CN118084734A - Preparation method of O- [2- [ [ tert-butoxycarbonyl ] amino ] ethyl ] -N- [ fluorenylmethoxycarbonyl ] -L-tyrosine - Google Patents
Preparation method of O- [2- [ [ tert-butoxycarbonyl ] amino ] ethyl ] -N- [ fluorenylmethoxycarbonyl ] -L-tyrosine Download PDFInfo
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- CN118084734A CN118084734A CN202410461408.2A CN202410461408A CN118084734A CN 118084734 A CN118084734 A CN 118084734A CN 202410461408 A CN202410461408 A CN 202410461408A CN 118084734 A CN118084734 A CN 118084734A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 229960004441 tyrosine Drugs 0.000 title claims abstract description 20
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 title claims abstract description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 title claims abstract description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 title claims abstract description 13
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 85
- 150000001875 compounds Chemical class 0.000 claims abstract description 67
- 238000000034 method Methods 0.000 claims abstract description 49
- 239000000047 product Substances 0.000 claims abstract description 31
- 239000012535 impurity Substances 0.000 claims abstract description 25
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 20
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims abstract description 20
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 16
- 229910052751 metal Inorganic materials 0.000 claims abstract description 14
- 239000002184 metal Substances 0.000 claims abstract description 14
- 230000008569 process Effects 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 238000006751 Mitsunobu reaction Methods 0.000 claims abstract description 11
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 10
- GPTXCAZYUMDUMN-UHFFFAOYSA-N tert-butyl n-(2-hydroxyethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCO GPTXCAZYUMDUMN-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 230000009471 action Effects 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- 239000002904 solvent Substances 0.000 claims description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 30
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- 239000007787 solid Substances 0.000 claims description 27
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 24
- 238000001914 filtration Methods 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- 238000001816 cooling Methods 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 150000002825 nitriles Chemical class 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical group [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 239000012065 filter cake Substances 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 239000012296 anti-solvent Substances 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- ARXJGSRGQADJSQ-UHFFFAOYSA-N 1-methoxypropan-2-ol Chemical compound COCC(C)O ARXJGSRGQADJSQ-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 238000004140 cleaning Methods 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 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 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 230000020477 pH reduction Effects 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 239000003929 acidic solution Substances 0.000 claims description 3
- 150000001923 cyclic compounds Chemical class 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 3
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 claims description 3
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000002386 leaching Methods 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 2
- 239000000347 magnesium hydroxide Substances 0.000 claims description 2
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- 238000012805 post-processing Methods 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- 150000005846 sugar alcohols Polymers 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims 7
- 238000005984 hydrogenation reaction Methods 0.000 claims 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims 1
- 239000006227 byproduct Substances 0.000 abstract description 18
- 238000009776 industrial production Methods 0.000 abstract description 8
- 150000008553 L-tyrosines Chemical class 0.000 abstract description 7
- 238000000926 separation method Methods 0.000 abstract description 7
- 230000008901 benefit Effects 0.000 abstract description 6
- 238000000746 purification Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 125000003277 amino group Chemical group 0.000 abstract description 2
- -1 phosphorus alkoxide Chemical class 0.000 description 18
- 239000000543 intermediate Substances 0.000 description 12
- 230000000694 effects Effects 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 9
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000006266 etherification reaction Methods 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000001308 synthesis method Methods 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 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
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 3
- XDJWZONZDVNKDU-UHFFFAOYSA-N 1314-24-5 Chemical compound O=POP=O XDJWZONZDVNKDU-UHFFFAOYSA-N 0.000 description 3
- 230000006978 adaptation Effects 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 238000005580 one pot reaction Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- VSAISIQCTGDGPU-UHFFFAOYSA-N phosphorus trioxide Inorganic materials O1P(O2)OP3OP1OP2O3 VSAISIQCTGDGPU-UHFFFAOYSA-N 0.000 description 3
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- TZRQZPMQUXEZMC-UHFFFAOYSA-N tert-butyl n-(2-bromoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCBr TZRQZPMQUXEZMC-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 230000009435 amidation Effects 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 208000012839 conversion disease Diseases 0.000 description 2
- 230000032798 delamination Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 150000004714 phosphonium salts Chemical group 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 231100000572 poisoning Toxicity 0.000 description 2
- 230000000607 poisoning effect Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- 238000006677 Appel reaction Methods 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- PJGVHBLZZQDFFM-RSAXXLAASA-N benzyl (2s)-2-amino-3-(4-hydroxyphenyl)propanoate;4-methylbenzenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.C([C@H](N)C(=O)OCC=1C=CC=CC=1)C1=CC=C(O)C=C1 PJGVHBLZZQDFFM-RSAXXLAASA-N 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of O- [2- [ [ tert-butoxycarbonyl ] amino ] ethyl ] -N- [ fluorenylmethoxycarbonyl ] -L-tyrosine, belonging to the technical field of synthesis of compounds. The method of the invention is that a compound shown in a formula < II > is taken as a raw material, and is subjected to Mitsunobu reaction with N- (tert-butoxycarbonyl) ethanolamine and triphenylphosphine, the obtained product is subjected to hydrolysis reaction with inorganic base to form a metal salt intermediate, and then the metal salt intermediate is acidified, hydrogenated under the action of Pd/C catalyst and subjected to protection of amino groups to prepare the compound shown in the formula < I >. The invention provides the preparation method of the L-tyrosine derivative, which has the advantages of simple and stable process, controllable operation, low preparation cost, effective removal of byproducts in the reaction process, easy separation and purification, low impurity content, high yield, high purity and high yield of the target compound, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of synthesis of compounds, and particularly relates to a preparation method of O- [2- [ [ tert-butoxycarbonyl ] amino ] ethyl ] -N- [ fluorenylmethoxycarbonyl ] -L-tyrosine.
Background
L-tyrosine derivatives are important pharmaceutical intermediates, and are widely applied to synthesis and screening of various pharmaceutical molecules such as antagonist molecules, inhibitors and polycyclic peptide polypeptide drugs, preparation of cell culture media and the like. O- (2-aminoethyl) -L-tyrosine is an important one of L-tyrosine derivatives, which is increasingly being focused and used by pharmaceutical chemists as an important linker (linker) in PDC drugs, and has a chemical structural formula shown as the following formula < I >:
with respect to the synthetic methods of the above compounds represented by the formula < I >, there are few references, and the only synthetic methods are two Chinese patent documents.
Patent document one (CN 110015978B) discloses a process for preparing O- [2- [ [ t-butoxycarbonyl ] amino ] ethyl ] -N- [ fluorenylmethoxycarbonyl ] -L-tyrosine, which adopts the following preparation process route:
In the synthetic route, L-tyrosine benzyl ester p-toluenesulfonate is adopted as a starting material, so that the problems of difficult acquisition in the market and high price exist. In preparing the starting material, L-tyrosine is generally used for selectively feeding benzyl, however, since the active amino and phenolic hydroxyl groups of L-tyrosine are not protected, more than equivalent amount of p-toluenesulfonic acid is needed to reduce the by-products of benzyl on amino and phenolic hydroxyl groups. When the method is used for benzyl, the p-toluenesulfonic acid added in the reaction process can be rapidly salified with a substrate, so that the solubility of the substrate is greatly reduced, the reaction system is pasty, stirring is difficult, the conversion rate of the reaction is low, the yield of the product is low, and the subsequent purification step is difficult to carry out, so that the method is not beneficial to industrial scale-up production. In addition, the N-BOC bromoethylamine has high market price and is not easy to obtain, when the N-BOC bromoethylamine and phenolic hydroxyl are subjected to substitution reaction, the activity is low, the reaction conversion rate is low, the yield is low, and more than 3 times of equivalent use amount is needed, so that more N-BOC bromoethylamine can remain, and further the purification of the product is affected.
The patent document II (CN 112920086B) uses L-tyrosine as a starting material, and O-alkyl-N- [ fluorenylmethoxycarbonyl ] -L-tyrosine is prepared by esterification, amidation, etherification/hydrolysis and amidation in sequence, and the reaction route is as follows:
The above reaction scheme is that Mitsunobu reaction is adopted for etherification, and triphenylphosphine can generate a large amount of phosphorus trioxide by-product and hydrazide by-product generated by DEAD during the reaction. In particular, in the process of synthesizing O-alkyl-N- [ fluorenylmethoxycarbonyl ] -L-tyrosine, the conversion rate of etherification reaction is very low, and the phenomenon is mainly caused by the strong electron-withdrawing conjugation and induction effect of trifluoroacetyl, so that the acidity of 4-phenolic hydroxyl is weakened and deprotonation is difficult, and the quaternary phosphonium salt formed by DEAD and triphenylphosphine is difficult to carry out the protonation reaction with the quaternary phosphonium salt, so that the etherification reaction is difficult to carry out, the conversion rate is low, and the industrial production is not favored.
The Mitsunobu reaction involved in the above synthesis method comprises the reactions of Wittig, staudinger, appel and the like, and has a major difficulty in separating and removing by-product phosphorus trioxide, wherein the structure of phosphorus Trioxide (TPPO) is shown as follows:
Whether TPPO can be effectively removed will directly affect the progress of the subsequent reaction and the quality and yield of the product. Although etherification by the Mitsunobu reaction is an economical and effective method for the synthesis of O-alkyl-N- [ fluorenylmethoxycarbonyl ] -L-tyrosine, conventional methods for removing the phosphorus-by-product of tamoxifen and the hydrazide by-product produced by DIAD (e.g., the methods described in chem. Eur. J. 2006, 12, 4091-4100) are often required to be accomplished by cumbersome, expensive and time-consuming column chromatography.
If the byproducts of the Mitsunobu reaction, especially the phosphorus alkoxide, cannot be effectively removed, the poisoning of the palladium catalyst is caused when the residual phosphorus alkoxide is small, so that the problems of incapability of subsequent reaction, low reaction conversion rate and the like are caused, but the separation and purification are carried out by adopting a column chromatography or preparation separation mode, the process steps are complicated, the production cost is high, the commercial productivity is severely limited, and the production amplification is not facilitated.
Therefore, in the process of realizing industrial production and obtaining the L-tyrosine derivative with high quality and low cost, development of a green and environment-friendly process route which has the advantages of simple preparation method, convenient operation and low cost, can obviously improve productivity, effectively remove byproducts, is easy to separate and purify and obtains high yield is still needed to meet the market demands. However, this problem needs to be solved.
Disclosure of Invention
The invention aims to solve the technical problems, thereby providing a preparation method of O- [2- [ [ tert-butoxycarbonyl ] amino ] ethyl ] -N- [ fluorenylmethoxycarbonyl ] -L-tyrosine. The preparation method provided by the invention has the technical purpose that: the preparation method of the L-tyrosine derivative has the advantages of simple and stable process, controllable operation, low preparation cost, effective removal of byproducts in the reaction process, easy separation and purification, low impurity content, high yield, high purity and high yield of the target compound, and is suitable for industrial production.
In order to achieve the technical purpose, the invention adopts the following technical scheme:
A preparation method of O- [2- [ [ tert-butoxycarbonyl ] amino ] ethyl ] -N- [ fluorenylmethoxycarbonyl ] -L-tyrosine takes a compound shown as a formula < II > as a raw material, and takes Mitsunobu reaction with N- (tert-butoxycarbonyl) ethanolamine and triphenylphosphine, the obtained product takes hydrolysis reaction with inorganic base to form a metal salt intermediate, and then the metal salt intermediate is hydrogenated under the action of Pd/C catalyst after acidification, and the amino is protected to prepare the compound shown as the formula < I >;
The synthesis method provided by the invention adopts two one-pot methods, firstly, the product obtained by Mitsunobu reaction and inorganic base are subjected to hydrolysis reaction to obtain a metal salt intermediate, and then, the metal salt intermediate is subjected to subsequent catalytic hydrogenation and amino protection by the one-pot method, so that the L-tyrosine derivative shown in the formula < I > is successfully prepared, the process operation is greatly simplified, the restriction factors of the prior art are solved, the high-purity intermediate and the high-purity target product are obtained, the quality of the product is ensured, the yield of the product is improved, and industrial production can be well realized.
The specific synthetic route of the invention is as follows:
The method provided by the invention is that the protected L-tyrosine derivative (formula II) and N-BOC-ethanolamine are subjected to Mitsunobu reaction to obtain an intermediate III, and then the intermediate III (formula III) is hydrolyzed into metal salt in a solvent to obtain a compound IV (formula IV). According to the method, after the compound of the formula II obtained through the Mitsunobu reaction is simply treated, the generated byproducts can be effectively removed without further treatment to remove the phosphorus tribenzoxide byproducts and the hydrazide byproducts generated by DIAD, so that a process of obtaining the intermediate IV (formula IV) with high purity is realized.
The inventors of the present invention have systematically analyzed the synthesis methods reported in the prior art, and thought that the residual by-products in the compound (formula IV) obtained by etherification of Mitsunobu reaction will have significant adverse effects on the progress of subsequent reactions and the quality of the product, but the removal of by-products, particularly TPPO, is difficult, which has become a problem in the industry. The inventors of the present invention have found that, after preparing compound V having a very high purity by column chromatography, it is difficult to solidify it in an oily form, and therefore, it is difficult to remove by-products generated by Mitsunobu other than column chromatography.
In order to solve the problem in the existing synthesis method, the inventor changes the physical form of the product and obtains a good solid form by a comprehensive experimental method in a mode of preparing the compound IV into monosodium salt or potassium salt, thereby effectively removing related byproducts such as TPPO and the like and solving the technical defects caused by column chromatography or preparation separation in the prior art. On the other hand, the high-purity intermediate IV without TPPO is prepared by the method, so that the poisoning of the catalyst is avoided, the subsequent reaction is smoothly carried out, and the reaction yield and the product quality are improved.
Meanwhile, the inventor finds that the amino acid compound VI obtained by removing the protecting group of the compound V has poor solubility in various solvents, is indissolvable, and after the reaction is finished, the compound VI is mixed with the catalyst Pd/C, and a great amount of solvent is needed to partially elute the compound VI, so that a great amount of products are lost, and the operation difficulty is increased. The inventor discovers that the intermediate VI obtained by adopting the high-purity intermediate V has high purity by analyzing the purity condition of a reaction system, so that the product VI is directly used for the next reaction without separation in the one-pot operation in the step, the post-treatment operation is simplified, the material loss in the treatment process is reduced, the yield is improved, the production cost is reduced, and the remarkable effect is achieved.
Therefore, the synthesis method provided by the invention has the advantages of safety, environmental protection, low impurity production amount and high yield, can obtain products with quality meeting the requirements without complicated purification operation, and provides an effective new method for the industrial production of O-alkyl-N- [ fluorenylmethoxycarbonyl ] -L-tyrosine.
Further, the inorganic base is a monovalent metal inorganic base and/or a divalent metal inorganic base.
Further, the inorganic base comprises one or more than two of potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide and magnesium hydroxide.
Further, the inorganic base is sodium hydroxide and/or potassium hydroxide.
Further, the molar ratio of the compound represented by the formula < II > to the inorganic base is 0.9:1 to 1:3.
Further, the molar ratio of the compound represented by the formula < II > to the inorganic base is 1:1 to 1:2.5.
Further, the hydrolysis reaction is performed in a solvent selected from at least one of an ether solvent, an alcohol solvent, and a nitrile solvent.
Further, the ether solvent is a chain compound or a cyclic compound having an ether bond-O-, and having 1 to 10 carbon atoms.
Further, the ether solvent comprises at least one of diethyl ether, propylene glycol methyl ether, ethylene glycol dimethyl ether, methyl tertiary butyl ether, 1, 4-dioxane and methyl cyclopentyl ether.
Further, the alcohol solvent is a monohydric alcohol or a polyhydric alcohol having one or more hydroxyl-substituted linear or branched alkyl groups having 1 to 6 carbon atoms.
Further, the alcohol solvent comprises at least one of methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol and trifluoroethanol.
Further, the nitrile solvent is a nitrile having one or more cyano-substituted straight-chain or branched alkyl groups having 1 to 6 carbon atoms.
Further, the nitrile solvent comprises acetonitrile and/or propionitrile.
Further, the solvent is acetonitrile or methyl tert-butyl ether, preferably methyl tert-butyl ether.
Further, the solvent is used in an amount of 1 to 20 times, preferably 1 to 10 times, more preferably 3 to 5 times, the weight of the compound represented by the formula < II >.
Further, the metal salt intermediate is obtained by adding an anti-solvent for crystallization during the hydrolysis reaction.
Further, the anti-solvent is a mixture of alcohol and aromatic hydrocarbon.
Further, the alcohol is at least one of methanol, ethanol, isopropanol and n-propanol.
Further, the aromatic hydrocarbon is at least one of toluene, ethylbenzene and xylene.
Further, the anti-solvent is a mixture of isopropanol and toluene in a volume ratio of 1:3.
Further, the reaction temperature is 0 to 100 ℃, preferably 20 to 60 ℃, more preferably 15 to 25 ℃; the reaction time is 5min-24h, preferably 1-3h.
Further, the acid used for the acidification is an inorganic acid and/or an organic acid.
Further, the inorganic acid is selected from one or more of sulfuric acid, hydrochloric acid and phosphoric acid, preferably hydrochloric acid.
Further, the organic acid is selected from one or more of trifluoroacetic acid, formic acid, acetic acid and trifluoromethanesulfonic acid.
Further, the protection of the amino group is performed by adopting N-fluorenylmethoxycarbonyl.
The invention provides a preparation method of O- [2- [ [ tert-butoxycarbonyl ] amino ] ethyl ] -N- [ fluorenylmethoxycarbonyl ] -L-tyrosine, which specifically comprises the following steps:
(1) Mixing a compound shown in a formula < II > with N- (tert-butoxycarbonyl) ethanolamine and triphenylphosphine, dissolving the mixture, cooling to below 0 ℃, adding diisopropyl azodicarboxylate, stirring, and heating for reaction to obtain a compound shown in a formula < III >;
(2) Dissolving a compound shown in a formula < III >, adding alkali liquor into the solution to react, adding isopropanol and toluene into the solution, cooling to 0-5 ℃, stirring the solution to react, filtering precipitated solid, and cleaning and removing impurities to obtain the compound shown in the formula < IV >;
(3) Dissolving a compound shown in a formula < IV >, adding an acidic solution to adjust the pH value to be between 2 and 3, standing for layering, taking a lower water phase, extracting and concentrating under reduced pressure to obtain a compound shown in a formula < V >;
(4) Dissolving a compound shown in a formula < V >, adding a Pd/C catalyst, introducing hydrogen under the protection of nitrogen to react, after the reaction is completed, obtaining a compound shown in a formula < VI >, adding alkali liquor to adjust the pH value, then adding 9-fluorenylmethyl-N-succinimidyl carbonate to react, after the reaction is completed, adjusting the pH value to be between 2 and 3, standing for layering, taking a lower water phase, extracting and concentrating under reduced pressure, cleaning and filtering, collecting solids, and carrying out post treatment on the solids to obtain the compound shown in the formula < I >, namely O- [2- [ [ tert-butoxycarbonyl ] amino ] ethyl ] -N- [ fluorenylmethoxycarbonyl ] -L-tyrosine;
in the above formula, me is methyl, cbz is benzyloxycarbonyl, boc is tert-butyloxycarbonyl, fmoc is fluorenylmethylcarbonyl, and M is any one of lithium, sodium, potassium, calcium and magnesium.
Further, the molar ratio of the compound shown in the formula < II > in the step (1), N- (tert-butoxycarbonyl) ethanolamine and triphenylphosphine is 1:1.0:1.0-1:1.6:1.6, preferably 1:1.2:1.2.
Further, in the step (1), the mixture is dissolved with toluene.
Further, the temperature-rising reaction is to raise the temperature to 20-25 ℃ for 4-5 hours.
Further, in the step (2), the compound represented by the formula < III > is dissolved with methyl tert-butyl ether.
Further, the alkali liquor is sodium hydroxide solution or potassium hydroxide solution.
Further, in the step (2), alkali liquor is added for reaction for 2-3 hours at 20-25 ℃.
Further, the stirring reaction time in the step (2) is 2 hours or more.
Further, the volume ratio of the isopropanol to the toluene is 1:3.
Further, the step of cleaning and impurity removing in the step (2) is as follows: and adding a mixed solvent of ethyl acetate and methyl tertiary butyl ether into the filter cake obtained by filtering, heating to 40 ℃, stirring and washing for 1 hour, cooling to room temperature, filtering, leaching the filter cake with the methyl tertiary butyl ether, and drying the obtained solid.
Further, in the step (3), the compound represented by the formula < IV > is dissolved with acetonitrile.
Further, the acidic solution is a 10wt% aqueous hydrochloric acid solution.
Further, the extraction was performed 2 times with ethyl acetate, and then washed 2 times with saturated saline.
Further, in the step (4), the compound represented by the formula < V > is dissolved with tetrahydrofuran.
Further, the concentration of the Pd/C catalyst is 5 wt%.
Further, the pressure of the reaction by introducing hydrogen was 1atm, and the reaction time was 30 hours.
Further, in the step (4), the added alkali liquor is sodium bicarbonate solution.
Further, the reaction temperature of adding 9-fluorenylmethyl-N-succinimidyl carbonate is 20-25 ℃, and the reaction time is 10 hours.
Further, the post-processing is performed as follows: adding ethyl acetate, heating to 50-55 ℃, adding n-heptane into the reaction system, keeping the temperature at 50-55 ℃ for 1 hour, cooling to 10-20 ℃, filtering, collecting solids, and drying to obtain the catalyst.
The beneficial effects of the invention are as follows:
The invention provides a preparation method of O- [2- [ [ tert-butoxycarbonyl ] amino ] ethyl ] -N- [ fluorenylmethoxycarbonyl ] -L-tyrosine, which has the characteristics of simple preparation process, controllable operation, low preparation cost and suitability for industrial production;
The method can avoid the generation of byproducts, and the obtained target product has high yield, good purity and good quality.
Drawings
FIG. 1 is a graph of purity of a compound of formula < V >;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of a compound represented by the formula < V >:
FIG. 3 is a graph of purity of compounds of formula < I >;
FIG. 4 is a nuclear magnetic resonance hydrogen spectrum of a compound shown in formula < I >.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be specifically described with reference to the following examples, which are provided for explaining and illustrating the present invention only and are not intended to limit the present invention. Some non-essential modifications and adaptations of the invention according to the foregoing summary will still fall within the scope of the invention.
"Alkyl" as used herein refers to straight or branched chain alkyl groups containing 1 to 20 carbon atoms and includes, for example, "C1-6 alkyl", "C1-4 alkyl", and the like, and specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like.
The "ether solvent" as used herein refers to a chain compound or cyclic compound containing an ether bond-O-and having 1 to 10 carbon atoms, and specific examples include, but are not limited to: tetrahydrofuran, diethyl ether, propylene glycol methyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, 1, 4-dioxane or methyl cyclopentyl ether.
As used herein, "alcohol solvent" refers to a radical derived from one or more "hydroxy" groups substituted for one or more hydrogen atoms on "C1-6 alkyl" as defined above, specific examples include, but are not limited to: methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol or trifluoroethanol.
"Nitrile solvent" as used herein refers to a group derived from one or more "cyano" groups substituted for one or more hydrogen atoms on "C1-6 alkyl" as defined above, specific examples include, but are not limited to: acetonitrile or propionitrile.
The term "content" as used herein refers to the proportion of a target component to the total weight of a substance, and represents the amount of a certain component contained in the substance in terms of percentage.
The instrument and method for measuring the content of the related substances in the product obtained in the preparation process in the embodiment are as follows:
test instrument for experiments:
Instrument: agilent 1220
Chromatographic column: octadecylsilane chemically bonded silica gel as filler
Column temperature: 40 DEG C
Flow rate: 1.0ml/min
Detection wavelength: 210nm of
Elution procedure:
Mobile phase a:0.1% H 3PO4+H2 O
Mobile phase B: acetonitrile
Gradient elution was performed as follows in table 1:
TABLE 1 gradient elution procedure
The experimental methods of the present invention, in which specific conditions are not specified, are generally performed according to conventional conditions or according to conditions suggested by the manufacturer of the raw materials or goods. The reagents of specific origin are not noted and are commercially available conventional reagents.
Example 1
Preparation of methyl S-2- ((benzyloxycarbonyl) amino) -3- (4- (2- (tert-butoxycarbonylamino) ethoxy) phenyl) propanoate (formula III) the reaction scheme is as follows:
100kg of toluene is added into a reaction kettle, then 20kg of compound II is added into the reaction kettle, 10kg of N- (tert-butoxycarbonyl) ethanolamine is added into the reaction kettle under stirring, 16.7kg of triphenylphosphine is added, the reaction system is cooled to below 0 ℃, DIAD (diisopropyl azodicarboxylate) is added into the reaction kettle, stirring is continued for 1 hour, the temperature is naturally raised to room temperature, stirring is continued for 5 hours, sampling and detection are carried out, and the reaction is stopped after the reaction is qualified. Then, after toluene was removed by concentration under vacuum, the crude product of methyl S-2- ((benzyloxycarbonyl) amino) -3- (4- (2- (tert-butoxycarbonylamino) ethoxy) phenyl) propanoate (formula III) was obtained, and the product oil was directly used in the next reaction in 100% yield.
Example 2
Preparation of potassium S-2- ((benzyloxycarbonyl) amino) -3- (4- (2- (tert-butoxycarbonylamino) ethoxy) propanoate (formula IV) the reaction scheme is as follows:
50kg of the crude S-2- ((benzyloxycarbonyl) amino) -3- (4- (2- (tert-butoxycarbonylamino) ethoxy) phenyl) propanoic acid methyl ester obtained in example 1 was added to the reaction vessel, 150L of methyl tert-butyl ether was added, and the mixture was stirred and dissolved completely. 6.8kg of potassium hydroxide was dissolved in 10kg of water and then added dropwise to the reaction vessel. After the addition, continuously reacting for 2-3 hours at room temperature, adding 30L of isopropanol and 60L of toluene into a reaction kettle, slowly cooling to 0-5 ℃, continuously stirring for 10-20 hours, filtering precipitated solids, adding 20kg of ethyl acetate and 30kg of methyl tertiary butyl ether mixed solvent into a filter cake, heating to 40 ℃, stirring and washing for 1 hour, cooling to room temperature, filtering, eluting the filter cake with methyl tertiary butyl ether, and drying the obtained solids to obtain 27.8kg of white solids with the yield of 93%.
Example 3
Preparation of sodium S-2- ((benzyloxycarbonyl) amino) -3- (4- (2- (tert-butoxycarbonylamino) ethoxy) propanoate (formula IV) the reaction scheme is as follows:
5kg of the crude S-2- ((benzyloxycarbonyl) amino) -3- (4- (2- (tert-butoxycarbonylamino) ethoxy) phenyl) propanoic acid methyl ester obtained in example 1 was added to the reaction vessel, and 15L of methyl tert-butyl ether was added thereto and stirred and dissolved completely. 480g of sodium hydroxide was dissolved in 1kg of water and then added dropwise to the reaction vessel. After the addition, continuously reacting for 2-3 hours at room temperature, adding 3L of isopropanol and 6L of toluene into a reaction kettle, slowly cooling to 0-5 ℃, continuously stirring for 2-5 hours, filtering precipitated solids, adding 2kg of ethyl acetate and 3kg of methyl tertiary butyl ether mixed solvent into a filter cake, heating to 40 ℃, stirring and washing for 1 hour, cooling to room temperature, filtering, eluting the filter cake with methyl tertiary butyl ether, and drying the obtained solids to obtain 2.7kg of white solids with the yield of 92%.
Example 4
Preparation of S-2- ((benzyloxycarbonyl) amino) -3- (4- (2- (tert-butoxycarbonylamino) ethoxy) propionic acid (formula V) by the following reaction scheme:
After 50kg of water was added to the reaction vessel, 25kg of potassium S-2- ((benzyloxycarbonyl) amino) -3- (4- (2- (t-butoxycarbonylamino) ethoxy) phenyl) propionate of example 3 was further added, 50kg of acetonitrile was further added, a 10% aqueous hydrochloric acid solution was slowly added to the reaction system with stirring, the pH was adjusted to 2 to 3, and after standing for delamination, the lower aqueous phase was extracted 2 times (25 kg. Times.2) with ethyl acetate. The organic phases were combined and then washed 2 times with saturated brine ((10 kg×2), concentrated under reduced pressure to give 23kg of a viscous oil in 100% yield, 99.1% purity, no specific impurity TPPO detected, max mono-impurity 0.5% (see fig. 1).
1H NMR (400 MHz, CDCl3): d=7.34 (brs, 5H),6.99 (d, J=8.5 Hz, 2H), 6.80 (d, J=8.5 Hz, 2H), 5.30–4.98(m, 4H), 4.64–4.60 (m, 1H), 3.98(t, J=5.1 Hz, 2H), 3.70 (s, 3H), 3.47–3.55 (m, 2H), 3.10–2.98 (m, 2H), 1.45 ppm (s, 9H)（ See fig. 2).
Example 5
Preparation of S-2- ((benzyloxycarbonyl) amino) -3- (4- (2- (tert-butoxycarbonylamino) ethoxy) propionic acid (formula I) by the following reaction scheme:
After 150kg of tetrahydrofuran was added to the reaction vessel, then, 23kg of S-2- ((benzyloxycarbonyl) amino) -3- (4- (2- (tert-butoxycarbonylamino) ethoxy) propionic acid obtained in the preparation method of example 4 was added, 5% of Pd/C (3 kg) was added, after the air in the reaction vessel was replaced with nitrogen, the reaction was carried out at room temperature for 30 hours under the pressure of 1atm, sampling and detection were carried out, after the reaction was completed, after the hydrogen in the reaction vessel was replaced with nitrogen, 80kg of water and 8.4kg of sodium bicarbonate were added to the reaction vessel, then, after the reaction was carried out for 10 hours under stirring, sampling and detection were carried out, after the reaction was completed, the pH value was adjusted to 2 to 3 with hydrochloric acid, the reaction vessel was allowed to stand for delamination, the lower aqueous phase was extracted with ethyl acetate until the end, then, 2 times (20 kg. Times. 2) with saturated brine, the reaction vessel was concentrated under reduced pressure, then, 80kg of ethyl acetate was added to the reaction vessel, after the reaction vessel was replaced with nitrogen, 80kg of water and 8.4kg of sodium bicarbonate was added, after the reaction vessel was cooled to 100 ℃, the reaction vessel was cooled to a maximum of 5.2.82% under the temperature of water, the reaction vessel was cooled to a maximum purity of 5.2.95%, and after the reaction vessel was cooled, the solid was cooled to a maximum of 5.3.6%, and the solid was obtained after the filtration, after the filtration was cooled, and after the filtration was continued, the filtration, and after the filtration was continued for 10 hours, after the filtration, the solid was cooled, and after the filtration, 2.3 kg was 100.3 kg was cooled.
1H NMR (400 MHz, CDCl3): d=7.75 (d, J=8.0 Hz, 2H),7.57 (t, 2H), 7.40 (t, J=8.0 Hz, 2H), 7.30 (t, J=8.0 Hz, 2H),7.03 (d, J=8.0Hz, 2H), 6.78 (d, J=4.0Hz, 2H),5.24 (d, J=8.0Hz, 1H), 5.05(brs,1H),4.67(d, J=8.0Hz, 1H), 4.44(m, 1H), 4.34(m, 1H ),4.19(m, 1H), 3.96 (s, 2H), 3.50 (s, 2H), 3.11–2.82 (m, 2H), 1.45 ppm (s, 9H) （ As in fig. 4).
Comparison of different route reaction conditions:
To compare the effects of the different experimental modes on obtaining the product, the inventors conducted a comparison of the reaction conditions for the process of obtaining S-2- ((benzyloxycarbonyl) amino) -3- (4- (2- (tert-butoxycarbonylamino) ethoxy) propionic acid (formula V) using typical experimental operations in the process of technological exploration.
Comparative example 1
To the reaction flask was added 100g of methyl S-2- ((benzyloxycarbonyl) amino) -3- (4- (2- (tert-butoxycarbonylamino) ethoxy) phenyl) propanoate obtained in example 1, 300mL of methyl tert-butyl ether was added, and the mixture was stirred and dissolved completely. 13.6g of potassium hydroxide was dissolved in 20g of water and then added dropwise to the reaction vessel. After the addition, continuously reacting for 2 to 3 hours at room temperature, adding 3L of isopropanol and 120mL of toluene into a reaction kettle, slowly cooling to 0 to 5 ℃, continuously stirring for 2 to 5 hours, and separating out a viscous solid, continuously prolonging the time, wherein the solid form is unchanged. And pouring the supernatant, adding 40g of ethyl acetate and 60g of methyl tertiary butyl ether into the lower viscous solid to mix and dissolve, heating to 40 ℃, stirring for 1 hour, cooling to room temperature, pouring the supernatant, washing the lower viscous solid once again by using the methyl tertiary butyl ether, and concentrating under reduced pressure to obtain 116g of yellow viscous solid, wherein the yield is more than 100%.
Comparative example 2
To the reaction flask was added 100g of methyl S-2- ((benzyloxycarbonyl) amino) -3- (4- (2- (tert-butoxycarbonylamino) ethoxy) phenyl) propanoate obtained in example 1, 300mL of methyl tert-butyl ether was added, and the mixture was stirred and dissolved completely. 9.6g of sodium hydroxide was dissolved in 20g of water and then added dropwise to the reaction vessel. After the addition, continuously reacting for 2 to 3 hours at room temperature, adding 600mL of water into a reaction kettle, stirring to ensure that the reaction system is fully dissolved and layered; the aqueous phase is extracted with MTBE for 3-4 times, the organic phases are combined, the product in the organic phase is extracted with 10% aqueous potassium hydroxide solution for 2 times, all the aqueous phases are combined, the pH is regulated to 1-2 by concentrated hydrochloric acid, the product is extracted with ethyl acetate until the end, the extracted phase is concentrated to dryness, and 80g of viscous oily matter (formula V) is separated out after continuous stirring for 2-5 hours, and the yield is 83%.
The experimental results obtained in comparative examples 1 and 2 were compared with the experimental results obtained in inventive example 5 as follows:
table 2 comparison of different route response cases
Note that: [1] the compound of formula IV and the compound of formula V have the same peak time on HPLC and formula V is not specially treated, so the purity of the compound of formula V represents the purity of the compound of formula IV;
[2] Impurity 1 and impurity 2 are the maximum two other impurities after treatment, and the impurity structures of each method are possibly different, so that comparison is mainly facilitated.
[3] The impurity detection method has high separation degree, and each impurity can be effectively distinguished.
The experimental findings in table 2 are as follows:
The column chromatography method can effectively remove main impurities including TPPO, but the impurity removing process is easy to cross, so that the quality and the yield of the product are affected, and the operation mode of the method is complex and is not suitable for industrial amplification; the method of comparative example 1 uses, in addition to the solvents in the typical experiment, other different solvents and combinations thereof, and the effect is nearly even worse, mainly because only slurry can be obtained but solid cannot be obtained in the salt forming process, so that a large amount of impurities cannot be removed effectively, and the yield exceeds the theoretical value because of the large amount of impurities; the method of comparative example 2 uses some conceivable chemical properties of the product by an acid-base adjustment method, but impurities can always only remove part of the impurities, and cannot be removed completely, and because of the aromatic ring property of the product, the aqueous solution salt of the product can be partially dissolved in the extraction solvent, and part of the product can be lost in the impurity removal process, so that the method cannot achieve satisfactory effects; according to the technical method, a plurality of batches of experiments prove that the excellent effect is achieved.
Comparative example 3
The procedure of example 5 was followed, using the compounds of formula V obtained in comparative examples 1 and 2, in different purities, to prepare the reaction pairs for the compounds of formula I as shown in Table 3:
TABLE 3 comparison of compounds of formula I prepared from formula V of different purities
The experimental findings of table 3 show that: in the method of comparative example 1, since the product contains more phosphorus oxychloride, pd/C is partially deactivated, and the reaction is difficult to react only by a small amount; in the method of comparative example 2, because of more impurities, repeated recrystallization is needed during treatment, so that the loss of the product is large, the yield is low, part of impurities are difficult to remove, and the purity cannot reach the ideal effect; according to the technical method of the invention, excellent effect can be obtained only by one recrystallization during post-treatment.
Experimental example 1
Using the different batches of the compound of formula V obtained in example 4, the reaction of the compound of formula I prepared by the procedure of example 5 is shown in Table 4:
TABLE 4 comparison of compounds of formula I prepared using different batches of compounds of formula V
Note that: the total yield was calculated using the finished product obtained in example 5.
As shown in the experimental data of Table 4, the purity of the compound of formula I prepared by the three-batch method is similar, the purity can reach more than 99.8%, the yield is not great, the maximum single impurity is less than 0.2%, and the method is stable. The method has the characteristics of stable process, simple operation, high product quality and yield, low cost, safety, suitability for industrial production and the like, and has remarkable social and economic benefits.
The foregoing is merely a preferred embodiment of the present invention, and it should be noted that the above-mentioned preferred embodiment should not be construed as limiting the invention, and the scope of the invention should be defined by the appended claims. It will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the spirit and scope of the invention, and such modifications and adaptations are intended to be comprehended within the scope of the invention.
Claims (10)
1. A preparation method of O- [2- [ [ tert-butoxycarbonyl ] amino ] ethyl ] -N- [ fluorenylmethoxycarbonyl ] -L-tyrosine is characterized in that a compound shown in a formula < II > is taken as a raw material, and is subjected to Mitsunobu reaction with N- (tert-butoxycarbonyl) ethanolamine and triphenylphosphine, the obtained product is subjected to hydrolysis reaction with inorganic base to form a metal salt intermediate, and then is subjected to hydrogenation reaction under the action of Pd/C catalyst after acidification, and the amino is protected to obtain the compound shown in the formula < I >;
。
2. The preparation method according to claim 1, wherein the inorganic base is a monovalent metal inorganic base and/or a divalent metal inorganic base, wherein the inorganic base comprises one or a combination of two or more of potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide; the mol ratio of the compound shown in the formula < II > to the inorganic base is 0.9-1:1-3.
3. The production method according to claim 1 or2, wherein the hydrolysis reaction is performed in a solvent selected from at least one of an ether solvent, an alcohol solvent, and a nitrile solvent; the ether solvent is a chain compound or a cyclic compound containing ether bonds-O-and having 1 to 10 carbon atoms, wherein the ether solvent comprises at least one of diethyl ether, propylene glycol methyl ether, ethylene glycol dimethyl ether, methyl tertiary butyl ether, 1, 4-dioxane and methyl cyclopentyl ether; the alcohol solvent is monohydric alcohol or polyhydric alcohol formed by straight-chain or branched-chain alkyl with one or more hydroxyl groups substituted and having 1 to 6 carbon atoms, wherein the alcohol solvent comprises at least one of methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol and trifluoroethanol; the nitrile solvent is nitrile formed by straight-chain or branched-chain alkyl with one or more cyano groups substituted and having 1 to 6 carbon atoms, wherein the nitrile solvent comprises acetonitrile and/or propionitrile; the solvent is used in an amount of 1 to 20 times by weight of the compound represented by the formula < II >.
4. The preparation method according to claim 1 or 2, wherein the metal salt intermediate is obtained by adding an antisolvent for crystallization during the hydrolysis reaction; the anti-solvent is a mixture of alcohol and aromatic hydrocarbon, wherein the alcohol is at least one of methanol, ethanol, isopropanol and n-propanol; the aromatic hydrocarbon is at least one of toluene, ethylbenzene and xylene.
5. The method according to claim 4, wherein the antisolvent is a mixture of isopropanol and toluene in a volume ratio of 1:3.
6. The preparation method according to claim 1 or 2, wherein the temperature of the hydrogenation reaction is 0-100 ℃; the hydrogenation reaction time is 5min-24h; the acid adopted by the acidification is inorganic acid and/or organic acid; the inorganic acid is selected from one or more of sulfuric acid, hydrochloric acid and phosphoric acid; the organic acid is selected from one or more of trifluoroacetic acid, formic acid, acetic acid and trifluoromethanesulfonic acid.
7. The preparation method according to claim 1 or 2, characterized in that the preparation method comprises the steps of:
(1) Mixing a compound shown in a formula < II > with N- (tert-butoxycarbonyl) ethanolamine and triphenylphosphine, adding a reaction solvent, cooling to below 0 ℃, and then adding diisopropyl azodicarboxylate for reaction to obtain the compound shown in the formula < III >;
(2) Adding a reaction solvent into a compound shown in a formula < III >, adding inorganic alkali for hydrolysis, then adding an anti-solvent, cooling to 0-5 ℃, crystallizing, separating out solids, filtering the separated solids, and cleaning and removing impurities to obtain the compound shown in the formula < IV >;
(3) Adding a reaction solvent into a compound shown in a formula < IV >, adding an acidic solution to adjust the pH value to be between 2 and 3, standing for layering, taking a lower water phase, extracting and concentrating under reduced pressure to obtain a compound shown in a formula < V >;
(4) Adding a reaction solvent into a compound shown in a formula < V >, adding a Pd/C catalyst, introducing hydrogen under the protection of nitrogen to react, after the reaction is completed, obtaining the compound shown in the formula < VI >, adding alkali liquor to adjust the pH value, then adding 9-fluorenylmethyl-N-succinimidyl carbonate to react, after the reaction is completed, adjusting the pH value to be between 2 and 3, standing for layering, taking a lower water phase, extracting and concentrating under reduced pressure, washing and filtering, collecting solids, and carrying out post treatment on the solids to obtain the compound shown in the formula < I >, namely O2- [ [ tert-butoxycarbonyl ] amino ] ethyl ] -N- [ fluorenylmethoxycarbonyl ] -L-tyrosine;
；
in the above formula, me is methyl, cbz is benzyloxycarbonyl, boc is tert-butyloxycarbonyl, fmoc is fluorenylmethylcarbonyl, and M is any one of lithium, sodium, potassium, calcium and magnesium.
8. The process according to claim 7, wherein in the step (1), the molar ratio of the compound represented by the formula < II >, N- (t-butoxycarbonyl) ethanolamine and triphenylphosphine is 1:1.0 to 1.6:1.0 to 1.6; the reaction solvent comprises toluene, the reaction temperature is 20-25 ℃, and the reaction time is 4-5 hours; in the step (2), the reaction solvent comprises at least one of an ether solvent, a nitrile solvent and an alcohol solvent, wherein the ether solvent comprises tetrahydrofuran, dioxane, N-methylpyrrolidone and methyl tertiary butyl ether; the nitrile solvent comprises acetonitrile; the alcohol solvent comprises methanol and ethanol; the amount of the reaction solvent is 1 to 20 times the molar amount of the compound represented by the formula < III >.
9. The method according to claim 7, wherein the step of cleaning and removing impurities in the step (2) is: adding a mixed solvent of ethyl acetate and methyl tertiary butyl ether into a filter cake obtained by filtering, heating to 40 ℃, stirring and washing for 1 hour, cooling to room temperature, filtering, leaching the filter cake with the methyl tertiary butyl ether, and drying the obtained solid; in the step (3), the compound shown in the formula < IV > is dissolved by acetonitrile; the acid solution is 10wt% hydrochloric acid aqueous solution; the extraction is carried out by adopting ethyl acetate for 2 times, and then washing with saturated saline water for 2 times; in the step (4), the compound represented by the formula < V > is dissolved with tetrahydrofuran.
10. The method according to claim 7, wherein in the step (4), the concentration of the Pd/C catalyst is 5 wt%; introducing hydrogen to react at 1atm for 30 hr; the added alkali liquor is sodium bicarbonate solution; adding 9-fluorenylmethyl-N-succinimidyl carbonate for reaction at 20-25 ℃ for 10 hours; the post-processing operation is as follows: adding ethyl acetate, heating to 50-55 ℃, then adding n-heptane into the reaction system, continuously preserving heat at 50-55 ℃ for 1 hour, cooling to 10-20 ℃, filtering, collecting solids, and drying to obtain the catalyst.
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