CN118063339A - Preparation method of sodium 8- (2-hydroxybenzoylamino) octoate - Google Patents
Preparation method of sodium 8- (2-hydroxybenzoylamino) octoate Download PDFInfo
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- CN118063339A CN118063339A CN202410060498.4A CN202410060498A CN118063339A CN 118063339 A CN118063339 A CN 118063339A CN 202410060498 A CN202410060498 A CN 202410060498A CN 118063339 A CN118063339 A CN 118063339A
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- sodium
- octoate
- ethyl
- acetoxy
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- 238000002360 preparation method Methods 0.000 title claims abstract description 59
- 125000005474 octanoate group Chemical group 0.000 title claims description 35
- -1 2-hydroxybenzoylamino Chemical group 0.000 title claims description 31
- 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 title claims description 31
- 239000011734 sodium Substances 0.000 title claims description 31
- 229910052708 sodium Inorganic materials 0.000 title claims description 31
- 238000006243 chemical reaction Methods 0.000 claims abstract description 95
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 24
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 23
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 21
- 239000003513 alkali Substances 0.000 claims abstract description 18
- 239000002994 raw material Substances 0.000 claims abstract description 12
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims abstract description 11
- 238000006482 condensation reaction Methods 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 87
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 29
- NJEKDCUDSORUJA-UHFFFAOYSA-N 8-[(2-hydroxybenzoyl)amino]octanoic acid Chemical compound OC(=O)CCCCCCCNC(=O)C1=CC=CC=C1O NJEKDCUDSORUJA-UHFFFAOYSA-N 0.000 claims description 27
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 19
- 239000000047 product Substances 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- MARYNTIOKYZZQK-UHFFFAOYSA-N ethyl 8-aminooctanoate;hydrochloride Chemical compound Cl.CCOC(=O)CCCCCCCN MARYNTIOKYZZQK-UHFFFAOYSA-N 0.000 claims description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 16
- 239000007788 liquid Substances 0.000 claims description 16
- 239000012044 organic layer Substances 0.000 claims description 16
- 239000011541 reaction mixture Substances 0.000 claims description 16
- KGHXFBVYXDFJGG-UHFFFAOYSA-N (2-carbamoylphenyl) acetate Chemical compound CC(=O)OC1=CC=CC=C1C(N)=O KGHXFBVYXDFJGG-UHFFFAOYSA-N 0.000 claims description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- 239000008367 deionised water Substances 0.000 claims description 6
- 229910021641 deionized water Inorganic materials 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 6
- 238000012544 monitoring process Methods 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 238000000967 suction filtration Methods 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 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
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 3
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 3
- YYZUSRORWSJGET-UHFFFAOYSA-N ethyl octanoate Chemical compound CCCCCCCC(=O)OCC YYZUSRORWSJGET-UHFFFAOYSA-N 0.000 claims description 3
- 238000005755 formation reaction Methods 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 230000020477 pH reduction Effects 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- 239000007858 starting material Substances 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 13
- 239000003480 eluent Substances 0.000 description 13
- 239000003208 petroleum Substances 0.000 description 13
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 6
- 238000009776 industrial production Methods 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 5
- UQXNEWQGGVUVQA-UHFFFAOYSA-N 8-aminooctanoic acid Chemical compound NCCCCCCCC(O)=O UQXNEWQGGVUVQA-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical compound NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 208000018522 Gastrointestinal disease Diseases 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 229960000581 salicylamide Drugs 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 206010025476 Malabsorption Diseases 0.000 description 2
- 208000004155 Malabsorption Syndromes Diseases 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UOENJXXSKABLJL-UHFFFAOYSA-M sodium;8-[(2-hydroxybenzoyl)amino]octanoate Chemical compound [Na+].OC1=CC=CC=C1C(=O)NCCCCCCCC([O-])=O UOENJXXSKABLJL-UHFFFAOYSA-M 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 description 1
- 229930192334 Auxin Natural products 0.000 description 1
- VKJGBAJNNALVAV-UHFFFAOYSA-M Berberine chloride (TN) Chemical compound [Cl-].C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 VKJGBAJNNALVAV-UHFFFAOYSA-M 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000002363 auxin Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940124447 delivery agent Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- ZFTFAPZRGNKQPU-UHFFFAOYSA-N dicarbonic acid Chemical class OC(=O)OC(O)=O ZFTFAPZRGNKQPU-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- SEOVTRFCIGRIMH-UHFFFAOYSA-N indole-3-acetic acid Chemical compound C1=CC=C2C(CC(=O)O)=CNC2=C1 SEOVTRFCIGRIMH-UHFFFAOYSA-N 0.000 description 1
- 239000010842 industrial wastewater Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of 8- (2-hydroxybenzoyl amino) sodium octoate, which comprises the steps of firstly utilizing 8-amino ethyl octoate hydrochloride and 2- (acetoxy) benzoic acid to generate condensation reaction under the action of condensing agent and alkali to generate 8- (2-acetoxy benzoyl amino) ethyl octoate, then carrying out hydrolysis reaction on the 8- (2-acetoxy benzoyl amino) ethyl octoate under the action of alkali, and then salifying by alkali to obtain the 8- (2-hydroxybenzoyl) sodium octoate. The method has the advantages of low-cost and easily-obtained raw materials, simple operation, mild reaction conditions and lower equipment requirements, and is suitable for the requirements of industrial mass production.
Description
Technical Field
The invention belongs to the technical field of chemical medicine preparation methods, and particularly relates to a preparation method of 8- (2-hydroxybenzoylamino) sodium octoate.
Background
Sodium 8- (2-hydroxybenzoamido) octoate, abbreviated as SNAC, is an oral absorption enhancer developed by the company Emisphere of the united states of america. SNAC has potential as a delivery agent for various protein drugs such as heparin, insulin and human auxin in oral form, and can be clinically used for gastrointestinal diseases, in particular for the treatment of gastrointestinal diseases caused by malabsorption of dicarbonate compounds. As a newer product of the malabsorption medicine for gastrointestinal diseases, the pharmaceutical composition has the characteristics of higher efficacy, safer efficacy and the like, is expected to become a star auxiliary material product, and has wide market application prospect. Therefore, the development of an efficient synthesis method for preparing sodium 8- (2-hydroxybenzoylamino) caprylate is of great importance.
The literature studies show that the synthesis of the 8- (2-hydroxybenzoylamino) sodium octoate at present mainly comprises the following methods:
The method comprises the following steps: chinese patent CN 108689876B reports a method for obtaining target sodium 8- (2-hydroxybenzoylamino) octoate by sequentially performing ring closure, substitution, hydrolysis and salification reactions using salicylamide and carbonyl diimidazole as starting materials. The carbonyl diimidazole used in the method is high in price, and imidazole as a byproduct is generated after the reaction, so that the method does not accord with the concept of atom economy; and the route has a large amount of industrial wastewater, does not meet the requirement of green chemistry, and is not suitable for industrial production.
The second method is as follows: in Chinese patent CN113861062A, it is reported that target sodium 8- (2-hydroxybenzoylamino) octoate is obtained by transesterification and salification of methyl o-hydroxybenzoate and 8-aminocaprylate as starting materials. Although this method is short in route, 8-aminocaprylic acid as a starting material is expensive and thus unsuitable for mass production.
And a third method: chinese patent CN104974060a reports that 8- (2-hydroxybenzoylamino) sodium octoate is synthesized from 2-hydroxybenzoamide and ethyl chloroformate as starting materials by four steps of cyclization, nucleophilic substitution, hydrolysis and salification in sequence. The ethyl chloroformate used by the method has genotoxicity, has great harm to human and environment, and does not meet the requirement of industrial production.
The method four: chinese patent CN112898220a reports that sodium 8- (2-hydroxybenzoylamino) octoate is obtained by four steps of cyclization, substitution, hydrolysis and salification in sequence using salicylamide and 2, 2-dimethoxypropane as starting materials. The 2, 2-dimethoxy propane used by the method can irritate eyes, respiratory systems and skin, is highly flammable and difficult to store, and therefore, the method also does not meet the requirements of industrial production.
And a fifth method: chinese patent CN112661662a reports that the target product sodium 8- (2-hydroxybenzoylamino) octoate is obtained by sequentially performing cyclization, nucleophilic substitution, hydrolysis and salt formation reactions using salicylamide and oxalyl chloride as starting materials. Although the method has relatively high atom economy, the raw material oxalyl chloride has strong irritation, has a plurality of side reactions and is not easy to store, so that the method also does not meet the industrial production conditions.
The method six: literature (Development and In Vitro and In Vivo Evaluation of Microspheres Containing Sodium N-[8-(2-hydroxybenzoyl)amino]caprylate for the Oral Delivery of BerberinHydrochloride,Molecules2020,25,1957) reports that the target product sodium 8- (2-hydroxybenzoylamino) octoate is obtained by five steps of reactions of acylation, esterification, condensation, hydrolysis and salification in sequence by taking 8-aminocaprylic acid as a starting material. The method has the advantages of long process route, low yield, high price of the raw material 8-amino octanoic acid, strong-irritation medicaments such as thionyl chloride, oxalyl chloride and the like, and strong reaction and large pollution, so that the method is not suitable for industrial production.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide the preparation method of the 8- (2-hydroxybenzoyl amino) sodium octoate which has the advantages of low-cost and easily-obtained raw materials, simple synthesis method operation, mild reaction conditions, low equipment requirements, technical feasibility, reasonable economy and high cost performance and is suitable for industrial production.
The preparation method of the 8- (2-hydroxybenzoylamino) sodium octoate comprises the following steps:
Step 1: utilizing 8-amino ethyl octoate hydrochloride and 2- (acetoxy) benzoic acid to generate condensation reaction under the action of condensing agent and alkali to generate 8- (2-acetoxy benzamide) ethyl octoate;
Step 2: carrying out hydrolysis reaction on the ethyl 8- (2-acetoxy benzamide) octoate obtained in the step 1 under the action of alkali, and then acidizing to generate 8- (2-hydroxybenzoamido) octoate;
Step 3: and (3) carrying out salt formation reaction on the 8- (2-hydroxybenzoamido) caprylic acid obtained in the step (2) under the action of alkali to generate sodium 8- (2-hydroxybenzoamido) caprylate.
The reaction scheme is as follows:
In step 1, the condensing agent is Dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), O- (7-azabenzotriazol-1-yl) -N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HATU), O- (benzotriazol-1-yl) -N, N, N ', any of N ' -tetramethyluronium Hexafluorophosphate (HBTU), 6-chlorobenzotriazol-1, 3-tetramethyluronium Hexafluorophosphate (HCTU), N ' -Carbonyldiimidazole (CDI) or 1H-benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (catter condensing agent, BOP), preferably 1H-benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (catter condensing agent, BOP).
In step 1, the base is any one of triethylamine, N-Diisopropylethylamine (DIPEA), N-dimethylaniline or pyridine, preferably N, N-diisopropylethylamine.
In step 1, the molar ratio of 2- (acetoxy) benzoic acid, ethyl 8-aminocaprylate hydrochloride, condensing agent and base is 1:1.0-1.5:1.0-1.5:1.0-2.0, e.g., 1:1.0:1.0:1.0:1.0, 1:1.1:1.2, 1:1.1:1.2:1.5, 1:1.1:1.3:1.5, or 1:1.5:1.5:2.0, etc.
In step 1, the reaction is carried out in the presence of a solvent selected from one or more of dichloromethane, ethyl acetate, tetrahydrofuran, 1, 4-dioxane, acetonitrile, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone and toluene, preferably N, N-dimethylformamide.
In the step 1, the reaction is carried out at a suitable temperature, for example, from room temperature to the boiling point of the solvent used, for example, 10 ℃,20 ℃, 25 ℃, 30 ℃, 35 ℃,40 ℃, 45 ℃, 50 ℃, 60 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃, etc., or at the boiling point of the solvent, i.e., in a reflux state.
In step 2, the alkali is any one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate, preferably sodium hydroxide or potassium hydroxide.
In the step 2, the acid used for acidification is any one of hydrochloric acid, sulfuric acid or phosphoric acid, preferably hydrochloric acid.
In step 2, the molar ratio of ethyl 8- (2-acetoxybenzamide) octoate to base is 1:1.0-5.0, e.g., 1:1.0, 1:2.0, 1:3.0, 1:4.0, or 1:5.0, etc.
In the step 2, the hydrolysis reaction is carried out in a mixed solvent of any one or more of water, methanol, ethanol, tetrahydrofuran or 1, 4-dioxane, preferably one or more of water, methanol or ethanol.
In step 3, the salification reaction is carried out in the presence of an alkaline substance, wherein the alkaline substance is any one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium hydroxide, sodium carbonate or sodium bicarbonate, and preferably sodium hydroxide or sodium bicarbonate.
In step 3, the reaction is carried out in the presence of a solvent which is a mixed solvent of methanol/water, ethanol/water or isopropanol/water, preferably ethanol/water, isopropanol/water.
Further, the reaction process of generating the ethyl 8- (2-acetoxy-benzamide) octoate by utilizing the condensation reaction of the ethyl 8-aminocaprylate hydrochloride and the 2- (acetoxy) benzoic acid under the action of a condensing agent and alkali in the step 1 comprises the following steps:
2- (Acetyloxy) benzoic acid was dissolved in N, N-dimethylformamide, and a Kate condensing agent (BOP), N-diisopropylethylamine and ethyl 8-aminocaprylate hydrochloride were added in this order at room temperature. After the addition of the starting material system, the reaction was completed for 3h at room temperature, and when the TLC monitored that the reaction was no longer running, the reaction was terminated. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a pale yellow oily liquid, which was a crude product of ethyl 8- (2-acetoxybenzamide) octanoate. The crude product was directly subjected to the next reaction without purification.
Further, in the step 2, the ethyl 8- (2-acetoxy benzamide) octoate is utilized to carry out hydrolysis reaction under the action of alkali, and then the reaction process of acidizing to generate the 8- (2-hydroxybenzoamido) octoate comprises the following steps:
dissolving the crude product of ethyl 8- (2-acetoxy benzamide) octoate obtained in the last step by using a proper amount of methanol, adding a sodium hydroxide aqueous solution under stirring at room temperature, and reacting for 2.5 hours at 65 ℃ after the addition of a raw material system. After TLC monitoring and finishing the reaction, the reaction is finished, the reaction liquid is decompressed and concentrated, the pH value of the system is regulated to be 1-2 by hydrochloric acid, and white solid is obtained by suction filtration, namely the product 8- (2-hydroxybenzoamide amino) octanoic acid.
Further, the reaction process for generating the sodium 8- (2-hydroxybenzoylamino) octoate by utilizing the salification reaction of the 8- (2-hydroxybenzoylamino) octoate under the action of alkali comprises the following steps:
Taking a reaction bottle, sequentially adding 8- (2-hydroxybenzoamido) caprylic acid and a proper amount of isopropanol, stirring at 50 ℃ for dissolving, adding deionized water into the system after dissolving sodium hydroxide, preserving heat for reacting for 1h at 50 ℃, and then cooling to room temperature for crystallization for 4-6h. And (3) carrying out suction filtration, washing a filter cake with isopropanol, and drying to obtain a light pink solid, namely the product of 8- (2-hydroxybenzoamide amino) sodium octoate.
Compared with the prior art, the invention has the beneficial effects that:
The method for preparing the 8- (2-hydroxybenzoylamino) sodium octoate has the advantages of simple reaction operation, mild reaction conditions, low-cost and easily obtained raw materials, low equipment requirements and capability of meeting the requirements of industrial mass production.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of ethyl 8- (2-acetoxybenzamide) octanoate.
FIG. 2 is a nuclear magnetic spectrum of 8- (2-hydroxybenzoamido) octanoic acid.
FIG. 3 is a nuclear magnetic resonance spectrum of sodium 8- (2-hydroxybenzoamido) octoate.
FIG. 4 is an HPLC chromatogram of sodium 8- (2-hydroxybenzoamido) octoate.
Detailed Description
The technical scheme of the invention is further described by specific examples. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
Example 1:
(1) The preparation method of the 8- (2-acetoxy benzamide) ethyl octanoate comprises the following specific preparation method:
A50 mL three-necked flask was taken, 2- (acetoxy) benzoic acid (1.46 g,8.10mmol,1.0 eq) was dissolved in 25mLN, N-dimethylformamide, and a Kate condensing agent (BOP, 4.30g,9.72mmol,1.2 eq), N-diisopropylethylamine (1.57 g,12.16mmol,1.5 eq) and ethyl 8-aminocaprylate hydrochloride (1.99 g,8.91mmol,1.1 eq) were added sequentially at room temperature. After the addition of the starting material system, the reaction was completed for 3h at room temperature, and when the TLC monitored that the reaction was no longer running, the reaction was terminated. To the reaction mixture was added 20mL of water, the reaction was quenched, extracted with ethyl acetate (25 mL of 3), and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give ethyl 8- (2-acetoxybenzamide) octanoate (2.69 g yield: 95%) as a pale yellow oily liquid. The product was directly subjected to the next reaction without purification.
(2) The preparation method of the 8- (2-hydroxybenzoamido) caprylic acid comprises the following specific preparation method:
A50 mL three-necked flask was taken, and the crude product ethyl 8- (2-acetoxybenzamide) octoate obtained in the previous step was dissolved in 20mL of methanol, and a solution of 20mL of sodium hydroxide (1.30 g,32.40mmol,4.0 eq) in water was added with stirring at room temperature, and the reaction was carried out at 65℃for 2.5 hours. TLC monitoring, after the raw materials are reacted, ending the reaction, concentrating the reaction solution under reduced pressure, regulating the pH value of the residue to 1-2 with hydrochloric acid, and suction filtering to obtain white solid, namely the product 8- (2-hydroxybenzoamido) octanoic acid (2.147 g, yield) ：95％).1H NMR(400MHz,DMSO-d6)δ12.33(s,1H),8.79(s,1H),7.83(d,J＝7.9Hz,1H),7.38(t,J＝7.8Hz,1H),6.92-6.83(m,2H),3.28(q,J＝6.6Hz,2H),2.18(t,J＝7.4Hz,2H),1.56-1.46(m,4H),1.29(s,6H).
(3) The preparation method of the 8- (2-hydroxybenzoamide amino) sodium octoate comprises the following steps:
A50 mL three-necked flask was taken, 8- (2-hydroxybenzoamido) octanoic acid (2.00 g,7.16mmol,1.0 eq) and isopropyl alcohol (30 mL) were sequentially added, dissolved by stirring at 50℃and sodium hydroxide (291.82 mg,7.3mmol,1.02 eq) was dissolved by deionized water (1.5 mL) and added to the above system, the reaction was carried out at 50℃for 1 hour, and then the system was cooled to room temperature (20 ℃) and crystallized for 4-6 hours. Suction filtration, washing the filter cake with 5mL of isopropanol, and drying to obtain a pale pink solid, namely the product sodium 8- (2-hydroxybenzoamide amino) octoate (2.07 g, yield) ：95.8％).1HNMR(400MHz,Methanol-d4)δ7.76(d,J＝7.9Hz,1H),7.34(t,J＝7.8Hz,1H),6.92-6.80(m,2H),4.91(s,2H),3.37(t,J＝7.1Hz,2H),2.16(t,J＝7.6Hz,2H),1.66-1.57(m,4H),1.38(s,6H).
Example 2:
(1) The preparation method of the 8- (2-acetoxy benzamide) ethyl octanoate comprises the following specific preparation method:
A50 mL three-necked flask was used, 2- (acetoxy) benzoic acid (2.42 g,13.43mmol,1.0 eq) was dissolved in 30mL tetrahydrofuran, N' -carbonyldiimidazole (CDI, 2.18g,13.43mmol,1.0 eq) was added under stirring at room temperature, and after 1.5h incubation, ethyl 8-aminocaprylate hydrochloride (3.01 g,13.43mmol,1.0 eq) and triethylamine (1.63 g,16.12mmol,1.2 eq) were added. After the addition of the starting material system, the reaction was completed for 28h at room temperature, and when the TLC monitored that the reaction was no longer performed, the reaction was ended. The reaction mixture was quenched by adding 3M hydrochloric acid, extracted with dichloromethane (25 ml x 3), the organic layer was washed with saturated sodium bicarbonate, saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate=4:1) to give ethyl 8- (2-acetoxybenzamide) octanoate (1.90 g, yield) as a colorless oily liquid ：40.5％).1H NMR(400MHz,Chloroform-d)δ7.69(d,J＝7.7Hz,1H),7.44(t,J＝7.7Hz,1H),7.28(t,J＝7.1Hz,1H),7.08(d,J＝8.1Hz,1H),6.25(s,1H),4.10(q,J＝7.1Hz,2H),3.37(q,J＝6.4Hz,2H),2.31(s,3H),2.27(t,J＝7.8Hz,2H),1.65-1.52(m,4H),1.34(br s,6H),1.24(t,J＝7.1Hz,3H).
(2) The preparation method of the 8- (2-hydroxybenzoamido) caprylic acid comprises the following specific preparation method:
A100 mL three-necked flask was used, ethyl 8- (2-acetoxybenzamide) octoate (1.90 g,5.44mmol,1.0 eq) was dissolved in 30mL ethanol, and a 30mL aqueous solution of sodium hydroxide (869.95 mg,21.75mmol,4.0 eq) was added with stirring at room temperature, and the reaction was carried out at 78℃for 2.5 hours. TLC monitoring, after the raw materials are reacted, finishing the reaction, concentrating the reaction solution under reduced pressure, regulating the pH value of the residue to 1-2 by using hydrochloric acid, and suction-filtering to obtain white solid, namely the product 8- (2-hydroxybenzoamido) octanoic acid (0.76 g, yield) ：50％).1H NMR(400MHz,DMSO-d6)δ12.33(s,1H),8.79(s,1H),7.83(d,J＝7.9Hz,1H),7.38(t,J＝7.8Hz,1H),6.92-6.83(m,2H),3.28(q,J＝6.6Hz,2H),2.18(t,J＝7.4Hz,2H),1.56-1.46(m,4H),1.29(s,6H).
(3) The preparation method of the 8- (2-hydroxybenzoamide amino) sodium octoate comprises the following steps:
A50 mL three-necked flask was taken, 8- (2-hydroxybenzoamido) octanoic acid (1.60 g,5.73mmol,1.0 eq) and ethanol (30 mL) were sequentially added, dissolved by stirring at 50℃and sodium hydroxide (233.45 mg,5.84mmol,1.02 eq) was dissolved with deionized water (1.0 mL) and added to the above system, the reaction was carried out at 50℃for 1 hour, and then the system was cooled to room temperature (20 ℃) and crystallized for 4-6 hours. Suction filtering, washing the filter cake with 5mL ethanol, and drying to obtain light pink solid, namely the product 8- (2-hydroxybenzoamide amino) sodium octoate (1.211 g, yield) ：70％).1H NMR(400MHz,Methanol-d4)δ7.76(d,J＝7.9Hz,1H),7.34(t,J＝7.8Hz,1H),6.92-6.80(m,2H),4.91(s,2H),3.37(t,J＝7.1Hz,2H),2.16(t,J＝7.6Hz,2H),1.66-1.57(m,4H),1.38(s,6H).
Example 3:
(1) The preparation method of the 8- (2-acetoxy benzamide) ethyl octanoate comprises the following specific preparation method:
a100 mL three-necked flask was taken, 2- (acetoxy) benzoic acid (3.00 g,16.65mmol,1.0 eq) was dissolved in 50mL dichloromethane, and ethyl 8-aminocaprylate hydrochloride (4.47 g,19.98mmol,1.2 eq), 4-dimethylaminopyridine (3.05 g,24.98mmol,1.5 eq) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI, 3.51g,18.315mmol,1.1 eq) were added sequentially at 0deg.C. After the addition of the starting material system was completed, the reaction was carried out overnight at room temperature, and when the TLC monitored that the reaction was no longer running, the reaction was terminated. The reaction mixture was quenched with 30mL of water, extracted with dichloromethane (30 mL of 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate=4:1) to give ethyl 8- (2-acetoxybenzamide) octanoate (3.20 g, yield) as a colorless oily liquid ：55％).1H NMR(400MHz,Chloroform-d)δ7.69(d,J＝7.7Hz,1H),7.44(t,J＝7.7Hz,1H),7.28(t,J＝7.1Hz,1H),7.08(d,J＝8.1Hz,1H),6.25(s,1H),4.10(q,J＝7.1Hz,2H),3.37(q,J＝6.4Hz,2H),2.31(s,3H),2.27(t,J＝7.8Hz,2H),1.65-1.52(m,4H),1.34(br s,6H),1.24(t,J＝7.1Hz,3H).
(2) The preparation method of the 8- (2-hydroxybenzoamido) caprylic acid comprises the following specific preparation method:
A100 mL three-necked flask was used, ethyl 8- (2-acetoxybenzamide) octoate (3.00 g,8.59mmol,1.0 eq) was dissolved in 30mL methanol, and a 30mL aqueous solution of potassium hydroxide (1.93 g,34.34mmol,4.0 eq) was added with stirring at room temperature, and the reaction was carried out at 65℃for 2.5 hours. TLC monitoring, after the raw materials are reacted, finishing the reaction, concentrating the reaction solution under reduced pressure, regulating the pH value of the residue to 1-2 by using hydrochloric acid, and suction-filtering to obtain white solid, namely the product 8- (2-hydroxybenzoamido) octanoic acid (1.44 g, yield) ：60％).1H NMR(400MHz,DMSO-d6)δ12.33(s,1H),8.79(s,1H),7.83(d,J＝7.9Hz,1H),7.38(t,J＝7.8Hz,1H),6.92-6.83(m,2H),3.28(q,J＝6.6Hz,2H),2.18(t,J＝7.4Hz,2H),1.56-1.46(m,4H),1.29(s,6H).
(3) The preparation method of the 8- (2-hydroxybenzoamide amino) sodium octoate comprises the following steps:
a50 mL three-necked flask was taken, 8- (2-hydroxybenzoamido) octanoic acid (2.50 g,8.95mmol,1.0 eq) and ethanol (30 mL) were sequentially added, dissolved by stirring at 50℃and sodium bicarbonate (766.14 mg,9.12mmol,1.02 eq) was dissolved with deionized water (2.0 mL) and added to the above system, the reaction was carried out at 50℃for 1h, and then the system was cooled to room temperature (20 ℃) for crystallization for 4-6h. Suction filtering, washing the filter cake with 5mL ethanol, and drying to obtain light pink solid, namely the product sodium 8- (2-hydroxybenzoamide amino) octoate (2.03 g, yield) ：75.19％).1H NMR(400MHz,Methanol-d4)δ7.76(d,J＝7.9Hz,1H),7.34(t,J＝7.8Hz,1H),6.92-6.80(m,2H),4.91(s,2H),3.37(t,J＝7.1Hz,2H),2.16(t,J＝7.6Hz,2H),1.66-1.57(m,4H),1.38(s,6H).
Example 4:
(1) The preparation method of the 8- (2-acetoxy benzamide) ethyl octanoate comprises the following specific preparation method:
A100 mL three-necked flask was taken, 2- (acetoxy) benzoic acid (5.00 g,27.75mmol,1.0 eq) was dissolved in 50mLN, N-dimethylformamide, and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (HATU, 11.61g,30.53mmol,1.1 eq), N, N-diisopropylethylamine (3.95 g,30.53mmol,1.1 eq) and ethyl 8-aminocaprylate hydrochloride (6.83 g,30.53mmol,1.1 eq) were added sequentially at room temperature. After the addition of the starting material, the reaction was completed for 1h at room temperature, and when the TLC monitored that the reaction was no longer running, the reaction was terminated. The reaction mixture was quenched with 30mL of water, extracted with ethyl acetate (30 mL of 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate=4:1) to give ethyl 8- (2-acetoxybenzamide) octanoate (5.63 g, yield) as a colorless oily liquid ：58％).1H NMR(400MHz,Chloroform-d)δ7.69(d,J＝7.7Hz,1H),7.44(t,J＝7.7Hz,1H),7.28(t,J＝7.1Hz,1H),7.08(d,J＝8.1Hz,1H),6.25(s,1H),4.10(q,J＝7.1Hz,2H),3.37(q,J＝6.4Hz,2H),2.31(s,3H),2.27(t,J＝7.8Hz,2H),1.65-1.52(m,4H),1.34(br s,6H),1.24(t,J＝7.1Hz,3H).
(2) The preparation method of the 8- (2-hydroxybenzoamido) caprylic acid comprises the following specific preparation method:
A250 mL three-necked flask was used, ethyl 8- (2-acetoxybenzamide) octoate (5.00 g,14.31mmol,1.0 eq) was dissolved in 50mL ethanol, and 50mL aqueous potassium hydroxide (3.21 g,57.24mmol,4.0 eq) was added with stirring at room temperature, and the reaction was carried out at 78℃for 2.5 hours. TLC monitoring, after the raw materials are reacted, finishing the reaction, concentrating the reaction solution under reduced pressure, regulating the pH value of the residue to 1-2 by using hydrochloric acid, and suction-filtering to obtain white solid, namely the product 8- (2-hydroxybenzoamido) octanoic acid (2.56 g, yield) ：64％).1H NMR(400MHz,DMSO-d6)δ12.33(s,1H),8.79(s,1H),7.83(d,J＝7.9Hz,1H),7.38(t,J＝7.8Hz,1H),6.92-6.83(m,2H),3.28(q,J＝6.6Hz,2H),2.18(t,J＝7.4Hz,2H),1.56-1.46(m,4H),1.29(s,6H).
(3) The preparation method of the 8- (2-hydroxybenzoamide amino) sodium octoate comprises the following steps:
A50 mL three-necked flask was taken, 8- (2-hydroxybenzoamido) octanoic acid (4.00 g,14.32mmol,1.0 eq) and isopropyl alcohol (30 mL) were sequentially added, dissolved by stirring at 50℃and sodium bicarbonate (1.23 g,14.59mmol,1.02 eq) was dissolved by deionized water (2.0 mL) and added to the above system, the reaction was carried out at 50℃for 1h, and then the system was cooled to room temperature (20 ℃) for crystallization for 4-6h. Suction filtration, washing the filter cake with 5mL of isopropanol, and drying to obtain a pale pink solid, namely the product sodium 8- (2-hydroxybenzoamide amino) octoate (3.10 g, yield) ：71.93％).1H NMR(400MHz,Methanol-d4)δ7.76(d,J＝7.9Hz,1H),7.34(t,J＝7.8Hz,1H),6.92-6.80(m,2H),4.91(s,2H),3.37(t,J＝7.1Hz,2H),2.16(t,J＝7.6Hz,2H),1.66-1.57(m,4H),1.38(s,6H).
Example 5:
(1) The preparation method of the 8- (2-acetoxy benzamide) ethyl octanoate comprises the following specific preparation method:
A50 mL three-necked flask was taken, 2- (acetoxy) benzoic acid (2.00 g,11.10mmol,1.0 eq) was dissolved in 25mL dichloromethane and the catter condensing agent (BOP, 5.89g,13.32mmol,1.2 eq), N-diisopropylethylamine (2.15 g,16.65mmol,1.5 eq) and ethyl 8-aminocaprylate hydrochloride (2.73 g,12.21mmol,1.1 eq) were added sequentially at room temperature. After the addition of the starting material system, the reaction was completed for 3h at room temperature, and when the TLC monitored that the reaction was no longer running, the reaction was terminated. The reaction mixture was quenched with 20mL of water, extracted with ethyl acetate (25 mL of 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate=4:1) to give ethyl 8- (2-acetoxybenzamide) octanoate (2.35 g, yield) as a colorless oily liquid ：60.6％).1H NMR(400MHz,Chloroform-d)δ7.69(d,J＝7.7Hz,1H),7.44(t,J＝7.7Hz,1H),7.28(t,J＝7.1Hz,1H),7.08(d,J＝8.1Hz,1H),6.25(s,1H),4.10(q,J＝7.1Hz,2H),3.37(q,J＝6.4Hz,2H),2.31(s,3H),2.27(t,J＝7.8Hz,2H),1.65-1.52(m,4H),1.34(br s,6H),1.24(t,J＝7.1Hz,3H).
The preparation methods of 8- (2-hydroxybenzoylamino) caprylic acid and sodium 8- (2-hydroxybenzoylamino) caprylate were the same as in steps (2) and (3) in example 1.
Example 6:
(1) The preparation method of the 8- (2-acetoxy benzamide) ethyl octanoate comprises the following specific preparation method:
A50 mL three-necked flask was taken, 2- (acetoxy) benzoic acid (1.50 g,8.33mmol,1.0 eq) was dissolved in 25mL tetrahydrofuran, and a Kate condensing agent (BOP, 4.42g,9.99mmol,1.2 eq), N-diisopropylethylamine (1.61 g,12.49mmol,1.5 eq) and ethyl 8-aminocaprylate hydrochloride (2.05 g,9.16mmol,1.1 eq) were added sequentially at room temperature. After the addition of the starting material system, the reaction was completed for 3h at room temperature, and when the TLC monitored that the reaction was no longer running, the reaction was terminated. The reaction mixture was quenched with 20mL of water, extracted with ethyl acetate (25 mL of 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate=4:1) to give ethyl 8- (2-acetoxybenzamide) octanoate (2.04 g, yield) as a colorless oily liquid ：70.1％).1H NMR(400MHz,Chloroform-d)δ7.69(d,J＝7.7Hz,1H),7.44(t,J＝7.7Hz,1H),7.28(t,J＝7.1Hz,1H),7.08(d,J＝8.1Hz,1H),6.25(s,1H),4.10(q,J＝7.1Hz,2H),3.37(q,J＝6.4Hz,2H),2.31(s,3H),2.27(t,J＝7.8Hz,2H),1.65-1.52(m,4H),1.34(br s,6H),1.24(t,J＝7.1Hz,3H).
The preparation methods of 8- (2-hydroxybenzoylamino) caprylic acid and sodium 8- (2-hydroxybenzoylamino) caprylate were the same as in steps (2) and (3) in example 1.
Example 7:
(1) The preparation method of the 8- (2-acetoxy benzamide) ethyl octanoate comprises the following specific preparation method:
A50 mL three-necked flask was taken, 2- (acetoxy) benzoic acid (2.50 g,13.88mmol,1.0 eq) was dissolved in 25mL dimethylsulfoxide, and a Kate condensing agent (BOP, 7.36g,16.65mmol,1.2 eq), N-diisopropylethylamine (2.69 g,20.82mmol,1.5 eq) and ethyl 8-aminocaprylate hydrochloride (3.42 g,15.26mmol,1.1 eq) were added sequentially at room temperature. After the addition of the starting material system, the reaction was completed for 3h at room temperature, and when the TLC monitored that the reaction was no longer running, the reaction was terminated. The reaction mixture was quenched with 20mL of water, extracted with ethyl acetate (25 mL of 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate=4:1) to give ethyl 8- (2-acetoxybenzamide) octanoate (3.15 g, yield) as a colorless oily liquid ：65％).1H NMR(400MHz,Chloroform-d)δ7.69(d,J＝7.7Hz,1H),7.44(t,J＝7.7Hz,1H),7.28(t,J＝7.1Hz,1H),7.08(d,J＝8.1Hz,1H),6.25(s,1H),4.10(q,J＝7.1Hz,2H),3.37(q,J＝6.4Hz,2H),2.31(s,3H),2.27(t,J＝7.8Hz,2H),1.65-1.52(m,4H),1.34(br s,6H),1.24(t,J＝7.1Hz,3H).
The preparation methods of 8- (2-hydroxybenzoylamino) caprylic acid and sodium 8- (2-hydroxybenzoylamino) caprylate were the same as in steps (2) and (3) in example 1.
Example 8:
(1) The preparation method of the 8- (2-acetoxy benzamide) ethyl octanoate comprises the following specific preparation method:
A50 mL three-necked flask was taken, 2- (acetoxy) benzoic acid (2.00 g,11.10mmol,1.0 eq) was dissolved in 25mL toluene, and a catter condensing agent (BOP, 5.89g,13.32mmol,1.2 eq), N-diisopropylethylamine (2.15 g,16.65mmol,1.5 eq) and ethyl 8-aminocaprylate hydrochloride (2.73 g,12.21mmol,1.1 eq) were added sequentially at room temperature. After the addition of the starting material system, the reaction was completed for 3h at room temperature, and when the TLC monitored that the reaction was no longer running, the reaction was terminated. The reaction mixture was quenched with 20mL of water, extracted with ethyl acetate (25 mL of 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate=4:1) to give ethyl 8- (2-acetoxybenzamide) octanoate (1.16 g, yield) as a colorless oily liquid ：29.9％).1H NMR(400MHz,Chloroform-d)δ7.69(d,J＝7.7Hz,1H),7.44(t,J＝7.7Hz,1H),7.28(t,J＝7.1Hz,1H),7.08(d,J＝8.1Hz,1H),6.25(s,1H),4.10(q,J＝7.1Hz,2H),3.37(q,J＝6.4Hz,2H),2.31(s,3H),2.27(t,J＝7.8Hz,2H),1.65-1.52(m,4H),1.34(br s,6H),1.24(t,J＝7.1Hz,3H).
The preparation methods of 8- (2-hydroxybenzoylamino) caprylic acid and sodium 8- (2-hydroxybenzoylamino) caprylate were the same as in steps (2) and (3) in example 1.
Example 9:
(1) The preparation method of the 8- (2-acetoxy benzamide) ethyl octanoate comprises the following specific preparation method:
A50 mL three-necked flask was taken, 2- (acetoxy) benzoic acid (2.40 g,13.32mmol,1.0 eq) was dissolved in 25mLN, N-dimethylformamide, and a Kate condensing agent (BOP, 7.07g,15.99mmol,1.2 eq), triethylamine (2.02 g,19.98mmol,1.5 eq) and ethyl 8-aminocaprylate hydrochloride (3.28 g,14.65mmol,1.1 eq) were added sequentially at room temperature. After the addition of the starting material system, the reaction was completed for 3h at room temperature, and when the TLC monitored that the reaction was no longer running, the reaction was terminated. The reaction mixture was quenched with 20mL of water, extracted with ethyl acetate (25 mL of 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate=4:1) to give ethyl 8- (2-acetoxybenzamide) octanoate (3.49 g, yield ：75.1％).1H NMR(400MHz,Chloroform-d)δ7.69(d,J＝7.7Hz,1H),7.44(t,J＝7.7Hz,1H),7.28(t,J＝7.1Hz,1H),7.08(d,J＝8.1Hz,1H),6.25(s,1H),4.10(q,J＝7.1Hz,2H),3.37(q,J＝6.4Hz,2H),2.31(s,3H),2.27(t,J＝7.8Hz,2H),1.65-1.52(m,4H),1.34(br s,6H),1.24(t,J＝7.1Hz,3H).
The preparation methods of 8- (2-hydroxybenzoylamino) caprylic acid and sodium 8- (2-hydroxybenzoylamino) caprylate were the same as in steps (2) and (3) in example 1.
Example 10:
(1) The preparation method of the 8- (2-acetoxy benzamide) ethyl octanoate comprises the following specific preparation method:
A50 mL three-necked flask was taken, 2- (acetoxy) benzoic acid (2.70 g,14.99mmol,1.0 eq) was dissolved in 25mLN, N-dimethylformamide, and a Kate condensing agent (BOP, 7.95g,17.98mmol,1.2 eq), pyridine (1.78 g,22.48mmol,1.5 eq) and ethyl 8-aminocaprylate hydrochloride (3.69 g,16.49mmol,1.1 eq) were added sequentially at room temperature. After the addition of the starting material system, the reaction was completed for 3h at room temperature, and when the TLC monitored that the reaction was no longer running, the reaction was terminated. The reaction mixture was quenched with 20mL of water, extracted with ethyl acetate (25 mL of 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate=4:1) to give ethyl 8- (2-acetoxybenzamide) octanoate (2.62 g, yield) as a colorless oily liquid ：50％).1H NMR(400MHz,Chloroform-d)δ7.69(d,J＝7.7Hz,1H),7.44(t,J＝7.7Hz,1H),7.28(t,J＝7.1Hz,1H),7.08(d,J＝8.1Hz,1H),6.25(s,1H),4.10(q,J＝7.1Hz,2H),3.37(q,J＝6.4Hz,2H),2.31(s,3H),2.27(t,J＝7.8Hz,2H),1.65-1.52(m,4H),1.34(br s,6H),1.24(t,J＝7.1Hz,3H).
The preparation methods of 8- (2-hydroxybenzoylamino) caprylic acid and sodium 8- (2-hydroxybenzoylamino) caprylate were the same as in steps (2) and (3) in example 1.
Example 11:
(1) The preparation method of the 8- (2-acetoxy benzamide) ethyl octanoate comprises the following specific preparation method:
A50 mL three-necked flask was taken, 2- (acetoxy) benzoic acid (2.10 g,11.66mmol,1.0 eq) was dissolved in 25mLN, N-dimethylformamide, and a Kate condensing agent (BOP, 6.19g,13.99mmol,1.2 eq), N-dimethylaniline (2.12 g,17.48mmol,1.5 eq) and ethyl 8-aminocaprylate hydrochloride (2.87 g,12.82mmol,1.1 eq) were added sequentially at room temperature. After the addition of the starting material system, the reaction was completed for 3h at room temperature, and when the TLC monitored that the reaction was no longer running, the reaction was terminated. The reaction mixture was quenched with 20mL of water, extracted with ethyl acetate (25 mL of 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate=4:1) to give ethyl 8- (2-acetoxybenzamide) octanoate (1.83 g, yield) as a colorless oily liquid ：45％).1H NMR(400MHz,Chloroform-d)δ7.69(d,J＝7.7Hz,1H),7.44(t,J＝7.7Hz,1H),7.28(t,J＝7.1Hz,1H),7.08(d,J＝8.1Hz,1H),6.25(s,1H),4.10(q,J＝7.1Hz,2H),3.37(q,J＝6.4Hz,2H),2.31(s,3H),2.27(t,J＝7.8Hz,2H),1.65-1.52(m,4H),1.34(br s,6H),1.24(t,J＝7.1Hz,3H).
The preparation methods of 8- (2-hydroxybenzoylamino) caprylic acid and sodium 8- (2-hydroxybenzoylamino) caprylate were the same as in steps (2) and (3) in example 1.
Example 12:
(1) The preparation method of the 8- (2-acetoxy benzamide) ethyl octanoate comprises the following specific preparation method:
a50 mL three-necked flask was taken, 2- (acetoxy) benzoic acid (2.00 g,11.10mmol,1.0 eq) was dissolved in 25mLN, N-dimethylformamide, and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (HATU, 5.07g,13.32mmol,1.2 eq), N, N-diisopropylethylamine (2.15 g,16.65mmol,1.5 eq) and ethyl 8-aminocaprylate hydrochloride (2.73 g,12.21mmol,1.1 eq) were added sequentially at room temperature. After the addition of the starting material system, the reaction was completed for 3h at room temperature, and when the TLC monitored that the reaction was no longer running, the reaction was terminated. The reaction mixture was quenched with 20mL of water, extracted with ethyl acetate (25 mL of 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate=4:1) to give ethyl 8- (2-acetoxybenzamide) octanoate (2.13 g, yield) as a colorless oily liquid ：54.9％).1H NMR(400MHz,Chloroform-d)δ7.69(d,J＝7.7Hz,1H),7.44(t,J＝7.7Hz,1H),7.28(t,J＝7.1Hz,1H),7.08(d,J＝8.1Hz,1H),6.25(s,1H),4.10(q,J＝7.1Hz,2H),3.37(q,J＝6.4Hz,2H),2.31(s,3H),2.27(t,J＝7.8Hz,2H),1.65-1.52(m,4H),1.34(br s,6H),1.24(t,J＝7.1Hz,3H).
The preparation methods of 8- (2-hydroxybenzoylamino) caprylic acid and sodium 8- (2-hydroxybenzoylamino) caprylate were the same as in steps (2) and (3) in example 1.
Example 13:
(1) The preparation method of the 8- (2-acetoxy benzamide) ethyl octanoate comprises the following specific preparation method:
A50 mL three-necked flask was taken and 2- (acetoxy) benzoic acid (2.50 g,13.88mmol,1.0 eq) was dissolved in 25mLN, N-dimethylformamide, and O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate (HBTU, 6.32g,16.65mmol,1.2 eq), N, N-diisopropylethylamine (2.69 g,20.82mmol,1.5 eq) and ethyl 8-aminocaprylate hydrochloride (3.42 g,15.26mmol,1.1 eq) were added sequentially at room temperature. After the addition of the starting material system, the reaction was completed for 3h at room temperature, and when the TLC monitored that the reaction was no longer running, the reaction was terminated. The reaction mixture was quenched with 20mL of water, extracted with ethyl acetate (25 mL of 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate=4:1) to give ethyl 8- (2-acetoxybenzamide) octanoate (2.52 g, yield) as a colorless oily liquid ：52％).1H NMR(400MHz,Chloroform-d)δ7.69(d,J＝7.7Hz,1H),7.44(t,J＝7.7Hz,1H),7.28(t,J＝7.1Hz,1H),7.08(d,J＝8.1Hz,1H),6.25(s,1H),4.10(q,J＝7.1Hz,2H),3.37(q,J＝6.4Hz,2H),2.31(s,3H),2.27(t,J＝7.8Hz,2H),1.65-1.52(m,4H),1.34(br s,6H),1.24(t,J＝7.1Hz,3H).
The preparation methods of 8- (2-hydroxybenzoylamino) caprylic acid and sodium 8- (2-hydroxybenzoylamino) caprylate were the same as in steps (2) and (3) in example 1.
Example 14:
(1) The preparation method of the 8- (2-acetoxy benzamide) ethyl octanoate comprises the following specific preparation method:
A50 mL three-necked flask was taken, 2- (acetoxy) benzoic acid (2.30 g,12.77mmol,1.0 eq) was dissolved in 25mLN, N-dimethylformamide, and N, N' -carbonyldiimidazole (CDI, 2.48g,15.32mmol,1.2 eq), N-diisopropylethylamine (2.47 g,19.15mmol,1.5 eq) and ethyl 8-aminocaprylate hydrochloride (3.14 g,14.04mmol,1.1 eq) were added sequentially at room temperature. After the addition of the starting material system, the reaction was completed for 3h at room temperature, and when the TLC monitored that the reaction was no longer running, the reaction was terminated. The reaction mixture was quenched with 20mL of water, extracted with ethyl acetate (25 mL of 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate=4:1) to give ethyl 8- (2-acetoxybenzamide) octanoate (1.78 g, yield) as a colorless oily liquid ：40％).1H NMR(400MHz,Chloroform-d)δ7.69(d,J＝7.7Hz,1H),7.44(t,J＝7.7Hz,1H),7.28(t,J＝7.1Hz,1H),7.08(d,J＝8.1Hz,1H),6.25(s,1H),4.10(q,J＝7.1Hz,2H),3.37(q,J＝6.4Hz,2H),2.31(s,3H),2.27(t,J＝7.8Hz,2H),1.65-1.52(m,4H),1.34(br s,6H),1.24(t,J＝7.1Hz,3H).
The preparation methods of 8- (2-hydroxybenzoylamino) caprylic acid and sodium 8- (2-hydroxybenzoylamino) caprylate were the same as in steps (2) and (3) in example 1.
Content detection of the target compound sodium 8- (2-hydroxybenzoamido) octoate:
The solution containing about 0.5mg of the above product (sodium 8- (2-hydroxybenzoamido) octoate) per 1mL was quantitatively diluted with methanol and purified by using a high performance liquid chromatograph equipped with WATERS ALLIANCE E2695 separation module or equivalent, using InnovalODS-2 chromatographic column (250mm x 4.6mm x 5 μm); an ultraviolet-visible light or photodiode array (PDA) detector detecting 254nm; the temperature of the sample cooler is 25 ℃, the sample injection volume is 10 mu L, and the running time is 60min; taking 1mL of 70% perchloric acid, placing the mixture into a measuring flask containing 1000mL of water, fully and uniformly mixing the mixture, and passing the mixture through a 0.2 mu m membrane filter to obtain a mobile phase A; taking 500mL of acetonitrile and 500mL of methanol respectively, fully and uniformly mixing, and performing gradient elution according to the following table as a mobile phase B (ultrasonic treatment is needed before the mobile phase is used); the flow rate was 1.0mL/min and the column temperature was 30 ℃.
The HPLC chromatogram is shown in figure 4, and the result shows that the purity of the 8- (2-hydroxybenzoamide amino) sodium octoate prepared by the method can reach more than 99.9 percent.
The present invention is illustrated by the above examples for the preparation of sodium 8- (2-hydroxybenzoamido) octoate according to the present invention, but the present invention is not limited to the above examples, i.e., it is not meant that the present invention must be practiced by the above examples. It should be apparent to those skilled in the art that any modifications of the present invention, equivalent substitutions of raw materials for the products of the present invention, selection of specific modes, etc., are within the scope of the present invention and the scope of the disclosure.
Claims (10)
1. A method for preparing 8- (2-hydroxybenzoylamino) sodium octoate, which is characterized by comprising the following steps:
Step 1: utilizing 8-amino ethyl octoate hydrochloride and 2- (acetoxy) benzoic acid to generate condensation reaction under the action of condensing agent and alkali to generate 8- (2-acetoxy benzamide) ethyl octoate;
Step 2: carrying out hydrolysis reaction on the ethyl 8- (2-acetoxy benzamide) octoate obtained in the step 1 under the action of alkali, and then acidizing to generate 8- (2-hydroxybenzoamido) octoate;
Step 3: and (3) carrying out salt formation reaction on the 8- (2-hydroxybenzoamido) caprylic acid obtained in the step (2) under the action of alkali to generate sodium 8- (2-hydroxybenzoamido) caprylate.
2. The method of manufacturing according to claim 1, characterized in that:
In the step 1, the condensing agent is any one of dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, O- (7-azabenzotriazol-1-yl) -N, N, N ', N ' -tetramethylurea hexafluorophosphate, O- (benzotriazol-1-yl) -N, N, N ', N ' -tetramethylurea hexafluorophosphate, 6-chlorobenzotriazole-1, 3-tetramethylurea hexafluorophosphate, N, N ' -carbonyldiimidazole or 1H-benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate; the base is any one of triethylamine, N-Diisopropylethylamine (DIPEA), N-dimethylaniline or pyridine.
3. The preparation method according to claim 2, characterized in that:
In the step 1, the molar ratio of the 2- (acetoxyl) benzoic acid to the ethyl 8-aminocaprylate hydrochloride to the condensing agent to the base is 1:1.0-1.5:1.0-1.5:1.0-2.0.
4. The method of manufacturing according to claim 1, characterized in that:
In step 1, the reaction is carried out in the presence of a solvent which is any one or more of dichloromethane, ethyl acetate, tetrahydrofuran, 1, 4-dioxane, acetonitrile, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone and toluene.
5. The method of manufacturing according to claim 1, characterized in that:
In the step 2, the alkali is any one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate; the acid used for acidification is any one of hydrochloric acid, sulfuric acid or phosphoric acid.
6. The method of manufacturing according to claim 1, characterized in that:
In the step 2, the molar ratio of the ethyl 8- (2-acetoxy benzamide) octoate to the alkali is 1:1.0-5.0.
7. The method of manufacturing according to claim 1, characterized in that:
In the step 3, the salification reaction is carried out in the presence of an alkaline substance, wherein the alkaline substance is any one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium hydroxide, sodium carbonate or sodium bicarbonate; the salt forming reaction is carried out in the presence of a solvent which is a mixed solvent of methanol/water, ethanol/water or isopropanol/water.
8. The method of manufacturing according to claim 1, characterized in that:
the reaction process for generating the 8- (2-acetoxy-benzamide) ethyl octoate by utilizing the condensation reaction of the 8-amino ethyl octoate hydrochloride and the 2- (acetoxy) benzoic acid under the action of a condensing agent and alkali in the step 1 comprises the following steps:
Dissolving 2- (acetoxyl) benzoic acid with N, N-dimethylformamide, sequentially adding a Kate condensing agent BOP, N-diisopropylethylamine and 8-ethyl aminocaprylate hydrochloride at room temperature, reacting at room temperature, and ending the reaction when TLC monitors that the reaction is no longer carried out; the reaction mixture was quenched with water, extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a pale yellow oily liquid, which was a crude product of ethyl 8- (2-acetoxybenzamide) octanoate.
9. The method of manufacturing according to claim 1, characterized in that:
In the step 2, the ethyl 8- (2-acetoxy benzamide) octoate is utilized to carry out hydrolysis reaction under the action of alkali, and then the reaction process of acidizing to generate the 8- (2-hydroxybenzoamido) octoate comprises the following steps:
Dissolving the crude product 8- (2-acetoxy benzamide) ethyl octanoate obtained in the step 1 by methanol, adding sodium hydroxide aqueous solution under stirring at room temperature, reacting at 65 ℃, and ending the reaction after TLC monitoring the reaction of the raw materials; the reaction solution is decompressed and concentrated, the pH value of the system is regulated to be 1-2 by hydrochloric acid, and white solid is obtained by suction filtration, namely the product 8- (2-hydroxybenzoamide amino) octanoic acid.
10. The method of manufacturing according to claim 1, characterized in that:
The reaction process for generating the 8- (2-hydroxybenzoylamino) sodium octoate by utilizing the 8- (2-hydroxybenzoylamino) octoate to generate salt under the action of alkali in the step 3 comprises the following steps:
Sequentially adding 8- (2-hydroxybenzoamido) octanoic acid and isopropanol into a reactor, stirring and dissolving at 50 ℃, adding sodium hydroxide into a system after dissolving with deionized water, reacting for 1h at 50 ℃, and then cooling to room temperature for crystallization for 4-6h; and (3) carrying out suction filtration, washing a filter cake with isopropanol, and drying to obtain a light pink solid, namely the product of 8- (2-hydroxybenzoamide amino) sodium octoate.
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