. The method for synthesizing optically active halofuginone according to claim 10, wherein the base in step (3) is selected from any one of sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate; and/or the presence of a catalyst in the reaction mixture,
the amino protecting reagent in the step (3) is any one of chloroformate-9-fluorenylmethyl ester, 9-fluorenylmethyl-1-benzotriazolyl carbonate and 9-fluorenylmethyl-N-succinimidyl carbonate; and/or the presence of a catalyst in the reaction mixture,
the solvent for the reaction in the step (3) is a combination of an organic solvent and water, wherein the organic solvent is any one of 1, 4-dioxane and tetrahydrofuran; and/or the presence of a catalyst in the reaction mixture,
the molar ratio of the alkali and the amino protective reagent to the cis-2- (2-chloropropenyl) -3-hydroxypiperidine in the step (3) is 1-5: 1-2: 1; and/or the presence of a catalyst in the reaction mixture,
the reaction temperature in the step (3) is 0-20 ℃.
12. The method for synthesizing optically active halofuginone according to claim 10, wherein the olefin bromination reagent in step (4) is any one selected from the group consisting of N-bromosuccinimide and 1, 3-dibromo-5, 5-dimethylhydantoin; and/or the presence of a catalyst in the reaction mixture,
the solvent for the reaction in the step (4) is any one of acetonitrile, tetrahydrofuran and 1, 4-dioxane; and/or the presence of a catalyst in the reaction mixture,
the mol ratio of the alkene bromination reagent in the step (4) to the compound shown in the formula (+) -10 or (-) -10 is 0.9-1.2: 1; and/or the presence of a catalyst in the reaction mixture,
the reaction temperature of the reaction in the step (4) is-10-35 ℃.
13. The method for synthesizing optically active halofuginone according to claim 10, wherein the base in step (5) is selected from any one of potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium diisopropylamide, sodium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, and potassium bis (trimethylsilyl) amide; and/or the presence of a catalyst in the reaction mixture,
the solvent for the reaction in the step (5) is any one of acetonitrile, methanol, ethanol, N-dimethylacetamide, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1, 4-dioxane, toluene, dichloromethane and 1, 2-dichloroethane; and/or the presence of a catalyst in the reaction mixture,
the molar ratio of the compound of formula (+) -11 or formula (-) -11, the compound of formula 12 and the base in step (5) is 0.8-1.2: 1: 1-2; and/or the presence of a catalyst in the reaction mixture,
the reaction temperature of the reaction in the step (5) is-10-25 ℃; and/or the presence of a catalyst in the reaction mixture,
the step (5) of removing the 9-fluorenylmethyloxycarbonyl protecting group of the nitrogen on the piperidine ring is carried out under the action of second-level organic amine or third-level organic amine; and/or the presence of a catalyst in the reaction mixture,
the reaction temperature of the step (5) for removing the 9-fluorenylmethyloxycarbonyl protecting group of the nitrogen on the piperidine ring is-10 ℃ to 25 ℃.
14. The method of claim 13, wherein the secondary organic amine is diethylamine.
15. The method for synthesizing optically active halofuginone according to claim 10, wherein the solvent for the isomerization reaction in step (6) is selected from any one or a combination of two of water, ethanol, methanol, N-butanol, N-propanol, t-butanol, N-dimethylformamide, tetrahydrofuran and 1, 4-dioxane; and/or the presence of a catalyst in the reaction mixture,
the reaction temperature of the isomerization reaction in the step (6) is 50-80 ℃.
16. The method for synthesizing optically active halofuginone according to any one of claims 10 to 15, wherein the dibenzoyl tartaric acid of formula 15 or its derivative in step (1) is L- (-) -dibenzoyl tartaric acid or L- (-) -di-p-methoxybenzoyl tartaric acid, and the dibenzoyl tartaric acid of formula 16 or its derivative is D- (+) -dibenzoyl tartaric acid or D- (+) -di-p-methoxybenzoyl tartaric acid.
17. The method for synthesizing optically active halofuginone according to any one of claims 10 to 15, wherein the molar ratio of racemic cis-2- (2-chloropropenyl) -3-hydroxypiperidine to dibenzoyltartaric acid or a derivative thereof in the step (1) is 1: 1 to 2.
18. The method for synthesizing optically active halofuginone according to any one of claims 10 to 15, wherein the recrystallization is carried out in a volume ratio of 1 to 10: 1 in a mixed solvent of a third organic solvent and water; the third organic solvent is selected from any one or more of ethanol, methanol, isopropanol, acetonitrile, 1, 4-dioxane and acetone.
19. The method for synthesizing optically active halofuginone according to any one of claims 10 to 15, wherein the first organic solvent in step (1) is selected from one or more of ethanol, methanol, isopropanol, acetonitrile, dichloromethane, 1, 4-dioxane, tetrahydrofuran, toluene, acetone, and ethyl acetate; and/or the presence of a catalyst in the reaction mixture,
the second organic solvent in the step (2) is selected from any one or more of ethyl acetate, dichloromethane and trichloromethane.
20. The method for synthesizing optically active halofuginone according to any one of claims 10 to 15, wherein the temperature of the salt-forming reaction is 0 to 100 ℃; and/or the temperature of recrystallization is 0-30 ℃.
21. The method for synthesizing optically active halofuginone according to any one of claims 10 to 15, wherein the alkaline aqueous solution in step (2) is any one of an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, an aqueous lithium hydroxide solution, an aqueous potassium carbonate solution and an aqueous sodium carbonate solution, and the neutralization to alkalinity is to a pH of 8 to 14.
22. The method for synthesizing optically active halofuginone according to any one of claims 10 to 15, wherein the method for synthesizing racemic cis-2- (2-chloropropenyl) -3-hydroxypiperidine comprises the following steps:
(a) reacting diethyl acetylaminomalonate with 2, 3-dichloropropene under the action of alkali and a catalyst to generate a compound shown in a formula 2;
(b) the compound of the formula 2 undergoes a hydrolysis decarboxylation reaction under the catalysis of acid to generate a compound of a formula 3;
(c) carrying out an esterification reaction on the compound of the formula 3 under the catalysis of acid to generate a compound of a formula 4;
(d) the compound of formula 4 and 4-halobutyrate are subjected to nitrogen alkylation reaction under the action of alkali and a catalyst, and then are subjected to nitrogen protection reaction with an amino protection reagent to generate a compound of formula 5;
(e) carrying out Dieckmann condensation reaction on the compound shown in the formula 5 under the action of alkali to generate a compound shown in a formula 6;
(f) the compound of the formula 6 undergoes decarboxylation under the action of inorganic salt to generate a compound of a formula 7;
(g) the compound of the formula 7 is subjected to a reduction reaction under the action of a reducing agent to generate a compound of a formula 8;
(h) deprotecting nitrogen in the compound of formula 8 to produce a compound of formula 9;
the reaction formula is as follows:
wherein:
R1selected from: methyl, ethyl, n-propyl, isopropyl or tert-butyl;
R2selected from: methyl, ethyl;
R3selected from: methoxy formyl, ethoxy formyl, tert-butoxy formyl, benzyloxy formyl, trichloroethoxy formyl or benzyl.
23. The method for synthesizing optically active halofuginone according to claim 22, wherein R is1Selected from: methyl or ethyl.
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| PCT/CN2019/106485 WO2020134212A1 (en) | 2018-12-28 | 2019-09-18 | Synthesis method for halofuginone and intermediate thereof |
| EP19902141.1A EP3904340B1 (en) | 2018-12-28 | 2019-09-18 | Synthesis method for halofuginone and intermediate thereof |
| US17/359,661 US20220371995A1 (en) | 2018-12-28 | 2021-06-28 | Synthesis method for halofuginone and halofuginone intermediates |
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