CN116730962A - Preparation method of 2-hydroxyethyl-3-pentoxy-4-pyrone - Google Patents
Preparation method of 2-hydroxyethyl-3-pentoxy-4-pyrone Download PDFInfo
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- CN116730962A CN116730962A CN202210198852.0A CN202210198852A CN116730962A CN 116730962 A CN116730962 A CN 116730962A CN 202210198852 A CN202210198852 A CN 202210198852A CN 116730962 A CN116730962 A CN 116730962A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- -1 2-hydroxyethyl-3-pentoxy-4-pyrone Chemical compound 0.000 title claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 108
- 238000006243 chemical reaction Methods 0.000 claims abstract description 55
- 238000000034 method Methods 0.000 claims abstract description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 12
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 8
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 7
- 239000001632 sodium acetate Substances 0.000 claims description 7
- 235000017281 sodium acetate Nutrition 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- 239000011230 binding agent Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 150000007524 organic acids Chemical class 0.000 claims description 6
- 235000011056 potassium acetate Nutrition 0.000 claims description 6
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 claims description 5
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 5
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- 230000001590 oxidative effect Effects 0.000 claims description 4
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 claims description 4
- 238000007670 refining Methods 0.000 claims description 4
- 229950009390 symclosene Drugs 0.000 claims description 4
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 claims description 4
- 239000005456 alcohol based solvent Substances 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- XIXADJRWDQXREU-UHFFFAOYSA-M lithium acetate Chemical compound [Li+].CC([O-])=O XIXADJRWDQXREU-UHFFFAOYSA-M 0.000 claims description 3
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 6
- 230000036632 reaction speed Effects 0.000 abstract description 3
- 230000003321 amplification Effects 0.000 abstract description 2
- 159000000007 calcium salts Chemical class 0.000 abstract description 2
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 2
- 238000007086 side reaction Methods 0.000 abstract description 2
- 239000002910 solid waste Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000006460 hydrolysis reaction Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 206010022000 influenza Diseases 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 241000712461 unidentified influenza virus Species 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- RZVPBGBYGMDSBG-GGAORHGYSA-N baloxavir marboxil Chemical compound COC(=O)OCOc1c2C(=O)N3CCOC[C@H]3N([C@H]3c4ccc(F)c(F)c4CSc4ccccc34)n2ccc1=O RZVPBGBYGMDSBG-GGAORHGYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- ZVJWBAOEJGXYKJ-UHFFFAOYSA-N 2H-oxazine pyridine triazine Chemical group N1=CC=CC=C1.O1NC=CC=C1.N1=NN=CC=C1 ZVJWBAOEJGXYKJ-UHFFFAOYSA-N 0.000 description 1
- 229940123734 Endonuclease inhibitor Drugs 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000005727 virus proliferation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
- C07D309/40—Oxygen atoms attached in positions 3 and 4, e.g. maltol
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application provides a novel preparation method of 2-hydroxyethyl-3-pentoxy-4-pyrone (a compound shown in a formula I) which is a synthetic raw material of a key intermediate of Marbalol Sha Wei, which has the advantages that: by adopting a novel process, the 2-bromoethyl-3-pentoxy-4-pyrone (a compound shown in a formula I-1) is activated, so that the complete reaction is realized, the 2-hydroxyethyl-3-pentoxy-4-pyrone is obtained, the reaction speed is improved, the occurrence of side reaction is reduced, a large amount of calcium salt solid waste is reduced, and the reaction yield is improved to more than 80 percent from 50 percent; meanwhile, the application also provides a method for preparing the key intermediate (compound in formula III) of the balo Sha Wei by using the compound in formula I, the total yield can reach more than 30%, and the method is a feasible process for industrial amplification implementation.
Description
Technical Field
The application belongs to the field of medicine synthesis, and in particular relates to a preparation method of 2-hydroxyethyl-3-pentoxy-4-pyrone.
Background
BaloxavirMarbocil Chinese name is Mabalo Sha Wei, which is a new anti-influenza drug developed by Japanese salt wild-type pharmaceutical (Shionogi) company and has the trade name of Xofluza. Xofluza is an innovative Cap-dependent endonuclease inhibitor and is a new drug for inhibiting influenza virus proliferation in a small number of the world. Aiming at the key link of influenza virus replication, the CAP structure of the 5' -end of host mRNA obtained from host cells is inhibited, so that transcription of the mRNA of the influenza virus is inhibited. Month 2 of 2018, the drug was approved in japan for the treatment of influenza a and B in adult and pediatric patients. FDA approval was obtained for marketing 10 in 2018 for treatment of complications-free acute influenza patients aged 12 years and older for no more than 48 hours.
Marbalol Sha Wei is a prodrug, and is hydrolyzed into active substance Balol Sha Wei in vivo to exert anti-influenza virus activity.
Oxazine pyridine triazine ring segment is a key intermediate for synthesis of Marbalo Sha Wei, and the chemical name is: (12 AR) -3,4,12,12A-tetrahydro-7-pentyloxy-1H- [1,4] oxazino [3,4-C ] pyrido [2,1-F ] [1,2,4] triazine-6, 8-dione (compound of formula III).
The compound of formula III can be prepared from a compound of formula II-1:
patent WO2019070059 discloses a method for the synthesis of compounds of formula II-1: the compound of the formula I-1 is hydrolyzed and oxidized to obtain the target compound. For the first hydrolysis reaction, acetonitrile-water is used as a solvent by a former research company, and calcium carbonate is added into a compound shown as a formula I-1 for reflux hydrolysis reaction, but the reaction is very slow, 10% of raw materials remain after 24 hours of reaction, more ring-opening impurities are generated, and the reaction yield is lower than 50%.
As marbalo Sha Wei is marketed in various markets worldwide and anti-influenza drugs are increasingly being used, demand for marbalo Sha Wei is increasing. Therefore, there is a need to develop an industrial synthetic route for key intermediates of marballo Sha Wei in high yields, high purity, and low cost.
Disclosure of Invention
The application provides a novel preparation method of 2-hydroxyethyl-3-pentoxy-4-pyrone (a compound shown in a formula I) which is a synthetic raw material of a key intermediate of Marba Sha Wei. The application realizes the complete reaction by activating the 2-bromoethyl-3-pentoxy-4-pyrone (the compound shown in the formula I-1) to obtain the 2-hydroxyethyl-3-pentoxy-4-pyrone, reduces the occurrence of side reaction while improving the reaction speed, reduces a large amount of calcium salt solid waste, and improves the reaction yield from 50% to more than 80%; meanwhile, the application also provides a method for preparing the key intermediate (compound in formula III) of the balo Sha Wei by the compound in formula I, the total yield can reach more than 30%, and the method is a feasible process for industrial amplification implementation.
In a first aspect the present application provides a process for the preparation of 2-hydroxyethyl-3-pentoxy-4-pyrone (a compound of formula I), said process comprising the steps of:
(1) Adding alkali metal acetate into an organic solvent system containing a compound I-1, and reacting to obtain a mixed system A containing a compound I-2; and
(2) Adding alkali into the mixed system A, and reacting to obtain the compound I.
In another preferred embodiment, in step (1), the alkali metal acetate is selected from the group consisting of: sodium acetate, potassium acetate, lithium acetate, or combinations thereof, preferably sodium acetate and potassium acetate.
In another preferred embodiment, in step (1), the organic solvent is selected from the group consisting of C1-C6 alcohol solvents, preferably methanol, ethanol, isopropanol, or a combination thereof, more preferably ethanol.
In another preferred embodiment, in step (1), the reaction temperature is from 40 to 80℃and preferably from 50 to 65 ℃.
In another preferred embodiment, in step (2), the base is selected from the group consisting of: sodium hydroxide, potassium hydroxide, sodium ethoxide, potassium ethoxide, or a combination thereof, preferably sodium hydroxide.
In another preferred embodiment, in step (2), the reaction temperature is from-10 to 30 ℃, preferably from-5 to 10 ℃.
In another preferred embodiment, in step (2), the reaction is completed further comprising one or more post-treatment steps selected from the group consisting of: adding acid to neutralize, removing organic solvent in the reaction liquid, extracting, separating liquid and concentrating.
In another preferred embodiment, in step (2), the extraction solvent is selected from the group consisting of: ethyl acetate, methyl tertiary ether, isopropyl ether, tetrahydrofuran, toluene, or a combination thereof, ethyl acetate being preferred.
In a second aspect of the present application, there is provided a process for the preparation of a compound of formula II as an intermediate to balo Sha Wei, said process comprising the steps of:
(a) The compound I reacts under the action of an oxidant to obtain a compound II-1;
(b) Reacting the compound II-1 with dimethyl sulfate under alkaline conditions to obtain a compound II-2;
(c) The compound II-2 reacts with tert-butyl hydrazinoformate in a system containing pyridinium p-toluenesulfonate to obtain a compound II; and is also provided with
The step (a) is preceded by the step of preparing a compound of formula I by the method of the first aspect of the application.
In another preferred embodiment, the step (a) includes the steps of: the compound I is reacted in a reaction system containing sodium bicarbonate, sodium bromide, 2, 6-tetramethyl piperidine oxide and trichloroisocyanuric acid at 0-10 ℃.
In a third aspect of the present application, there is provided a process for the preparation of a compound of formula III, comprising the steps of:
(A) The compound II and the compound III-1 react under the action of a condensing agent to obtain a compound III-2, wherein the condensing agent is selected from one or more of 1, 8-diazabicyclo [5.4.0] -7-undecene, sodium methoxide, sodium ethoxide and sodium tert-butoxide;
(B) Adding organic acid into a reaction system containing the compound III-2, and reacting to obtain a compound III-3, wherein the organic acid is one or more selected from methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid and p-toluenesulfonic acid;
(C) Condensing the compound III-3 and the compound III-4 under the condition of an acid binding agent, and further refining after the reaction is finished to obtain an isomerically pure compound III-5, wherein the acid binding agent is one or more selected from triethylamine, diisopropylethylamine and pyridine;
(D) Removing a furoyl group of the compound III-5 under the action of 1, 8-diazabicyclo [5.4.0] -7-undecene to obtain the compound III; and is also provided with
The step (a) is preceded by the step of preparing a compound of formula II by the method of the second aspect of the application.
It is understood that within the scope of the present application, the above-described technical features of the present application and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Detailed Description
For the hydrolysis reaction of 2-bromoethyl-3-pentoxy-4-pyrone (compound of formula I-1), the original research company uses acetonitrile-water as solvent and adds calcium carbonate to carry out reflux hydrolysis reaction, and the process has low reaction speed, low conversion rate and more byproducts, so the inventor tries to optimize the step. In intensive and thorough research, conducted by the inventors, it was found that hydrolysis at 30 ℃ or lower was difficult to proceed using other alkaline water systems (including aqueous sodium carbonate, aqueous sodium hydroxide, aqueous sodium bicarbonate, etc.), and heating was required; however, the hydrolysis product is produced by heating reaction, but the raw material is ring-opened at high temperature to produce ring-opened byproducts, so that the burden of post-treatment is increased, and the yield and purity of the product are affected. According to the research of the inventor, after benzyl bromide is activated, the reactivity is improved, the hydrolysis reaction can be performed at a low temperature, the generation of byproducts is effectively reduced, the reaction time is shortened, and the reaction yield of the step is improved.
Terminology
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
As used herein, when used in reference to a specifically recited value, the term "about" means that the value can vary no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
As used herein, the term "comprising" or "including" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….
As used herein, the term "room temperature" or "normal temperature" refers to a temperature of 4-40 ℃, preferably 25±5 ℃.
In the present application, in the reaction system of each reaction step, each substance (except the solvent) may independently participate in the reaction in any suitable ratio between each two, such as 1: (0.1-10), 1: (0.2-5), 1: (0.5-2), 1: (0.8-1.5) or 1: (1.0-1.2).
Process for preparing 2-hydroxyethyl-3-pentoxy-4-pyrone (formula I compound)
The present application provides a process for the preparation of 2-hydroxyethyl-3-pentoxy-4-pyrone (a compound of formula I), comprising the steps of:
(1) Adding alkali metal acetate into an organic solvent system containing a compound I-1, and reacting to obtain a mixed system A containing a compound I-2; and
(2) Adding alkali into the mixed system A, and reacting to obtain the compound I.
In another preferred embodiment, in step (1), the alkali metal acetate is selected from the group consisting of: sodium acetate, potassium acetate, lithium acetate, or combinations thereof, preferably sodium acetate and potassium acetate.
In another preferred embodiment, in step (1), the organic solvent is selected from the group consisting of C1-C6 alcohol solvents, preferably methanol, ethanol, isopropanol, or a combination thereof, more preferably ethanol.
In another preferred embodiment, in step (1), the reaction temperature is 40 to 80 ℃.
In another preferred embodiment, in step (2), the base is selected from the group consisting of: sodium hydroxide, potassium hydroxide, sodium ethoxide, potassium ethoxide, or a combination thereof, preferably sodium hydroxide.
In another preferred embodiment, in step (2), the reaction temperature is from-10 to 30 ℃.
In another preferred embodiment, in step (2), the reaction is completed further comprising one or more post-treatment steps selected from the group consisting of: adding acid to neutralize, removing organic solvent in the reaction liquid, extracting, separating liquid and concentrating.
In another preferred embodiment, in step (2), the extraction solvent is selected from the group consisting of: ethyl acetate, methyl tertiary ether, isopropyl ether, tetrahydrofuran, toluene, or a combination thereof, ethyl acetate being preferred.
In another preferred embodiment, the method further comprises the steps of:
(a) The compound I reacts under the action of an oxidant to obtain a compound II-1;
in another preferred embodiment, the step (a) includes the steps of: the compound I is reacted in a reaction system containing sodium bicarbonate, sodium bromide, 2, 6-tetramethyl piperidine oxide and trichloroisocyanuric acid at 0-10 ℃.
Process for the preparation of compounds of formula II
The application further provides a preparation method of the balo Sha Wei intermediate compound of the formula II, which comprises the following steps:
(a) The compound I reacts under the action of an oxidant to obtain a compound II-1;
(b) Reacting the compound II-1 with dimethyl sulfate under alkaline conditions to obtain a compound II-2;
(c) And reacting the compound II-2 with tert-butyl hydrazinoformate in a system containing pyridinium p-toluenesulfonate to obtain the compound II.
Preferably, step (a) is preceded by the step of preparing a compound of formula I by the method of claim 1.
In another preferred embodiment, the step (a) includes the steps of: the compound I is reacted in a reaction system containing sodium bicarbonate, sodium bromide, 2, 6-tetramethyl piperidine oxide and trichloroisocyanuric acid at 0-10 ℃.
Process for the preparation of compounds of formula III
The application also discloses a preparation method of the compound shown in the formula III, which specifically comprises the following steps:
(A) The compound II and the compound III-1 react under the action of a condensing agent to obtain a compound III-2, wherein the condensing agent is selected from one or more of 1, 8-diazabicyclo [5.4.0] -7-undecene, sodium methoxide, sodium ethoxide and sodium tert-butoxide;
(B) Adding organic acid into a reaction system containing the compound III-2, and reacting to obtain a compound III-3, wherein the organic acid is one or more selected from methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid and p-toluenesulfonic acid;
(C) Condensing the compound III-3 and the compound III-4 under the condition of an acid binding agent, and further refining after the reaction is finished to obtain an isomerically pure compound III-5, wherein the acid binding agent is one or more selected from triethylamine, diisopropylethylamine and pyridine;
(D) Removing the furoyl group of the compound III-5 under the action of 1, 8-diazabicyclo [5.4.0] -7-undecene to obtain the compound III.
Preferably, prior to said step (a), said method further comprises the step of preparing a compound of formula II by said method of claim 8.
Preferably, the isomer purity of the compound III obtained in the present application is not less than 99.0%.
The application is further described below in conjunction with the specific embodiments. It is to be understood that these examples are illustrative of the present application and are not intended to limit the scope of the present application. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
Example 1
Preparation of Compounds of formula I
To 27.5g (0.10 mol) of I-1, 120mL of 95% ethanol and 11.5g (0.14 mol) of sodium acetate are sequentially added, the temperature is raised to 55-60 ℃ for reaction for 7 hours, the reaction is carried out on the reaction spot plate, and the raw materials are basically reacted completely; then cooling to-5 ℃, dropwise adding 4.8g (0.12 mol) of sodium hydroxide aqueous solution (sodium hydroxide is dissolved in 30mL of water) for 10-20 min, and continuing to react for 1.5 hours at-5 ℃ after the dropwise adding is finished; after the reaction is finished, 5mL of acetic acid is added, and then the reaction solution is concentrated to remove ethanol; extracting the aqueous phase twice by adding 40mL of ethyl acetate, combining the organic phases, and washing once by adding 20mL of water; finally, the ethyl acetate is removed by decompression concentration to obtain 18.2g of oily compound I with the purity of 96.4 percent and the yield of 85.8 percent.
Example 2
Preparation of Compounds of formula II-1
21.2g (0.10 mol) of compound I, 30.03g (0.30 mol) of sodium bicarbonate, 3.32g (0.02 mol) of sodium bromide and 0.31g (0.002 mol) of 2, 6-tetramethylpiperidine oxide (TEMPO) are weighed, 220mL of acetone and 80mL of water are then added, the temperature is reduced to 0-10 ℃, 22.27g (0.096 mol) of trichloroisocyanuric acid (TCCA) in acetone solution (dissolved by 80mL of acetone) is added dropwise, the mixture is reacted for 1.5h at 0-10 ℃ after the dropwise addition, and the raw materials are basically reacted completely. 14mL of methanol is added into the reaction solution, after stirring for 0.5h, 10.96g of sodium bisulphite is added, and stirring is carried out for 0.5h; filtering, concentrating the filtrate at 35 deg.C under reduced pressure until no obvious fraction flows out; adjusting pH to about 9 with sodium hydroxide, precipitating solid, adding 80mL of ethyl acetate, filtering, separating filtrate, collecting water phase, washing the water phase twice with 55mL of ethyl acetate+27 mL, combining the water phase, cooling to 0-10 ℃, adjusting pH to 2-3 with concentrated hydrochloric acid, filtering to obtain 21.09g of yellow solid, namely compound II-1, wherein the purity is 97.6%, and the yield is 91.0%.
Example 3
Preparation of Compounds of formula II-2
800mL of acetone was added to compound II-1 (91.75 g,0.41 mol) at room temperature, potassium carbonate (36.51 g,0.26 mol) was added, and stirred, dimethyl sulfate (58.91 g,0.47 mmol) was added dropwise, and the reaction was continued at room temperature until the starting material completely disappeared. The PH value of the hydrochloric acid is adjusted to 3-4, the hydrochloric acid is concentrated, acetone is removed, then ethyl acetate is used for extraction once, the aqueous phase is extracted by ethyl acetate after liquid separation, and organic phases are combined and concentrated to obtain oily matters which are directly used for the next reaction.
Example 4
Preparation of Compounds of formula II
300mLN, N-dimethylacetamide was added to the concentrate II-2 prepared in example 3 at room temperature, pyridinium p-toluenesulfonate (265.42 g,1.06 mol) was then added, the reaction system was heated to 60℃and then a solution of t-butyl carbazate (69.80 g,0.53 mmol) in N, N-dimethylacetamide (200 mL) was slowly added to the upper reaction mixture, after which the mixture was stirred at room temperature for 1 hour with heat preservation, and then room temperature was reached. Water and ethyl acetate were added, extraction was performed, and after separation, the organic phase was concentrated. 100mL of ethanol and 600mL of water are added to the concentrate for pulping, stirring is carried out for 1 hour, suction filtration and vacuum drying are carried out, 124.2g of compound II is obtained, the purity is 95.4%, and the yield is 86.3%.
Example 5
Preparation of Compounds of formula III-2
To 40ml of HF was added compound II (10.3 g,0.07 mol) and 1, 8-diazabicyclo [5.4.0] -7-undecene (8.9 g,0.058 mol) at room temperature, and to the solution was added compound III-1 (18.93 g,0.053 mol) and the solution was stirred for dissolution. The reaction system is heated to 60 ℃, and the temperature is kept and the reaction system is stirred until the substrate conversion is completed. The system is cooled to room temperature, water and acetic acid are added, and the PH is adjusted to 5 to 6. Then extracted with ethyl acetate, the organic phases were combined and concentrated to an oil. Methyl tert-butyl ether was added to the oil, stirred, solid precipitated and filtered to give 22.0g of pale yellow to off-white solid compound III-2, 92.1% pure, 87.4% yield.
Example 6
Preparation of Compounds of formula III-3
Compound III-2 (19.19 g,0.041 mol) was added to a mixed system of 170mL of acetonitrile and 30mL of water, stirred, then the reaction system was warmed to 60℃and methanesulfonic acid (11.70 g,0.12 mol) was slowly added dropwise, and the mixture was stirred at a constant temperature for 3 to 5 hours, followed by completion of the reaction. The system was cooled to room temperature, the pH was adjusted to 6 to 7 with 30% aqueous sodium hydroxide solution, acetonitrile in the reaction system was concentrated, the residue was stirred in water, the resulting yellow precipitate was collected by filtration, and 10.2g of Compound III-3 as yellow crystals was obtained after drying, purity was 94.1%, yield was 85.7%.
Example 7
Preparation of Compounds of formula III-5
Into the reaction flask were charged compound III-3 (9.4 g,0.03 mol), 80mLN, N-dimethylformamide and triethylamine (8.0 g,0.08 mol), and compound III-4 (5.38 g,0.04 mol) was added dropwise with the internal temperature controlled to be lower than 15 ℃. After the dripping is finished, stirring for 2 to 3 hours at room temperature, and finishing the reaction. Adding 80mL of dichloromethane, cooling, adding water, stirring, separating liquid, concentrating an organic phase, adding 50mL of ethyl acetate into the concentrate, stirring for 0.5h at 60-65 ℃, further cooling to 0-5 ℃, stirring for 0.5h, carrying out suction filtration, refining a filter cake by using 30mL of ethyl acetate again, carrying out suction filtration, and carrying out vacuum drying to obtain 5.8g of compound III-5, wherein the purity is 99.3%, and the yield is 47.1%.
Example 8
Preparation of Compounds of formula III
Compound III-5 (14.56 g,0.036 mol) was added to 120mL of ethyl acetate, and after stirring and dissolution, 1, 8-diazabicyclo [5.4.0] -7-undecene (DBU) (5.3 g,0.035 mol) was added, the reaction mixture was heated to 30℃and stirred for 1 hour with heat preservation, further cooled to 0-5℃and stirred for 0.5h, filtered and dried to give 10.76g of compound III as a white solid with a purity of 99.1% and a yield of 97.3%.
Comparative example 1
Compound I-1 (2.75 g,0.01 mol) was dissolved in a mixed solution of acetonitrile (55 mL) and water (55 mL), followed by addition of calcium carbonate (2.00 g,0.02 mol), and the reaction was stirred under reflux for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, ethyl acetate (50 ml×2) was added to extract twice, the organic phases were combined, washed once with saturated brine (20 mL), and then concentrated under reduced pressure to remove ethyl acetate to give 1.04g of compound I as an oil, yield 48.9%.
Comparative example 2
Compound I-1 (2.75 g,0.01 mol) was dissolved in a mixed solution of acetonitrile (55 mL) and water (55 mL), followed by addition of sodium bicarbonate (3.36 g,0.04 mol), and the reaction was stirred at room temperature for 24h, and HPLC showed 82.7% starting material in the reaction solution. After 12h of further reaction, ethyl acetate (50 mL x 2) was added to extract twice, the organic phases were combined, washed once with saturated brine (20 mL), and then concentrated under reduced pressure to remove ethyl acetate to give 0.33g of compound I as an oil in 15.7% yield.
Comparative example 3
Compound I-1 (2.75 g,0.01 mol) was dissolved in a mixed solution of acetonitrile (55 mL) and water (55 mL), then sodium bicarbonate (3.36 g,0.04 mol) was added, the reaction was stirred for 24h under reflux, TLC showed many impurities, after which the mixture was cooled to room temperature, extracted twice with ethyl acetate (50 mL. Times.2), the organic phases were combined, washed once with saturated brine (20 mL), and then concentrated under reduced pressure to remove ethyl acetate to give 0.85g of oil as Compound I in 40.1% yield.
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.
Claims (10)
1. A process for preparing 2-hydroxyethyl-3-pentoxy-4-pyrone (a compound of formula I), comprising the steps of:
(1) Adding alkali metal acetate into an organic solvent system containing a compound I-1, and reacting to obtain a mixed system A containing a compound I-2; and
(2) Adding alkali into the mixed system A, and reacting to obtain the compound I.
2. The method of claim 1, wherein in step (1), the alkali metal acetate is selected from the group consisting of: sodium acetate, potassium acetate, lithium acetate, or combinations thereof, preferably sodium acetate and potassium acetate.
3. The method of claim 1, wherein in step (1), the organic solvent is selected from C1-C6 alcohol solvents, preferably methanol, ethanol, isopropanol, or a combination thereof, more preferably ethanol.
4. The process of claim 1, wherein in step (1), the reaction temperature is 40 to 80 ℃.
5. The method of claim 1, wherein in step (2), the base is selected from the group consisting of: sodium hydroxide, potassium hydroxide, sodium ethoxide, potassium ethoxide, or a combination thereof, preferably sodium hydroxide.
6. The process of claim 1, wherein in step (2), the reaction temperature is from-10 to 30 ℃.
7. The method of claim 1, wherein in step (2), the reaction is completed further comprising one or more post-treatment steps selected from the group consisting of: adding acid to neutralize, removing organic solvent in the reaction liquid, extracting, separating liquid and concentrating.
8. A process for the preparation of a balo Sha Wei intermediate compound of formula II, comprising the steps of:
(a) The compound I reacts under the action of an oxidant to obtain a compound II-1;
(b) Reacting the compound II-1 with dimethyl sulfate under alkaline conditions to obtain a compound II-2;
(c) The compound II-2 reacts with tert-butyl hydrazinoformate in a system containing pyridinium p-toluenesulfonate to obtain a compound II; and is also provided with
Prior to said step (a), further comprising the step of preparing a compound of formula I by said method of claim 1.
9. The method of claim 8, wherein the step (a) comprises the steps of: the compound I is reacted in a reaction system containing sodium bicarbonate, sodium bromide, 2, 6-tetramethyl piperidine oxide and trichloroisocyanuric acid at 0-10 ℃.
10. A process for the preparation of a compound of formula III, comprising the steps of:
(A) The compound II and the compound III-1 react under the action of a condensing agent to obtain a compound III-2, wherein the condensing agent is selected from one or more of 1, 8-diazabicyclo [5.4.0] -7-undecene, sodium methoxide, sodium ethoxide and sodium tert-butoxide;
(B) Adding organic acid into a reaction system containing the compound III-2, and reacting to obtain a compound III-3, wherein the organic acid is one or more selected from methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid and p-toluenesulfonic acid;
(C) Condensing the compound III-3 and the compound III-4 under the condition of an acid binding agent, and further refining after the reaction is finished to obtain an isomerically pure compound III-5, wherein the acid binding agent is one or more selected from triethylamine, diisopropylethylamine and pyridine;
(D) Removing a furoyl group of the compound III-5 under the action of 1, 8-diazabicyclo [5.4.0] -7-undecene to obtain the compound III; and is also provided with
Prior to said step (a), further comprising the step of preparing a compound of formula II by said method of claim 8.
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