CN105524129B - A kind of preparation method of Etimicin Sulfate - Google Patents
A kind of preparation method of Etimicin Sulfate Download PDFInfo
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- CN105524129B CN105524129B CN201510998419.5A CN201510998419A CN105524129B CN 105524129 B CN105524129 B CN 105524129B CN 201510998419 A CN201510998419 A CN 201510998419A CN 105524129 B CN105524129 B CN 105524129B
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- gentamicin
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- 229950009953 etimicin Drugs 0.000 title claims abstract description 25
- OEBISAUVQBGQKC-ZIZSAZPJSA-N (2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4-amino-3-[(2r,3r,6s)-3-amino-6-(aminomethyl)oxan-2-yl]oxy-6-(ethylamino)-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol;sulfuric acid Chemical compound OS(O)(=O)=O.O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](NC)[C@@](C)(O)CO1)O)NCC)[C@H]1O[C@H](CN)CC[C@H]1N OEBISAUVQBGQKC-ZIZSAZPJSA-N 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- VEGXETMJINRLTH-BOZYPMBZSA-N gentamycin C1a Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@@H](CN)O2)N)[C@@H](N)C[C@H]1N VEGXETMJINRLTH-BOZYPMBZSA-N 0.000 claims abstract description 74
- 239000003513 alkali Substances 0.000 claims abstract description 72
- 238000003756 stirring Methods 0.000 claims abstract description 64
- 238000006243 chemical reaction Methods 0.000 claims abstract description 59
- DNYGXMICFMACRA-UHFFFAOYSA-N gentamicin C1A Natural products O1C(CNC)CCC(N)C1OC1C(O)C(OC2C(C(NC)C(C)(O)CO2)O)C(N)CC1N DNYGXMICFMACRA-UHFFFAOYSA-N 0.000 claims abstract description 47
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 43
- 239000002904 solvent Substances 0.000 claims abstract description 28
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 22
- 238000001914 filtration Methods 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 21
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 17
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 16
- 230000021736 acetylation Effects 0.000 claims abstract description 16
- 238000006640 acetylation reaction Methods 0.000 claims abstract description 16
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 16
- 239000003223 protective agent Substances 0.000 claims abstract description 16
- 239000011347 resin Substances 0.000 claims abstract description 15
- 229920005989 resin Polymers 0.000 claims abstract description 15
- 239000008139 complexing agent Substances 0.000 claims abstract description 14
- VEGXETMJINRLTH-ALRICIOSSA-N etimicin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@H](O)[C@H]1O[C@@H]1[C@H](O)[C@H](O[C@@H]2[C@@H](CC[C@@H](CN)O2)N)[C@@H](N)C[C@H]1N VEGXETMJINRLTH-ALRICIOSSA-N 0.000 claims abstract description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000001179 sorption measurement Methods 0.000 claims abstract description 9
- 238000000926 separation method Methods 0.000 claims abstract description 8
- 238000001035 drying Methods 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims description 30
- 239000012295 chemical reaction liquid Substances 0.000 claims description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 18
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 14
- 239000012716 precipitator Substances 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- -1 sodium triacetoxyborohydride Chemical compound 0.000 claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 10
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 claims description 8
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 8
- 238000000746 purification Methods 0.000 claims description 8
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 8
- 238000001694 spray drying Methods 0.000 claims description 8
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 claims description 8
- 239000004246 zinc acetate Substances 0.000 claims description 8
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 7
- 239000012346 acetyl chloride Substances 0.000 claims description 7
- 238000004108 freeze drying Methods 0.000 claims description 7
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 7
- 235000011009 potassium phosphates Nutrition 0.000 claims description 7
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 7
- 239000004254 Ammonium phosphate Substances 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 6
- 229910000148 ammonium phosphate Inorganic materials 0.000 claims description 6
- 235000019289 ammonium phosphates Nutrition 0.000 claims description 6
- 229910000361 cobalt sulfate Inorganic materials 0.000 claims description 6
- 229940044175 cobalt sulfate Drugs 0.000 claims description 6
- KTVIXTQDYHMGHF-UHFFFAOYSA-L cobalt(2+) sulfate Chemical compound [Co+2].[O-]S([O-])(=O)=O KTVIXTQDYHMGHF-UHFFFAOYSA-L 0.000 claims description 6
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 claims description 6
- 229910052700 potassium Inorganic materials 0.000 claims description 6
- 239000011591 potassium Substances 0.000 claims description 6
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- ZNCPFRVNHGOPAG-UHFFFAOYSA-L sodium oxalate Chemical compound [Na+].[Na+].[O-]C(=O)C([O-])=O ZNCPFRVNHGOPAG-UHFFFAOYSA-L 0.000 claims description 6
- 229940039790 sodium oxalate Drugs 0.000 claims description 6
- 229960000583 acetic acid Drugs 0.000 claims description 5
- 229940011182 cobalt acetate Drugs 0.000 claims description 5
- QAHREYKOYSIQPH-UHFFFAOYSA-L cobalt(II) acetate Chemical compound [Co+2].CC([O-])=O.CC([O-])=O QAHREYKOYSIQPH-UHFFFAOYSA-L 0.000 claims description 5
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 5
- IRXRGVFLQOSHOH-UHFFFAOYSA-L dipotassium;oxalate Chemical compound [K+].[K+].[O-]C(=O)C([O-])=O IRXRGVFLQOSHOH-UHFFFAOYSA-L 0.000 claims description 5
- 239000012362 glacial acetic acid Substances 0.000 claims description 5
- 229940093916 potassium phosphate Drugs 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- VBIXEXWLHSRNKB-UHFFFAOYSA-N ammonium oxalate Chemical compound [NH4+].[NH4+].[O-]C(=O)C([O-])=O VBIXEXWLHSRNKB-UHFFFAOYSA-N 0.000 claims description 4
- 229940010556 ammonium phosphate Drugs 0.000 claims description 4
- 229910000085 borane Inorganic materials 0.000 claims description 4
- 229960001701 chloroform Drugs 0.000 claims description 4
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 4
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 4
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 claims description 4
- 229910000368 zinc sulfate Inorganic materials 0.000 claims description 4
- 229960001763 zinc sulfate Drugs 0.000 claims description 4
- 229910052782 aluminium Inorganic materials 0.000 claims description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 3
- 229960000355 copper sulfate Drugs 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- 239000001488 sodium phosphate Substances 0.000 claims description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 3
- 229960003339 sodium phosphate Drugs 0.000 claims description 3
- 235000011008 sodium phosphates Nutrition 0.000 claims description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 3
- 229960000314 zinc acetate Drugs 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims 3
- 239000002253 acid Substances 0.000 abstract description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract 1
- 239000005864 Sulphur Substances 0.000 abstract 1
- 239000000908 ammonium hydroxide Substances 0.000 abstract 1
- 230000000536 complexating effect Effects 0.000 abstract 1
- 239000000706 filtrate Substances 0.000 abstract 1
- 239000012467 final product Substances 0.000 abstract 1
- 230000001376 precipitating effect Effects 0.000 abstract 1
- 125000006239 protecting group Chemical group 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 38
- 230000008569 process Effects 0.000 description 12
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 6
- 208000015181 infectious disease Diseases 0.000 description 5
- JIVGSHFYXPRRSZ-UHFFFAOYSA-N 2,3-dimethoxybenzaldehyde Chemical compound COC1=CC=CC(C=O)=C1OC JIVGSHFYXPRRSZ-UHFFFAOYSA-N 0.000 description 4
- 238000007086 side reaction Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 206010006451 bronchitis Diseases 0.000 description 2
- 238000011097 chromatography purification Methods 0.000 description 2
- 238000010668 complexation reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- 230000008733 trauma Effects 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- 241000589291 Acinetobacter Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 241000588923 Citrobacter Species 0.000 description 1
- 206010063057 Cystitis noninfective Diseases 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- 208000032376 Lung infection Diseases 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 206010037597 Pyelonephritis acute Diseases 0.000 description 1
- 206010037601 Pyelonephritis chronic Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 241000607720 Serratia Species 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 description 1
- 201000001555 acute pyelonephritis Diseases 0.000 description 1
- 238000005882 aldol condensation reaction Methods 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 229940126574 aminoglycoside antibiotic Drugs 0.000 description 1
- 239000002647 aminoglycoside antibiotic agent Substances 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 201000003139 chronic cystitis Diseases 0.000 description 1
- 201000006368 chronic pyelonephritis Diseases 0.000 description 1
- 229910001429 cobalt ion Inorganic materials 0.000 description 1
- XLJKHNWPARRRJB-UHFFFAOYSA-N cobalt(2+) Chemical compound [Co+2] XLJKHNWPARRRJB-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- NZGMVSJQULXLHF-RAKCNUBFSA-N etimicin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](NC)[C@@](C)(O)CO1)O)NCC)[C@H]1O[C@H](CN)CC[C@H]1N NZGMVSJQULXLHF-RAKCNUBFSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 239000000413 hydrolysate Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
- C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
- C07H15/226—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
- C07H15/234—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2
- C07H15/236—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2 a saccharide radical being substituted by an alkylamino radical in position 3 and by two substituents different from hydrogen in position 4, e.g. gentamicin complex, sisomicin, verdamycin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of preparation method of Etimicin Sulfate, and this method includes the following steps：Take Gentamicin C1a alkali, it is dissolved in a certain proportion of solvent, add in a certain proportion of complexing agent complexing, add in a certain proportion of amino protecting agent, maintain certain time, it is filtered after adding in a certain proportion of precipitating reagent stirring, filtrate adds in a certain proportion of acetylation reagent reaction certain time, it adds a certain proportion of reducing agent reaction certain time and sloughs amino protecting group, a certain proportion of water is added to be concentrated in vacuo removal solvent under certain condition, macroporous resin adsorption is used after adjusting PH with ammonium hydroxide, Diluted Alcohol gradient separations purify, collect the Etimicin solution of certain purity, sulphur acid for adjusting pH is added in after being concentrated in vacuo under certain condition, add a certain proportion of activated carbon decolorizing filtering, meet the Etimicin Sulfate of relevant criterion after drying to obtain the final product.
Description
The technical field is as follows:
the invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of an aminoglycoside compound, and specifically relates to a preparation method of etimicin sulfate.
Background art:
etimicin sulfate (Etimicin sulfate) is a new-generation semisynthetic aminoglycoside antibiotic with high efficiency, low toxicity and drug-resistant bacteria, which is self-developed by Chinese researchers, has independent intellectual property rights and is the only anti-infective drug for obtaining a new drug certificate in China.
The etimicin sulfate injection is suitable for various infections caused by sensitive escherichia coli, klebsiella pneumoniae, serratia, citrobacter, enterobacter, acinetobacter, proteus, hemophilus influenza, pseudomonas aeruginosa, staphylococcus and the like. Clinical research shows that the product has better curative effect on the following infections. Respiratory tract infection: such as acute bronchitis, acute attack of chronic bronchitis, community lung infection, etc.; kidney and urogenital infections: such as acute pyelonephritis, cystitis, chronic pyelonephritis or chronic cystitis acute attack; cutaneous soft tissue and other infections: such as skin and soft tissue infections, infections after trauma, trauma and surgery and other sensitive bacterial infections.
At present, all the processes for industrially producing etimicin sulfate are the processes reported in patents (application number: 93112412.3). The method mainly comprises the following steps: dissolving gentamicin C1a alkali in solvent, adding cobalt acetate and acetic anhydride to generate 3, 2 ', 6', -tri-N-acetyl gentamicin C1a (P1), extracting and concentrating, introducing hydrogen sulfide gas into the concentrated solution to remove cobalt ions, drying to obtain P1 with the purity of 90% -95%, adding acetaldehyde, hydrogenating with a reducing agent in an ice-water bath at 0-5 ℃ to obtain 3, 2 ', 6', -tri-N-acetyl-1-N ethyl gentamicin C1a (P2), separating with an adsorption type macroporous resin to obtain P2 with high purity, adding 1N sodium hydroxide solution into P2 with high purity, hydrolyzing and refluxing for 48 hours, separating the hydrolysate with the adsorption type macroporous resin to obtain 1-N-ethyl gentamicin C1a (etimicin) solution with the purity of more than 90%, adding acid to form salt, decoloring by active carbon, and freeze-drying to obtain the etimicin salt. The process has the disadvantages of long synthetic route and low yield; performing macroporous resin purification twice to generate a large amount of waste liquid; when acetaldehyde is added, there is no protection step of functional group, and side reactions are more.
The invention content is as follows:
the invention aims to provide a method for preparing etimicin sulfate, which has the advantages of short synthetic route, less generated wastewater, good reaction specificity and less side reaction.
The preparation method comprises the following steps:
step 1) taking gentamicin C1a alkali, adding a solvent according to the proportion of 5-10 times of the weight of gentamicin C1a alkali, wherein the solvent is one of methanol, ethanol, DMSO, dichloromethane, trichloromethane, DMF, THF and acetonitrile, stirring and dissolving to obtain a solution,
step 2) adding a complexing agent into the solution according to an equivalent of 1-4 times of the gentamicin C1a alkali substance, wherein the complexing agent is one of cobalt acetate, copper acetate, zinc acetate, cobalt sulfate, copper sulfate and zinc sulfate, stirring to obtain a reaction solution 1,
step 3) adding an amino protective agent into the reaction solution 1 according to an equivalent 2-6 times of the amount of gentamicin C1a alkali substances, wherein the amino protective agent is one of trityl chloride, dimethoxybenzaldehyde, p-methoxybenzaldehyde and benzaldehyde, stirring and reacting for 1-5 hours to obtain a reaction solution 2,
step 4), adding a precipitator into the reaction liquid 2 according to an equivalent 2-6 times of the amount of gentamicin C1a alkali substances, stirring and filtering, wherein the precipitator is one of ammonium oxalate, potassium oxalate, sodium oxalate, ammonium phosphate, sodium phosphate and potassium phosphate to obtain a reaction liquid 3,
step 5), adding an acetylation reagent into the reaction liquid 3 according to an equivalent of 1-4 times of the amount of gentamicin C1a alkali substances, wherein the acetylation reagent is one of acetyl chloride, glacial acetic acid and acetic anhydride, stirring and reacting for 1-5 hours to obtain a reaction liquid 4,
step 6), adding a reducing agent into the reaction liquid 4 according to an equivalent of 5-10 times of the amount of gentamicin C1a alkali substances, wherein the reducing agent is one of sodium cyanoborohydride, red aluminum, sodium borohydride, sodium triacetoxyborohydride, potassium borohydride, borane and lithium aluminum hydride, stirring and reacting for 2-8 hours to obtain a reaction liquid 5,
step 7), adding 3-6 times of water into the reaction solution 5, performing vacuum concentration to remove the solvent under the condition that the vacuum degree is not higher than 0.2 atmospheric pressure below 80 ℃, adjusting the pH to 12-14 by using ammonia water, then using macroporous resin for adsorption, performing gradient separation and purification on 5% -40% of dilute ethanol, collecting etimicin solution with the purity of more than 95%, performing vacuum concentration under the condition that the vacuum degree is not higher than 0.2 atmospheric pressure below 80 ℃ to obtain a concentrated solution,
and 8) adding sulfuric acid into the concentrated solution to adjust the pH value to 4.0-7.0, adding active carbon accounting for 5-20% of the concentrated solution by weight, decoloring and filtering, and performing freeze-drying, vacuum drying or spray drying to obtain the product.
The etimicin sulfate prepared by the process is simple to operate and easy to industrialize, the whole synthesis reaction can be completed by matching a conventional reaction kettle with a transfer tank and a filtering device, and the process reported in the patent with the application number of 93112412.3 is much more complicated. Secondly, the etimicin sulfate can be obtained by performing macroporous resin chromatographic purification once, and compared with the process reported in the patent with the application number of 93112412.3, the process for performing macroporous resin chromatographic purification once is reduced, and the amount of waste liquid generated is greatly reduced; most of the synthetic solvent in the process provided by the invention can be distilled, recovered and treated in a centralized manner, which accords with the concept of green environmental protection, while the process reported in the patent with the application number of 93112412.3 is to incorporate the synthetic organic solvent such as DMSO and the like into wastewater for treatment. Thirdly, the synthesis principle adopted by the invention is that the 1-N amino of the mother nucleus gentamicin C1a is protected by transition metal complexation, amino protective agent is added to protect the amino at other parts, then the transition metal complexation is removed by precipitation and the 1-N amino is released, then adding acetylation reagent to acetylate the 1-N amino, finally directly reducing the amide group at the 1-N position to ethyl through amide reduction reaction, simultaneously removing amino protection groups at other positions, so as to directly obtain the target product, in the process of adding acetaldehyde into the ethyl group at the 1-N position of mother nucleus gentamicin C1a by the process reported by the patent with the application number of 93112412.3, acetaldehyde and hydroxyl exposed from a mother nucleus generate aldol condensation side reaction, so the process provided by the invention generates less impurities by side reaction and has better specificity.
The preparation method of the invention is obtained by screening, such as selection of used methods of solvent, amino protective agent, precipitant, acetylation reagent, reducing agent, gradient elution separation and purification and the like, and the preferred preparation method of the invention is shown in the examples.
The specific implementation mode is as follows:
the invention is further illustrated by the following examples, which are not to be construed as limiting the invention thereto.
Example 1
Taking gentamycin C1a alkali, adding methanol which is 6 times of the weight of gentamycin C1a alkali, stirring and dissolving to obtain a solution, adding 2 times of equivalent of cobalt acetate which is 2 times of the amount of gentamycin C1a alkali, stirring to obtain a reaction solution 1, adding p-methoxybenzaldehyde which is 4 times of the amount of gentamycin C1a alkali, stirring and reacting for 2 hours to obtain a reaction solution 2, adding 2 times of equivalent of ammonium oxalate which is 2 times of the amount of gentamycin C1a alkali, stirring and filtering to obtain a reaction solution 3, adding 2 times of equivalent of acetyl chloride which is 2 times of the amount of gentamycin C1a alkali, stirring and reacting for 2 hours to obtain a reaction solution 4, adding 7 times of equivalent of potassium borohydride which is 7 times of the amount of the gentamycin C1a alkali, stirring and reacting for 6 hours to obtain a reaction solution 5, adding 5 times of water, vacuum concentrating under the condition that the vacuum degree below 80 ℃ and the vacuum degree is not higher than 0.2 atmospheric pressure to remove the solvent, adjusting the pH to 13 by ammonia water, adsorbing by macroporous, gradient separating and purifying with 5-40% diluted ethanol, collecting etimicin solution with purity greater than 95%, vacuum concentrating at 80 deg.C under vacuum degree not higher than 0.2 atmospheric pressure to obtain concentrated solution, adding sulfuric acid to adjust pH to 4.5, adding 18% of active carbon, decolorizing, filtering, and lyophilizing.
Example 2
Taking gentamycin C1a alkali, adding dichloromethane which is 7 times of the weight of gentamycin C1a alkali, stirring and dissolving to obtain a solution, adding zinc acetate which is 3 times of the equivalent of gentamycin C1a alkali, stirring to obtain a reaction solution 1, adding trityl chloride which is 6 times of the equivalent of gentamycin C1a alkali, stirring and reacting for 3 hours to obtain a reaction solution 2, adding ammonium phosphate which is 2-4 times of the amount of gentamycin C1a alkali, stirring and filtering to obtain a reaction solution 3, adding glacial acetic acid which is 3 times of the amount of gentamycin C1a alkali, stirring and reacting for 3 hours to obtain a reaction solution 4, adding sodium triacetoxyborohydride which is 10 times of the amount of the gentamycin C1a alkali, stirring and reacting for 4 hours to obtain a reaction solution 5, adding water with the volume which is 5 times of the volume, performing vacuum concentration under the condition that the vacuum degree is not higher than 0.2 at the temperature of 80 ℃ to remove the solvent, adjusting the pH to 13.5 by ammonia water, and adsorbing by macroporous resin, gradient separating and purifying with 5-40% diluted ethanol, collecting etimicin solution with purity greater than 95%, vacuum concentrating at 80 deg.C under vacuum degree not higher than 0.2 atmospheric pressure to obtain concentrated solution, adding sulfuric acid to adjust pH to 6.0, adding 15% active carbon, decolorizing, filtering, and spray drying.
Example 3
Taking gentamycin C1a alkali, adding DMSO which is 10 times of the weight of gentamycin C1a alkali, stirring and dissolving to obtain a solution, adding zinc sulfate which is 2-3 times of the amount of gentamycin C1a alkali, stirring to obtain a reaction solution 1, adding dimethoxybenzaldehyde which is 3 times of the amount of gentamycin C1a alkali, stirring and reacting for 1 hour to obtain a reaction solution 2, adding potassium phosphate which is 2-4 times of the amount of gentamycin C1a alkali, stirring and filtering to obtain a reaction solution 3, adding acetic anhydride which is 1.5 times of the amount of gentamycin C1a alkali, stirring and reacting for 1 hour to obtain a reaction solution 4, adding sodium cyanoborohydride which is 5 times of the amount of gentamycin C1a alkali, stirring and reacting for 4 hours to obtain a reaction solution 5, adding water with the volume which is 3 times of the volume, vacuum concentrating under the condition that the vacuum degree of 80 ℃ is not higher than 0.2 atmospheres to remove a solvent, adjusting the pH to 13 by using macroporous resin for adsorption, gradient separating and purifying with 5-40% diluted ethanol, collecting etimicin solution with purity greater than 95%, vacuum concentrating at 80 deg.C under vacuum degree not higher than 0.2 atmospheric pressure to obtain concentrated solution, adding 10% active carbon, decolorizing, filtering, and vacuum drying.
Description of the drawings: the above embodiments are only used to illustrate the present invention and do not limit the technical solutions described in the present invention; thus, while the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted; all such modifications and variations are intended to be included herein within the scope of this disclosure and the present invention and protected by the following claims.
Claims (6)
1. The preparation method of etimicin sulfate is characterized by comprising the following steps:
step 1, adding a certain proportion of solvent into gentamicin C1a alkali, stirring and dissolving to obtain a solution,
step 2, adding a complexing agent in a certain proportion into the solution, stirring to obtain a reaction solution 1,
step 3, adding a certain proportion of amino protective agent into the reaction solution 1, stirring and reacting for a certain time to obtain a reaction solution 2,
step 4, adding a precipitator with a certain proportion into the reaction solution 2, stirring and filtering to obtain a reaction solution 3,
step 5, adding an acetylation reagent in a certain proportion into the reaction liquid 3, stirring and reacting for a certain time to obtain a reaction liquid 4,
step 6, adding a reducing agent in a certain proportion into the reaction solution 4, stirring and reacting for a certain time to obtain a reaction solution 5,
step 7, adding a certain proportion of water into the reaction solution 5, carrying out vacuum concentration under a certain condition to remove the solvent, adjusting the pH value with ammonia water, adsorbing with macroporous resin, carrying out gradient separation and purification on diluted ethanol, collecting an etimicin solution with a certain purity, carrying out vacuum concentration under a certain condition to obtain a concentrated solution,
step 8, adding sulfuric acid into the concentrated solution to adjust the pH value to a certain value, adding a certain proportion of active carbon to decolor and filter, drying to obtain the active carbon,
wherein,
the solvent in the step 1 is one of methanol, ethanol, DMSO, dichloromethane, trichloromethane, DMF, THF and acetonitrile, the adding proportion of the solvent is 5-10 times of the weight of gentamicin C1a alkali,
the complexing agent in the step 2 is one of cobalt acetate, copper acetate, zinc acetate, cobalt sulfate, copper sulfate and zinc sulfate, the adding proportion of the complexing agent is 1-4 times of the equivalent of the gentamicin C1a alkali substance,
the amino protective agent in the step 3 is trityl chloride, the adding proportion of the amino protective agent is 2-6 times of the equivalent of the gentamicin C1a alkali substance, the stirring reaction time is 1-5 hours,
the precipitator in the step 4 is one of ammonium oxalate, potassium oxalate, sodium oxalate, ammonium phosphate, sodium phosphate and potassium phosphate, the addition proportion of the precipitator is 2-6 times of the equivalent of gentamicin C1a alkali substance,
the acetylation reagent in the step 5 is one of acetyl chloride, glacial acetic acid and acetic anhydride, the addition ratio of the acetylation reagent is 1-4 times of the equivalent of gentamicin C1a alkali substance, the stirring reaction time is 1-5 hours,
the reducing agent in the step 6 is one of sodium cyanoborohydride, red aluminum, sodium borohydride, sodium triacetoxyborohydride, potassium borohydride, borane and lithium aluminum hydride, the adding proportion of the reducing agent is 5-10 times of the equivalent of gentamicin C1a alkali substance, the stirring reaction time is 2-8 hours,
the proportion of the water in the step 7 is 3-6 times of the volume of the reaction solution 5, the vacuum concentration condition is that the vacuum degree is not higher than 0.2 atmospheric pressure at the temperature of 80 ℃, the pH value of the ammonia water is adjusted to 12-14, the gradient of the dilute ethanol is 5% -40%, the purity is more than 95%,
the pH range of the step 8 is 4.0-7.0, the adding proportion of the activated carbon is 5% -20% of the weight of the concentrated solution, and the drying mode is one of freeze drying, vacuum drying and spray drying.
2. The method of claim 1, comprising the steps of:
step 1) taking gentamicin C1a alkali, adding a solvent according to the proportion of 5-10 times of the weight of gentamicin C1a alkali, wherein the solvent is one of methanol, ethanol, DMSO, dichloromethane, trichloromethane, DMF, THF and acetonitrile, stirring and dissolving to obtain a solution,
step 2) adding a complexing agent into the solution according to an equivalent of 1-4 times of the gentamicin C1a alkali substance, wherein the complexing agent is one of cobalt acetate, copper acetate, zinc acetate, cobalt sulfate, copper sulfate and zinc sulfate, stirring to obtain a reaction solution 1,
step 3) adding an amino protective agent into the reaction solution 1 according to the equivalent 2-6 times of the amount of gentamicin C1a alkali substances, wherein the amino protective agent is trityl chloride, stirring and reacting for 1-5 hours to obtain a reaction solution 2,
step 4), adding a precipitator into the reaction liquid 2 according to an equivalent 2-6 times of the amount of gentamicin C1a alkali substances, stirring and filtering, wherein the precipitator is one of ammonium oxalate, potassium oxalate, sodium oxalate, ammonium phosphate, sodium phosphate and potassium phosphate to obtain a reaction liquid 3,
step 5), adding an acetylation reagent into the reaction liquid 3 according to an equivalent of 1-4 times of the amount of gentamicin C1a alkali substances, wherein the acetylation reagent is one of acetyl chloride, glacial acetic acid and acetic anhydride, stirring and reacting for 1-5 hours to obtain a reaction liquid 4,
step 6), adding a reducing agent into the reaction liquid 4 according to an equivalent of 5-10 times of the amount of gentamicin C1a alkali substances, wherein the reducing agent is one of sodium cyanoborohydride, red aluminum, sodium borohydride, sodium triacetoxyborohydride, potassium borohydride, borane and lithium aluminum hydride, stirring and reacting for 2-8 hours to obtain a reaction liquid 5,
step 7), adding water with the volume of 3-6 times of that of the reaction solution 5 into the reaction solution, performing vacuum concentration to remove the solvent under the condition that the vacuum degree is not higher than 0.2 atmospheric pressure below 80 ℃, adjusting the pH to 12-14 by using ammonia water, then using macroporous resin for adsorption, performing gradient separation and purification on 5% -40% of dilute ethanol, collecting etimicin solution with the purity of more than 95%, performing vacuum concentration under the condition that the vacuum degree is not higher than 0.2 atmospheric pressure below 80 ℃ to obtain concentrated solution,
and 8) adding sulfuric acid into the concentrated solution to adjust the pH value to 4.0-7.0, adding active carbon accounting for 5-20% of the concentrated solution by weight, decoloring and filtering, and performing freeze-drying, vacuum drying or spray drying to obtain the product.
3. The method of claim 1, comprising the steps of:
step 1) taking gentamicin C1a alkali, adding a solvent according to the proportion of 5-8 times of the weight of gentamicin C1a alkali, wherein the solvent is one of methanol, dichloromethane, DMSO, trichloromethane and THF, stirring and dissolving to obtain a solution,
step 2) adding a complexing agent into the solution according to an equivalent of 2-4 times of the gentamicin C1a alkali substance, wherein the complexing agent is one of copper acetate, zinc acetate, copper sulfate and cobalt sulfate, stirring to obtain a reaction solution 1,
step 3) adding an amino protective agent into the reaction solution 1 according to the equivalent of 3-6 times of the quantity of gentamicin C1a alkali substances, wherein the amino protective agent is trityl chloride, stirring and reacting for 1-4 hours to obtain a reaction solution 2,
step 4), adding a precipitator into the reaction liquid 2 according to an equivalent 2-5 times of the amount of gentamicin C1a alkali substances, stirring and filtering, wherein the precipitator is one of potassium oxalate, sodium oxalate, ammonium phosphate and potassium phosphate to obtain a reaction liquid 3,
step 5), adding an acetylation reagent into the reaction liquid 3 according to an equivalent of 1-4 times of the amount of gentamicin C1a alkali substances, wherein the acetylation reagent is one of acetyl chloride and acetic anhydride, stirring and reacting for 1-4 hours to obtain a reaction liquid 4,
step 6), adding a reducing agent into the reaction liquid 4 according to an equivalent of 6-10 times of the amount of gentamicin C1a alkali substances, wherein the reducing agent is one of sodium cyanoborohydride, sodium borohydride, sodium triacetoxyborohydride, potassium borohydride and borane, stirring and reacting for 3-7 hours to obtain a reaction liquid 5,
step 7), adding water with the volume 3-5 times of that of the reaction solution 5 into the reaction solution, performing vacuum concentration to remove the solvent under the condition that the vacuum degree is not higher than 0.2 atmospheric pressure below 80 ℃, adjusting the pH to 13-14 by using ammonia water, then using macroporous resin for adsorption, performing gradient separation and purification on 5% -40% of dilute ethanol, collecting etimicin solution with the purity of more than 95%, performing vacuum concentration under the condition that the vacuum degree is not higher than 0.2 atmospheric pressure below 80 ℃ to obtain concentrated solution,
and 8) adding sulfuric acid into the concentrated solution to adjust the pH value to 4.0-6.0, adding active carbon with the weight of 10-20% of the concentrated solution for decoloring and filtering, and performing freeze-drying or spray-drying to obtain the product.
4. The method of claim 1, comprising the steps of:
step 1) taking gentamicin C1a alkali, adding a solvent according to the proportion of 5-7 times of the weight of gentamicin C1a alkali, wherein the solvent is one of methanol, dichloromethane, DMSO and THF, stirring and dissolving to obtain a solution,
step 2) adding a complexing agent into the solution according to an equivalent of 2-3 times of the gentamicin C1a alkali substance, wherein the complexing agent is one of copper acetate, zinc acetate and cobalt sulfate, stirring to obtain a reaction solution 1,
step 3) adding an amino protective agent into the reaction solution 1 according to the equivalent of 3-5 times of the quantity of gentamicin C1a alkali substances, wherein the amino protective agent is trityl chloride, stirring and reacting for 1-3 hours to obtain a reaction solution 2,
step 4), adding a precipitator into the reaction solution 2 according to an equivalent 2-4 times of the amount of gentamicin C1a alkali substances, stirring and filtering, wherein the precipitator is one of potassium oxalate, sodium oxalate and potassium phosphate to obtain a reaction solution 3,
step 5), adding an acetylation reagent into the reaction liquid 3 according to an equivalent of 1-3 times of the amount of gentamicin C1a alkali substances, wherein the acetylation reagent is one of acetyl chloride and acetic anhydride, stirring and reacting for 1-3 hours to obtain a reaction liquid 4,
step 6), adding a reducing agent into the reaction liquid 4 according to an equivalent of 6-9 times of the amount of gentamicin C1a alkali substances, wherein the reducing agent is one of sodium cyanoborohydride, sodium borohydride, sodium triacetoxyborohydride and potassium borohydride, stirring and reacting for 3-7 hours to obtain a reaction liquid 5,
step 7), adding 3-4 times of water into the reaction solution 5, performing vacuum concentration to remove the solvent under the condition that the vacuum degree is not higher than 0.2 atmospheric pressure below 80 ℃, adjusting the pH to 13-14 by using ammonia water, then using macroporous resin for adsorption, performing gradient separation and purification on 5% -40% of dilute ethanol, collecting etimicin solution with the purity of more than 95%, performing vacuum concentration under the condition that the vacuum degree is not higher than 0.2 atmospheric pressure below 80 ℃ to obtain a concentrated solution,
and 8) adding sulfuric acid into the concentrated solution to adjust the pH value to 4.0-5.5, adding active carbon with the weight of 10-15% of that of the concentrated solution for decoloring and filtering, and performing freeze-drying or spray-drying to obtain the product.
5. The method of claim 1, comprising the steps of:
step 1) taking gentamicin C1a alkali, adding a solvent according to the proportion of 5-6 times of the weight of gentamicin C1a alkali, wherein the solvent is one of methanol, dichloromethane and THF, stirring and dissolving to obtain a solution,
step 2) adding a complexing agent into the solution according to an equivalent of 2-3 times of the gentamicin C1a alkali substance, wherein the complexing agent is one of zinc acetate and cobalt sulfate, stirring to obtain a reaction solution 1,
step 3) adding an amino protective agent into the reaction solution 1 according to the equivalent of 3-4 times of the amount of gentamicin C1a alkali substances, wherein the amino protective agent is trityl chloride, stirring and reacting for 2-3 hours to obtain a reaction solution 2,
step 4), adding a precipitator into the reaction solution 2 according to an equivalent 2-3 times of the amount of gentamicin C1a alkali substances, stirring and filtering, wherein the precipitator is one of sodium oxalate and potassium phosphate to obtain reaction solution 3,
step 5), adding an acetylation reagent into the reaction liquid 3 according to an equivalent 2-3 times of the amount of gentamicin C1a alkali substances, wherein the acetylation reagent is one of acetyl chloride and acetic anhydride, stirring and reacting for 2-3 hours to obtain a reaction liquid 4,
step 6), adding a reducing agent into the reaction liquid 4 according to an equivalent of 8-9 times of the amount of gentamicin C1a alkali substances, wherein the reducing agent is one of sodium cyanoborohydride, sodium borohydride and sodium triacetoxyborohydride, stirring and reacting for 5-7 hours to obtain a reaction liquid 5,
step 7), adding 3-4 times of water into the reaction solution 5, performing vacuum concentration to remove the solvent under the condition that the vacuum degree is not higher than 0.2 atmospheric pressure below 80 ℃, adjusting the pH to 13-14 by using ammonia water, then using macroporous resin for adsorption, performing gradient separation and purification on 5% -40% of dilute ethanol, collecting etimicin solution with the purity of more than 95%, performing vacuum concentration under the condition that the vacuum degree is not higher than 0.2 atmospheric pressure below 80 ℃ to obtain a concentrated solution,
and 8) adding sulfuric acid into the concentrated solution to adjust the pH value to 4.5-5.5, adding active carbon accounting for 12-15% of the concentrated solution by weight, decoloring and filtering, and freeze-drying or spray-drying to obtain the product.
6. The method of claim 1, comprising the steps of:
taking gentamycin C1a alkali, adding dichloromethane which is 7 times of the weight of gentamycin C1a alkali, stirring and dissolving to obtain a solution, adding zinc acetate which is 3 times of the equivalent of gentamycin C1a alkali, stirring to obtain a reaction solution 1, adding trityl chloride which is 6 times of the equivalent of gentamycin C1a alkali, stirring and reacting for 3 hours to obtain a reaction solution 2, adding ammonium phosphate which is 2-4 times of the amount of gentamycin C1a alkali, stirring and filtering to obtain a reaction solution 3, adding glacial acetic acid which is 3 times of the amount of gentamycin C1a alkali, stirring and reacting for 3 hours to obtain a reaction solution 4, adding sodium triacetoxyborohydride which is 10 times of the amount of the gentamycin C1a alkali, stirring and reacting for 4 hours to obtain a reaction solution 5, adding water with the volume which is 5 times of the volume, performing vacuum concentration under the condition that the vacuum degree is not higher than 0.2 at the temperature of 80 ℃ to remove the solvent, adjusting the pH to 13.5 by ammonia water, and adsorbing by macroporous resin, gradient separating and purifying with 5-40% diluted ethanol, collecting etimicin solution with purity greater than 95%, vacuum concentrating at 80 deg.C under vacuum degree not higher than 0.2 atmospheric pressure to obtain concentrated solution, adding sulfuric acid to adjust pH to 6.0, adding 15% active carbon, decolorizing, filtering, and spray drying.
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Address after: 214028 Changjiang South Road, new Wu District, Wuxi, Jiangsu Province, No. 12 Co-patentee after: Jiangxi Jinshuibao Pharmaceutical Co.,Ltd. Patentee after: Wuxi Jiyu Shanhe Pharmaceutical Co., Ltd Address before: 214028 No. 12 Changjiang South Road, New District, Jiangsu, Wuxi Co-patentee before: JIANGXI JIMINKEXIN JINSHUIBAO PHARMACEUTICAL Co.,Ltd. Patentee before: WUXI JIMIN KEXIN SHANHE PHARMACEUTICAL Co.,Ltd. |