CN103435582B - A kind of preparation method of La Nina meter Wei monooctyl ester - Google Patents
A kind of preparation method of La Nina meter Wei monooctyl ester Download PDFInfo
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- 150000002148 esters Chemical class 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 99
- 150000001875 compounds Chemical class 0.000 claims abstract description 93
- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
- 239000011347 resin Substances 0.000 claims abstract description 29
- 229920005989 resin Polymers 0.000 claims abstract description 29
- 239000003513 alkali Substances 0.000 claims abstract description 25
- 239000002253 acid Substances 0.000 claims abstract description 18
- 229960001028 zanamivir Drugs 0.000 claims abstract description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims abstract description 13
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims abstract description 12
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 claims abstract description 11
- -1 zanamivir methyl esters Chemical class 0.000 claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 230000007935 neutral effect Effects 0.000 claims abstract description 4
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 claims abstract description 3
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 38
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 239000003960 organic solvent Substances 0.000 claims description 21
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 20
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 13
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 12
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 10
- QVQLCTNNEUAWMS-UHFFFAOYSA-N barium oxide Chemical compound [Ba]=O QVQLCTNNEUAWMS-UHFFFAOYSA-N 0.000 claims description 9
- CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 0.000 claims description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 150000003053 piperidines Chemical class 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 7
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- 239000011259 mixed solution Substances 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 229910052786 argon Inorganic materials 0.000 claims description 4
- ZUDYPQRUOYEARG-UHFFFAOYSA-L barium(2+);dihydroxide;octahydrate Chemical compound O.O.O.O.O.O.O.O.[OH-].[OH-].[Ba+2] ZUDYPQRUOYEARG-UHFFFAOYSA-L 0.000 claims description 4
- 239000003637 basic solution Substances 0.000 claims description 4
- 239000007789 gas Substances 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 229920001467 poly(styrenesulfonates) Polymers 0.000 claims 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 13
- 238000000034 method Methods 0.000 abstract description 13
- 239000002360 explosive Substances 0.000 abstract description 5
- 231100000614 poison Toxicity 0.000 abstract description 4
- 230000007096 poisonous effect Effects 0.000 abstract description 4
- 238000005265 energy consumption Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 17
- 238000003786 synthesis reaction Methods 0.000 description 17
- 239000007787 solid Substances 0.000 description 15
- 206010022000 influenza Diseases 0.000 description 13
- 239000003814 drug Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 241000700605 Viruses Species 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 150000002357 guanidines Chemical class 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- BQINXKOTJQCISL-GRCPKETISA-N keto-neuraminic acid Chemical class OC(=O)C(=O)C[C@H](O)[C@@H](N)[C@@H](O)[C@H](O)[C@H](O)CO BQINXKOTJQCISL-GRCPKETISA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 235000015320 potassium carbonate Nutrition 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000012266 salt solution Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 241000712461 unidentified influenza virus Species 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- QNRRHYPPQFELSF-CNYIRLTGSA-N Laninamivir Chemical compound OC[C@@H](O)[C@@H](OC)[C@@H]1OC(C(O)=O)=C[C@H](N=C(N)N)[C@H]1NC(C)=O QNRRHYPPQFELSF-CNYIRLTGSA-N 0.000 description 2
- SQVRNKJHWKZAKO-LUWBGTNYSA-N N-acetylneuraminic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)CC(O)(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-LUWBGTNYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N aminothiocarboxamide Natural products NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 229960002587 amitraz Drugs 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- RCTYPNKXASFOBE-UHFFFAOYSA-M chloromercury Chemical compound [Hg]Cl RCTYPNKXASFOBE-UHFFFAOYSA-M 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229950004244 laninamivir Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229960003752 oseltamivir Drugs 0.000 description 2
- NENPYTRHICXVCS-YNEHKIRRSA-N oseltamivir acid Chemical compound CCC(CC)O[C@@H]1C=C(C(O)=O)C[C@H](N)[C@H]1NC(C)=O NENPYTRHICXVCS-YNEHKIRRSA-N 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- SAEZBIIRXDZCAB-UHFFFAOYSA-N 1,1,1-trimethoxyoctane Chemical compound CCCCCCCC(OC)(OC)OC SAEZBIIRXDZCAB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical class O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 102000005348 Neuraminidase Human genes 0.000 description 1
- 108010006232 Neuraminidase Proteins 0.000 description 1
- 229940123424 Neuraminidase inhibitor Drugs 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- ITLHXEGAYQFOHJ-UHFFFAOYSA-N [diazo(phenyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(=[N+]=[N-])C1=CC=CC=C1 ITLHXEGAYQFOHJ-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical group 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
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- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- CERZMXAJYMMUDR-UHFFFAOYSA-N neuraminic acid Natural products NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO CERZMXAJYMMUDR-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- PGZUMBJQJWIWGJ-ONAKXNSWSA-N oseltamivir phosphate Chemical compound OP(O)(O)=O.CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 PGZUMBJQJWIWGJ-ONAKXNSWSA-N 0.000 description 1
- 150000004880 oxines Chemical class 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
A kind of preparation method of La Nina meter Wei monooctyl ester, proceed step by step in same reactor or in multiple reactor, described reaction process is followed successively by: 1) by zanamivir and methanol mixed, adds acid positive resin simultaneously, obtains zanamivir methyl esters after reaction; 2) by zanamivir methyl esters in the basic conditions, with dimethyl carbonate production compound (17); 3) by formula (17) compound in the basic conditions, formula (18) compound is obtained with iodomethane reaction; 4) formula (18) compound and alkali are reacted, then use positive resin adjust ph to neutral, obtained formula (19) compound; 5) by formula compound (19) in the basic conditions, react with capryl(yl)chloride, obtain target product La Nina meter Wei monooctyl ester.The invention provides a kind of method preparing La Nina meter Wei monooctyl ester, the method route is simple, cost is low, energy consumption is low, product purity is high and avoid the use of poisonous reagent and explosive reagent.
Description
Technical field
The present invention relates to the method for the neuraminic acid derivatives preparing neuraminic acid enzyme inhibition activity, and relate to synthetic intermediate and their preparation method of neuraminic acid derivatives.In addition, the present invention relates to there is highly purified neuraminic acid derivatives.
Background technology
In numerous viral infection disease, influenza is one of communicable disease that maximum, the pathogenic region of pathogenic number is the widest and lethality rate is the highest.The influenza caused by influenza virus is a kind of respiratory infection diseases.In April, 2009, the Influenza A H1N1 of outburst allowed the whole world shroud under haze especially.As can be seen here, influenza as a kind of viral infectious not only serious threat public health, and give country and society bring heavy economical load.Therefore, the research and development of Tamiflu become the study hotspot of people.
The resistance report of existing anti-influenza virus medicament is in recent years on the increase, and the danger of the global great outburst of novel influenza grows with each passing day.And existing anti-influenza virus medicament exists compliance problem, mostly need repeatedly to take medicine until fully recover.Under this background, for influenza infection disease, seek new therapy approach and scheme, make every effort to release the original intention only needing single-dose can reach therapeutic purpose medicine new drug development staff development this product just.
Long-acting selective neuraminidase (neuramidinase, NA) inhibitor/anti-influenza virus medicament plays an important role in influenza virus reproduction process.La Nina meter Wei monooctyl ester is the long-acting neuraminidase inhibitor of s-generation induction type, be used for the treatment of the infection symptoms caused with flu-prevention virus, in September, 2010 goes on the market in Japan first, also be the first pure domestic anti-influenza virus medicament of Japan, to all effective to the A type of adult, Type B influenza infection disease patient from children, and also effective to oseltamivir drug-resistant viral (A/H1N1).La Nina meter Wei monooctyl ester has the feature not available for existing anti-influenza virus medicament---inhalation, the medicine influenza viruses such as air flue that go directly copy objective, be distributed in these regions and give full play to drug effect, and rest on for a long time these regions be conducive to continue play drug effect; Another feature is single-dose, and compared with existing medicine, only need single-dose namely to demonstrate the equal curative effect of continuous 5d administration with oseltamivir, reach therapeutic purpose, this also becomes the maximum bright spot of this product.The appearance of La Nina meter Wei monooctyl ester, for treatment of influenza from now on provides a new selection scheme.
About the report of La Nina meter Wei monooctyl ester synthetic route a lot (1. Chinese pharmaceutical chemistry magazine, 2012,22 (4): 294-301. in document; 2. drug evaluation research, 2011,34 (2): 144-151.), sum up, mainly contain 2 thinkings.
Route one: using N-acetyl-neuraminate as starting raw material, through over-churning, acidylate, Cheng Huan, deprotection, protection, azide, methylate and hydrolysis etc. 13 steps reaction preparation La Nina meter Wei monooctyl esters, total recovery is that 16%(is shown in Fig. 1).This route is long, and yield is low, uses the explosive reagent such as sodium hydride, cannot use in industrialized production.
Route two ~ tri-: amine (I) and N, N'-bis--tertbutyloxycarbonyl thiocarbamide (II), under mercury chloride and triethylamine effect, condensation reaction occur; Or amine (1) and two-tertbutyloxycarbonyl-guanylpyrazole (III) obtain shielded guanidine derivative (IV) in tetrahydrofuran (THF) (THF) solution.Guanidine derivative (IV) is deacetylated under the effect of sodium methylate obtains compound (V); Meanwhile, guanidine derivative (IV), in the methanol solution of sodium hydroxide or salt of wormwood, obtains carboxylic acid (VI) by hydrolysis reaction.It is the result under diphenyl diazomethane and boron trifluoride ether solution acting in conjunction that acid (VI) changes into corresponding benzhydryl ester (VII).Benzhydryl ester (VII) in the basic conditions subsequently, reacts, the primary hydroxy group of selectively acylating with capryl(yl)chloride (VIII), 9-octanoate (Ⅸ) (see figure 2) obtained.Finally, react with trifluoroacetic acid and compound (Ⅸ), remove N-tertbutyloxycarbonyl and O-diphenyl-methyl, alkalize subsequently, reverse column chromatography obtains target product simultaneously.
Route four ~ five: or amino-5, the 6-dihydropyran derivatives (X) of 4-are obtained by reacting intermediate 4-guanidine radicals dihydropyrane with two-tertbutyloxycarbonyl-guanylpyrazole (III), and the latter is hydrolyzed and obtains carboxylic acid (VI) in the methanol aqueous solution of salt of wormwood.In other route, the preparation of carboxylic acid (VI) is with amino-5, the 6-dihydroxyl pyrans carboxylicesterss (Ⅹ) of sodium hydroxide hydrolysis 4-, and then is obtained by reacting with guanylpyrazole derivative (III).And stirring reaction deprotection obtains laninamivir(Ⅺ in the methanol solution of two-tertbutyloxycarbonyl intermediate (VI) at 80 DEG C), the latter in methanolic HCl solution with 1,1,1-trimethoxy octane optionally acidylate obtain target product.Laninamivir(Ⅺ) also can obtain in the following manner: the unhindered amina (Ⅹ III) that intermediate (X) obtains with sodium hydroxide hydrolysis, unhindered amina (Ⅹ III) is by reacting with pyrazoles-1-amitraz hydrochloride (Ⅹ IV), or it is also passable, 4-amino-5-2,6-dihydropyrane (X) and pyrazoles-1-amitraz hydrochloride (Ⅹ IV) react, and then under the effect of salt of wormwood, are hydrolyzed methyl esters (see figure 2).
From route two ~ five, we can see that reaction scheme is all very long, are substantially greater than 4 step reactions; Reaction conditions is violent, not easily manipulates; And starting material are not easily bought, the synthesis as starting raw material I need have passed through 7 step reactions; The technique multistep reported in document adopts column chromatography purification mode, complicated operation, and the usage quantity of organic solvent increases greatly, causes pollution to environment; In addition, also use the poisonous reagents such as mercury chloride in technological process, do not meet industrial requirement.
Summary of the invention
The object of the present invention is to provide a kind of method preparing La Nina meter Wei monooctyl ester, the method route is simple, cost is low, energy consumption is low, product purity is high and avoid the use of poisonous reagent and explosive reagent.
In order to achieve the above object, the invention provides following technical scheme: proceed step by step in same reactor or in multiple reactor, described reaction process is followed successively by (see Fig. 3):
1) by formula (15) compound zanamivir and methanol mixed, add acid positive resin simultaneously, after reaction, obtain formula (16) compound zanamivir methyl esters;
2) by formula (16) compound in the basic conditions, with dimethyl carbonate production (17) compound;
3) by formula (17) compound in the basic conditions with iodomethane reaction, obtain formula (18) compound;
4) formula (18) compound and alkali are reacted, then use acid positive resin adjust ph to neutral, obtain formula (19) compound;
5) by formula (19) compound in the basic conditions, react with capryl(yl)chloride, obtain target product formula (14) La Nina meter Wei monooctyl ester.
Reaction scheme is:
Wherein step 1) zanamivir formula (15) compound and methanol solution mixing, add acid positive resin, reaction conditions is normal pressure, and temperature is room temperature ~ 70 DEG C, and the reaction times is 10 ~ 72 hours, and preferable reaction temperature is room temperature, and the reaction times is 30 hours; Wherein the weight ratio of zanamivir and methyl alcohol and the positive resin of acidity is: 1.0: 20 ~ 100: 0.3 ~ 1.0; The weight ratio of preferred zanamivir and methyl alcohol and the positive resin of acidity is: 1.0: 50: 0.5; The positive resin of wherein said acidity is selected from Dowex50 (H+) or Bio-Rad (H+); The positive resin of preferred acidic is: Dowex50 (H+).
Wherein step 2) in formula (16) compound added organic solvent mixing, then add the methanol solution of methylcarbonate, sodium methylate respectively, by mixed solution heating reflux reaction 4 ~ 8 hours, preferably 5 hours reaction times; The mol ratio of its Chinese style (16) compound and methylcarbonate and sodium methylate is: 1: 1.1 ~ 5.0: 0.01 ~ 0.1; The mol ratio of preferred formula (16) compound and methylcarbonate and sodium methylate is: 1: 2.5: 0.02; Described temperature of reaction is 50 ~ 100 DEG C, is preferably 80 DEG C; Wherein said organic solvent is selected from benzene, toluene, methylene dichloride, Isosorbide-5-Nitrae-dioxane, DMF, tetrahydrofuran (THF), methyl-sulphoxide, Virahol, methyl alcohol, ethanol etc., preferred toluene.
Wherein in step 3), formula (17) compound is added in organic solvent, stirring 10 ~ 30 minutes under low temperature and under the existence of alkali, preferably 15 minutes; Then 35 ~ 60 hours are reacted with methyl iodide room temperature lucifuge, preferably 45 hours; Described organic solvent is selected from benzene, toluene, methylene dichloride, Isosorbide-5-Nitrae-dioxane, DMF, tetrahydrofuran (THF), methyl-sulphoxide, Virahol, methyl alcohol, ethanol etc., preferred DMF; Described low temperature is-10 ~ 10 DEG C, preferably 0 DEG C; Described alkali is selected from the one such as oxyhydroxide, carbonate, organic or inorganic aminated compounds, Pyrrolidine, piperidines, morpholine, piperazine or its combination, preferred barium hydroxide octahydrate and barium oxide; The mol ratio of its Chinese style (17) compound and alkali is: 1: 3 ~ 10; Wherein compound 17 with the mol ratio of barium hydroxide octahydrate and barium oxide and methyl iodide is: 1: 0.1 ~ 0.5: 3 ~ 10: 10 ~ 20, and preferred molar ratio is 1: 0.2: 4: 15.
Wherein in step 4), formula (18) compound is added in organic solvent, adds basic solution simultaneously, stirred at ambient temperature reaction 10 ~ 30 hours, preferably 24 hours; After completion of the reaction, add acid positive resin adjust ph 7 ~ 9, preferred pH is 8; The mol ratio of formula (18) compound and alkali is: 1: 2 ~ 5, preferred molar ratio 1: 3; Described organic solvent is selected from benzene, toluene, methylene dichloride, Isosorbide-5-Nitrae-dioxane, DMF, tetrahydrofuran (THF), methyl-sulphoxide, Virahol, methyl alcohol, ethanol etc., particular methanol; Described basic solution is selected from the one such as oxyhydroxide, carbonate, organic or inorganic aminated compounds, Pyrrolidine, piperidines, morpholine, piperazine or its combination, preferred sodium hydroxide; The positive resin of described acidity is selected from Dowex50 (H+) or Bio-Rad (H+); The positive resin of preferred acidic is: Dowex50 (H+), now preferable reaction temperature is room temperature.
Wherein step 5) reaction is under protection of inert gas, and at the temperature of-10 ~ 15 DEG C, added in organic solvent by formula (19) compound, then mix with alkali, then add capryl(yl)chloride, temperature rises to room temperature reaction 15 ~ 40 hours, and the preferred reaction time is 24 hours; React complete, add alkali adjust ph to neutral; The mol ratio of its Chinese style (19) compound and alkali and capryl(yl)chloride is: 1: 1.1 ~ 3.0: 1.0 ~ 1.5, preferably 1: 2: 1; Wherein said rare gas element is nitrogen, argon gas; Described alkali is selected from the one such as oxyhydroxide, carbonate, organic or inorganic aminated compounds, Pyrrolidine, piperidines, morpholine, piperazine or its combination, is preferably triethylamine; Described organic solvent is selected from benzene, toluene, methylene dichloride, Isosorbide-5-Nitrae-dioxane, DMF, tetrahydrofuran (THF), methyl-sulphoxide, Virahol, methyl alcohol, ethanol etc., particular methanol.
Positively effect of the present invention is, is raw materials usedly easy to get, and in the process of preparation La Nina meter Wei monooctyl ester, intermediate and end product quality easily control, and product yield is higher, and total recovery is about 50%; Purity is higher, is easy to separation and purification; And the equal recoverable of organic solvent that the present invention is used, reduce costs; Use without special, toxic reagent, be conducive to environmental protection; Atmospheric operation in building-up process, reaction conditions is gentle, and technique is simple and direct, and equipment is simple, and cost is low, is easy to industrialized production.
Improvement for conventional preparation techniques is mainly reflected in:
1) avoid the use of poisonous reagent and explosive reagent, improve the feasibility of test.
In the preparation process of product formula (17) compound, adopt the structure of 2-oxo-1,3-dioxolanes to replace the acetal of document or the structure of cyclic ethers to protect 8, the hydroxyl of 9, avoids the use of the unstable reagent such as Methanesulfonyl chloride;
The synthesis of product formula (18) compound, has done very large change compared with document: adopt methyl iodide as methylating reagent, has avoided the use of the severe toxicity such as methyl-sulfate and sodium hydride and explosive reagent, greatly improve the feasibility of experiment;
2) change purification process, reduce the use of organic solvent, reduce environmental pollution.
The compound related in the present invention's research all adopts the method for recrystallization, instead of the column chromatography for separation of bibliographical information, simple, convenient, quick, reproducible, decrease the pollution to environment while reducing organic solvent usage quantity, be applicable to industrial a large amount of manufacture.
Accompanying drawing explanation
Fig. 1 is using N-acetyl-neuraminate as initial preparation La Nina meter Wei monooctyl ester reacting flow chart.
Fig. 2 is for initial preparation La Nina meter Wei monooctyl ester reacting flow chart with amine and N, N'-bis--tertbutyloxycarbonyl thiocarbamide (II).
Fig. 3 is that the present invention prepares La Nina meter Wei monooctyl ester reacting flow chart.
Embodiment
Now in conjunction with the embodiments, the invention will be further described.In embodiment, various chemical used and reagent are commercially available purchase if no special instructions.
The preparation of embodiment 1 La Nina meter Wei monooctyl ester
The synthesis of formula 16 compound zanamivir methyl esters
In 20L reactor, zanamivir (109.7g, 0.33mol) and 6.9L methanol mixed are obtained suspension.In suspension, add acid positive resin be selected from Dowex50 (H+) (55g), react 30 hours under room temperature; Complete, cross and filter resin, with methanol wash (0.1L × 2), filtrate is concentrated obtains off-white color solid, i.e. compound 16, yield 98.1%.
The synthesis of formula 17 compound
By formula 16 compound (103.8g under room temperature, 0.30mol) mix with toluene (300ml), then add methylcarbonate (63.2ml) respectively, the methanol solution (0.3ml) of sodium methylate, mixed solution is heated to 80 DEG C, back flow reaction 5 hours; React complete, be cooled to 0 DEG C, stir 15 minutes, leave standstill crystallization, filter, toluene (50ml × 2) washs, and obtains faint yellow to yellow solid formula 17 compound, yield 85.4%.
The synthesis of formula 18 compound
Formula 17 compound (111.6g is added in 2L tri-neck reaction flask, 0.30mol) and N, N-diformamide (1080ml) mixes, Ba (OH) 2.8H2O (18.9g is added at 0 DEG C, 0.06mol) with BaO (183.6g, 1.20mol), mix and blend, after 15 minutes, adds methyl iodide (280.3ml).Room temperature lucifuge reacts 45 hours, react complete, with ethyl acetate (1.5L × 2) and 5% salt solution (0.5L), it is extracted, collect organic phase, with anhydrous sodium sulfate drying, be evaporated to 200mL, spend the night at being placed on-10 ~-5 DEG C, crystallization off-white color to faint yellow solid formula 18 compound, productive rate 76.3%.
The synthesis of formula 19 compound
By formula 18 compound (154.5g, 0.40mol) be dissolved in 3L methyl alcohol, then add sodium hydroxide (48g, 1.20mol), at room temperature stir 24 hours, TLC (plate layer chromatography) detection reaction is complete, then adds acid positive resin and is selected from Dowex50 (H+), regulates pH=8, filter, concentrated, obtain white to off-white color solid type 19 compound, productive rate 95.0%.
The synthesis of formula 14 compound
Argon shield borehole cooling is to-5 ~ 5 DEG C, by Formula 19 compound (138.5g, 0.40mol) be added in 5L reactor, add 2L methyl alcohol simultaneously, then triethylamine (111.0ml is added respectively, 0.80mol) with capryl(yl)chloride (60.2g, 0.40mol) mix, mixture at room temperature stirring reaction 24 hours, after, add ethyl acetate (2.5L), add 5% sodium bicarbonate (0.5L × 2) more respectively and saturated aqueous common salt (1.0L) washs organic layer, collect organic phase, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, dry, obtain white to off-white color solid type 14 compound, productive rate 84.8%.
The preparation of embodiment 2 La Nina meter Wei monooctyl ester
The synthesis of formula 16 compound
In 20L reactor, zanamivir (36.6g, 0.11mol) and 0.92L methanol mixed are obtained suspension.In suspension, add acid positive resin be selected from Bio-Rad (H+) (11.0g), react 10 hours under room temperature; Complete, cross and filter resin, with methanol wash (30mL × 2), filtrate is concentrated obtains off-white color solid, i.e. formula 16 compound, yield 90.6%.
The synthesis of formula 17 compound
By formula 16 compound (34.6g under room temperature, 0.10mol) mix with tetrahydrofuran (THF) (100ml), then methylcarbonate (9.3ml) is added respectively, the methanol solution (0.06ml) of sodium methylate, mixed solution is heated to 50 DEG C, back flow reaction 4 hours; React complete, be cooled to 0 DEG C, stir 20 minutes, leave standstill crystallization, filter, toluene (15ml × 2) washs, and obtains faint yellow to yellow solid formula 17 compound, yield 73.8%.
The synthesis of formula 18 compound
Formula 17 compound (37.2g is added in 2L tri-neck reaction flask, 0.10mol) mix with methyl-sulphoxide (360ml), add NaOH (12g, 0.30mol) mix and blend at-10 DEG C after 10 minutes, add methyl iodide (62.3ml).Room temperature lucifuge reacts 35 hours, react complete, with ethyl acetate (0.5L × 2) and 5% salt solution (0.15L), it is extracted, collect organic phase, with anhydrous sodium sulfate drying, be evaporated to 60mL, spend the night at being placed on-10 ~-5 DEG C, crystallization off-white color to faint yellow solid formula 18 compound, yield 63.2%.
The synthesis of formula 19 compound
By formula 18 compound (51.5g, 0.13mol) be dissolved in 1L toluene, then add triethylamine (36.1ml, 0.26mol), at room temperature stir 10 hours, TLC (plate layer chromatography) detection reaction is complete, then adds acid positive resin and is selected from Bio-Rad (H+), regulates pH=7, filter, concentrated, obtain white to off-white color solid type 19 compound, productive rate 82.1%.
The synthesis of formula 14 compound
Nitrogen protection borehole cooling is to-10 ~ 0 DEG C, by formula 19 compound (46.2g, 0.13mol) be added in 2L reactor, add 0.67L methyl-sulphoxide simultaneously, then piperidines (14.1ml is added respectively, 0.14mol) with capryl(yl)chloride (19.6g, 0.13mol) mix, mixture at room temperature stirring reaction 15 hours, after, add ethyl acetate (0.8L), add 5% sodium bicarbonate (0.15L × 2) more respectively and saturated aqueous common salt (0.3L) washs organic layer, collect organic phase, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, dry, obtain white to off-white color solid type 14 compound, yield 76.5%.
The preparation of embodiment 3 La Nina meter Wei monooctyl ester
The synthesis of formula 16 compound
In 20L reactor, zanamivir (54.8g, 0.16mol) and 6.94L methanol mixed are obtained suspension.In suspension, add acid positive resin be selected from Dowex50 (H+) (54.8g), react 72 hours at 70 DEG C; Complete, cross and filter resin, with methanol wash (50mL × 2), filtrate is concentrated obtains off-white color solid, i.e. Formula 16 compound, yield 94.2%.
The synthesis of formula 17 compound
By formula 16 compound (51.9g under room temperature, 0.15mol) with 1,4-dioxane (150ml) mixes, then methylcarbonate (63.2ml) is added respectively, the methanol solution (0.8ml) of sodium methylate, mixed solution is heated to 100 DEG C, back flow reaction 8 hours; React complete, be cooled to 0 DEG C, stir 15 minutes, leave standstill crystallization, filter, toluene (25ml × 2) washs, and obtains faint yellow to yellow solid formula 17 compound, yield 73.8%.
The synthesis of formula 18 compound
Formula 17 compound (55.8g is added in 2L tri-neck reaction flask, 0.15mol) mix with Isosorbide-5-Nitrae-dioxane (540ml), at 10 DEG C, add piperidines (148.1ml, 1.5mol) mix and blend is after 30 minutes, adds methyl iodide (187ml).Room temperature lucifuge reacts 60 hours, react complete, with ethyl acetate (0.8L × 2) and 5% salt solution (0.25L), it is extracted, collect organic phase, with anhydrous sodium sulfate drying, be evaporated to 100mL, spend the night at being placed on-10 ~-5 DEG C, crystallization off-white color to faint yellow solid formula 18 compound, productive rate 68.3%.
The synthesis of formula 19 compound
By formula 18 compound (77.3g, 0.20mol) be dissolved in 1.5L tetrahydrofuran (THF), then add salt of wormwood (138.0g, 1.0mol), at room temperature stir 30 hours, TLC (plate layer chromatography) detection reaction is complete, then adds acid positive resin and is selected from Dowex50 (H+), regulates pH=9, filter, concentrated, obtain white to off-white color solid type 19 compound, productive rate 88.6%.
The synthesis of formula 14 compound
Argon shield borehole cooling to 5 ~ 15 DEG C, by formula 19 compound (69.3g, 0.20mol) be added in 3L reactor, add 1L toluene simultaneously, then triethylamine (83.3ml is added respectively, 0.6mol) with capryl(yl)chloride (49.7g, 0.3mol) mix, mixture at room temperature stirring reaction 40 hours, after, add ethyl acetate (1.2L), add 5% sodium bicarbonate (0.25L × 2) more respectively and saturated aqueous common salt (0.5L) washs organic layer, collect organic phase, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, dry, obtain white to off-white color solid type 14 compound, productive rate 80.1%.
Claims (7)
1. the preparation method of Yi Zhong La Nina meter Wei monooctyl ester, preparation process is:
1) by formula (15) compound zanamivir and methanol mixed, add acid positive resin simultaneously, acid positive resin is selected from Dowex 50 (H+) or Bio-Rad (H+), obtains formula (16) compound zanamivir methyl esters after reaction;
2) by formula (16) compound in the basic conditions, with dimethyl carbonate production (17) compound;
3) by formula (17) compound in the basic conditions with iodomethane reaction, obtain formula (18) compound;
4) formula (18) compound and alkali are reacted, then use acid positive resin adjust ph 7 ~ 9, obtain formula (19) compound;
5) by formula (19) compound in the basic conditions, react with capryl(yl)chloride, obtain target product formula (14) La Nina meter Wei monooctyl ester;
Described alkali is selected from oxyhydroxide, carbonate, Pyrrolidine, piperidines, morpholine, piperazine one or its combination.
2. the preparation method of La Nina meter Wei monooctyl ester as claimed in claim 1, wherein
Step 1) in, reaction conditions is normal pressure, and temperature is room temperature ~ 70 DEG C, and the reaction times is 10 ~ 72 hours;
Step 2) in, add in organic solvent by formula (16) compound, add the methanol solution of methylcarbonate, sodium methylate, by mixed solution heating reflux reaction 4 ~ 8 hours, temperature of reaction was 50 ~ 100 DEG C;
Step 3) in, formula (17) compound is added in organic solvent, stirring 10 ~ 30 minutes at-10 ~ 10 DEG C and under the existence of alkali; Then 35 ~ 60 hours are reacted with methyl iodide room temperature lucifuge;
Step 4) in, formula (18) compound is added in organic solvent, adds basic solution simultaneously, stirred at ambient temperature reaction 10 ~ 30 hours; After completion of the reaction, acid positive resin adjust ph 7 ~ 9 is added;
Step 5) in, under protection of inert gas, at the temperature of-10 ~ 15 DEG C, first dissolved in organic solvent by compound 19, then mix with alkali, then add capryl(yl)chloride, temperature rises to room temperature reaction 15 ~ 40 hours; React complete, add alkali adjust ph to neutral.
3. La Nina meter Wei monooctyl ester preparation method as claimed in claim 2, wherein, described organic solvent is selected from benzene, toluene, methylene dichloride, Isosorbide-5-Nitrae-dioxane, DMF, tetrahydrofuran (THF), methyl-sulphoxide, Virahol, methyl alcohol, ethanol;
Described alkali is selected from a kind of or its combination such as oxyhydroxide, carbonate, Pyrrolidine, piperidines, morpholine, piperazine, and basic solution is the solution of a kind of or its combination preparation such as oxyhydroxide, carbonate, Pyrrolidine, piperidines, morpholine, piperazine.
4. the preparation method of La Nina meter Wei monooctyl ester as claimed in claim 2, wherein
Step 1) in, temperature of reaction is room temperature, and the reaction times is 30 hours;
Step 2) in, reflux time 5 hours, temperature of reaction is 80 DEG C;
Step 3) in, stirring 15 minutes at 0 DEG C and under the existence of alkali; 45 hours are reacted with methyl iodide room temperature lucifuge;
Step 4) in, stirred at ambient temperature reacts 24 hours; After completion of the reaction, adding acid positive resin adjust ph is 8;
Step 5) in, add capryl(yl)chloride, it is 24 hours that temperature rises to the room temperature reaction time.
5. the preparation method of La Nina meter Wei monooctyl ester as claimed in claim 2, wherein
Step 1) in, the weight ratio of formula (15) compound zanamivir and methyl alcohol and the positive resin of acidity is 1.0:20 ~ 100:0.3 ~ 1.0;
Step 2) in, organic solvent is toluene, and the mol ratio of formula (16) compound and methylcarbonate and sodium methylate is 1:1.1 ~ 5.0:0.01 ~ 0.1;
Step 3) in, organic solvent is DMF, and alkali is barium hydroxide octahydrate and barium oxide, and the mol ratio of formula (17) compound and alkali is 1:3 ~ 10;
Step 4) in, organic solvent is methyl alcohol, and alkali is sodium hydroxide, and the mol ratio of formula (18) compound and alkali is 1:2 ~ 5;
Step 5) in, rare gas element is nitrogen, argon gas, and alkali is triethylamine, and organic solvent is methyl alcohol, and the mol ratio of formula (19) compound and alkali and capryl(yl)chloride is 1:1.1 ~ 3.0:1.0 ~ 1.5.
6. the preparation method of La Nina meter Wei monooctyl ester as claimed in claim 5, wherein
Step 1) in, the weight ratio of formula (15) compound zanamivir and methyl alcohol and the positive resin of acidity is 1.0:50:0.5;
Step 2) in, the mol ratio of formula (16) compound and methylcarbonate and sodium methylate is 1:2.5:0.02;
Step 3) in, the mol ratio of formula (17) compound and barium hydroxide octahydrate and barium oxide and methyl iodide is 1:0.2:4:15;
Step 4) in, the mol ratio of formula (18) compound and alkali is 1:3;
Step 5) in, the mol ratio of formula (19) compound and alkali and capryl(yl)chloride is 1:2:1.
7. the preparation method of La Nina meter Wei monooctyl ester as claimed in claim 1, wherein, acid positive resin is Dowex 50 (H+).
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| Feng en-guang,et al.,.Improved synthesis of laninamivir octanoate.《中国药物化学杂志》.2012,第22卷(第4期),第294-301页. * |
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