CN114891025B - Preparation method of selenium-containing anti-influenza medicine - Google Patents
Preparation method of selenium-containing anti-influenza medicine Download PDFInfo
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- CN114891025B CN114891025B CN202210226404.7A CN202210226404A CN114891025B CN 114891025 B CN114891025 B CN 114891025B CN 202210226404 A CN202210226404 A CN 202210226404A CN 114891025 B CN114891025 B CN 114891025B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 206010022000 influenza Diseases 0.000 title abstract description 23
- 239000003814 drug Substances 0.000 title abstract description 17
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 title abstract description 13
- 229910052711 selenium Inorganic materials 0.000 title abstract description 13
- 239000011669 selenium Substances 0.000 title abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 19
- 230000008878 coupling Effects 0.000 claims abstract description 15
- 238000010168 coupling process Methods 0.000 claims abstract description 15
- 238000005859 coupling reaction Methods 0.000 claims abstract description 15
- GCKJFGIZAUKCIU-UHFFFAOYSA-N pyrido[3,2-d]triazine-4,6-dione Chemical class O=C1C=CC2=NN=NC(=O)C2=N1 GCKJFGIZAUKCIU-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 239000012445 acidic reagent Substances 0.000 claims description 20
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 19
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 17
- -1 alkyl phosphoric anhydride Chemical compound 0.000 claims description 15
- 230000008569 process Effects 0.000 claims description 14
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical group O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 14
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- MLFHJEHSLIIPHL-UHFFFAOYSA-N isoamyl acetate Chemical compound CC(C)CCOC(C)=O MLFHJEHSLIIPHL-UHFFFAOYSA-N 0.000 claims description 10
- PGMYKACGEOXYJE-UHFFFAOYSA-N pentyl acetate Chemical compound CCCCCOC(C)=O PGMYKACGEOXYJE-UHFFFAOYSA-N 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 8
- NJTZSWLQBQJUHK-UHFFFAOYSA-N CCCP(=O)=O Chemical group CCCP(=O)=O NJTZSWLQBQJUHK-UHFFFAOYSA-N 0.000 claims description 7
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 6
- 229940098779 methanesulfonic acid Drugs 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
- QLNYTCSELYEEPV-UHFFFAOYSA-N 2,2-dimethylpropyl acetate Chemical compound CC(=O)OCC(C)(C)C QLNYTCSELYEEPV-UHFFFAOYSA-N 0.000 claims description 5
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- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 5
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- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 claims description 5
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 claims description 5
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
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- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000012544 monitoring process Methods 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
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- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 claims description 3
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 3
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- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
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- 125000005843 halogen group Chemical group 0.000 claims description 2
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- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- 238000005352 clarification Methods 0.000 claims 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
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- 238000001308 synthesis method Methods 0.000 abstract 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 241000712461 unidentified influenza virus Species 0.000 description 7
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- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 5
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
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- 239000001530 fumaric acid Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000008039 phosphoramides Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to biological medicineThe field of preparation of selenium-containing anti-influenza medicine. The structure of the anti-influenza drug is shown as a formula (I), and the synthesis method comprises the following steps: the pyridotriazine dione derivative shown in the formula (II) and the dihydrodibenzoseleno flat derivative shown in the formula (III) selectively generate the compound shown in the formula (I) in the presence of a coupling reagent. The compound shown in the formula (I) can be used for treating influenza or preparing other medicaments for treating influenza.
Description
Technical Field
The invention relates to the field of biological medicine, in particular to a preparation method of a selenium-containing anti-influenza medicine.
Background
Influenza viruses belong to the Orthomyxoviridae (Orthomyxoviridae), which are enveloped viruses that contain a single-stranded negative-sense RNA genome. Over the past few decades, two general classes of therapies have been available for the treatment of influenza viruses: m2 ion channel inhibitors and neuraminidase inhibitors. However, influenza viruses not only exhibit broad resistance to M2 ion channel inhibitors, but also continue to develop antiviral resistance to neuraminidase inhibitors.
Cap dependent endonuclease inhibitors inhibit transcription of mRNA of influenza virus by controlling key links of replication of influenza virus and inhibiting virus from obtaining Cap structure of 5' end of host mRNA from host cells, thereby achieving effect of treating influenza. Furthermore, the Cap dependent endonuclease inhibitors do not affect the host cell because proteases of similar mechanisms are not present in the host cell. In 2018, the first cap-dependent endonuclease (CEN) inhibitor, balo Sha Weizhi (baloxavir marboxil) (trade name: xofluza)) was approved in the united states and japan for the treatment of influenza a and B. On month 29 of 2021, balo Sha Weizhi was approved for marketing in china by NMPA, indicated for the treatment of influenza patients 12 years old and older, including those at high risk of influenza complications. The prodrug balofluo Sha Weizhi is metabolically converted in vivo to the active ingredient balofluo Sha Wei. Balo Sha Wei inhibits the acid (PA) protein endonuclease of influenza virus polymerase, thus inhibiting the synthesis of viral RNA and effectively inhibiting influenza virus replication.
The patent CN109311911A of salt field company discloses a preparation method of balo Sha Wei, which has the following reaction route:
intermediate 13 was prepared by converting substituents (87.2% yield), coupling (84.6% yield), and deprotection (90.7% yield) to afford the balo Sha Wei of formula V. The above process has long reaction route and complicated operation, and the total yield of the balo Sha Wei shown in the formula V obtained from the intermediate 13 is only about 65%.
A novel selenium-containing anti-influenza drug is provided in the publication WO2021007506A1 as a Cap-dependent endonuclease inhibitor, which can be used to treat influenza, shows excellent bioactivity and pharmacokinetic properties including good oral bioavailability, and is not affected by feeding. When the selenium-containing anti-influenza drug was prepared using a method similar to that in CN109311911a, the reaction route was as follows:
intermediate 11-R is subjected to procedures of substituent conversion (yield is 78.2%), coupling (yield is 32.6%), deprotection (yield is 86.3%) and the like to obtain the selenium-containing anti-influenza drug shown in the formula B-1. Starting from the intermediate 11-R, the selenium-containing anti-influenza drug shown in B-1 is obtained through three steps of reactions, and the total yield is only 22%.
Finally, new preparation methods are required to be developed for selenium-containing anti-influenza drugs.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of a selenium-containing anti-influenza drug, which has the advantages of simple process route, good selectivity and high total yield and is suitable for industrial production. Specifically, the method can selectively generate the selenium-containing anti-influenza drug by a one-step coupling procedure without the procedures of converting substituent groups and removing protective groups, simplifies the reaction route, greatly improves the yield, and is very suitable for industrial production.
The selenium-containing anti-influenza drug is shown as a formula (I), and the compound shown as the formula (I) can be used for treating influenza or preparing other drugs for treating influenza, and the structure of the selenium-containing anti-influenza drug is shown as follows:
wherein R is 1 、R 2 、R 3 And R is 4 Each independently selected from hydrogen or halogen; preferably, R 1 、R 2 、R 3 And R is 4 One or both of which are halogen.
A process for the preparation of a compound of formula (I), the synthesis comprising: the pyridotriazine dione derivative shown in the formula (II) and the dihydrodibenzoseleno flat derivative shown in the formula (III) generate a compound shown in the formula (I) in the presence of a coupling reagent, and the reaction route is shown as follows:
wherein R is 1 、R 2 、R 3 And R is 4 Each independently selected from hydrogen or halogen; preferably, R 1 、R 2 、R 3 And R is 4 One or both of which are halogen; more preferably, R 1 And R is 2 Is hydrogen, R 3 And R is 4 Is fluorine;
p is a hydroxyl protecting group; preferably, the hydroxyl protecting group is benzyl (Bn), substituted benzyl, carbobenzoxy (Cbz), triphenylmethyl, t-butyldimethylsilyl (TBDMS), trimethylsilyl (TMS), t-butyldiphenylsilyl (TBDPS), triethylsilyl (TES), triisopropylsilyl (DIPS), 2- (trisilyl) ethoxymethyl, dihydropyranyl, bromopropenyl, ethylformyl, acetyl or benzoyl, and the like; more preferably, the hydroxyl protecting group is benzyl (Bn), or benzyl substituted on the benzene ring of benzyl with 1-2 methyl, methoxy, or halogen. The method comprises the steps of carrying out a first treatment on the surface of the
The coupling reagent is a phosphoric anhydride reagent, wherein the phosphoric anhydride reagent comprises alkyl phosphoric anhydrides and aryl phosphoric anhydrides, wherein the alkyl phosphoric anhydrides are as follows: propylphosphoric anhydride (T3P), ethylmethyl phosphinic anhydride (EMPA); aryl phosphoric anhydrides, such as: phenylphosphonic anhydride; the coupling reagent may also be other phosphates and phosphoramides condensing agents, such as: diphenylphosphoryl chloride (DPP-Cl), diethyl cyanophosphate (DECP), diphenyl azide phosphate (DPPA), thiodimethylphosphoryl azide (MPTA), bis (2-oxo-3-oxazolidinyl) phosphoryl chloride (BOP-Cl). Preferably, the phosphoric anhydride reagent is an alkyl phosphoric anhydride reagent, more preferably propyl phosphoric anhydride (T3P).
In some embodiments, the preparation method of the present invention further comprises the steps of:
step 1: dissolving a compound of the formula (II) and a compound of the formula (III) in an organic solvent 1 at room temperature (15-35 ℃), cooling the reaction solution to-10 ℃, dropwise adding an acidic reagent 1, and heating the reaction solution to room temperature until the reaction solution becomes turbid after the dropwise addition is finished;
step 2: dropwise adding a coupling reagent solution and an acidic reagent 2 into the turbid solution obtained in the step 1, heating to 40-100 ℃, and continuing to react for 12-48 hours;
step 3: after monitoring the completion of the reaction, a post-treatment is carried out to obtain the compound of formula (I).
In alternative embodiments, the organic solvent 1 described in step 1 is selected from one or more of lower alkane solvents, halogenated lower alkane solvents, ether solvents, nitrile solvents, ketone solvents, ester solvents, amide solvents, or sulfoxide solvents; preferably selected from the group consisting of ester solvents; more preferably, the ester solvent is selected from one or more of methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, n-pentyl acetate, isopentyl acetate and neopentyl acetate.
In alternative embodiments, the acidic reagent 1 described in step 1 and the acidic reagent 2 described in step 2, which are the same or different, are inorganic or organic acids; preferably, the mineral acid is selected from hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, and the like; preferably, the organic acid is formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, and the like; more preferably, the acidic reagent 1 and the acidic reagent 2 are the same or different and are respectively selected from one or more of benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid and ethanesulfonic acid. Most preferably, acidic reagent 1 is trifluoromethanesulfonic acid and acidic reagent 2 is methanesulfonic acid.
In alternative embodiments, the coupling reagent solution is produced from propyl phosphoric anhydride (T3P) dissolved in an ester solvent selected from one or more of methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, n-pentyl acetate, isopentyl acetate, and neopentyl acetate.
In an alternative embodiment, the coupling reagent itself is in a liquid state, or may be insoluble in other solvents and directly added dropwise to the reaction system.
In alternative embodiments, the molar equivalent ratio of the compound of formula (II) to the compound of formula (III) is from 1:1 to 1:1.5, more preferably from 1:1 to 1:1.2.
In alternative embodiments, the molar equivalent ratio of the compound of formula (II) to the acidic reagent 1 is from 1:1 to 1:2, more preferably from 1:1 to 1:1.5.
In alternative embodiments, the molar equivalent ratio of the compound of formula (II) to the acidic reagent 2 is from 1:1 to 1:5, more preferably from 1:2 to 1:5.
The beneficial effects of the invention are that
1. The process route is short (one-step method), the repeated protection and removal of the protecting group are avoided, the condition is mild, and the total yield is high; the ten-gram-grade process is stable and suitable for industrial production.
2. The invention has high process selection, can effectively reduce the generation of the enantiomer of the compound of the formula (I), the structure of the enantiomer of the compound of the formula (I) is shown as the formula (I-A), and when the reaction is completed, the content of the formula (I-A) in the reaction liquid is lower than 5 percent, R 1 、R 2 、R 3 And R is 4 The definition of (a) is as described in formula (I).
Drawings
FIG. 1 is a graph showing the results of HPLC detection of the reaction solution at the completion of the reaction in example 1 of the present invention.
FIG. 2 is a graph showing the results of HPLC detection of the final product of example 1 of the present invention.
FIG. 3 is a graph showing the results of HPLC detection of the reaction solution at the completion of the reaction in example 2 of the present invention.
FIG. 4 is a graph showing the results of HPLC detection of the final product of example 2 of the present invention.
Detailed Description
The following examples are illustrative and are intended to be illustrative of the invention and are not to be construed as limiting the invention. Meanwhile, some terms appearing herein are explained and illustrated for convenience of understanding only to those skilled in the art, and should not be construed as limiting the scope of the present invention.
Reference to "halogen" means fluorine, chlorine, bromine or iodine.
Reference to a "hydroxy protecting group" refers to the functionality that a substituent of a hydroxy group serves to block or protect the hydroxy group, and suitable protecting groups include, but are not limited to, benzyl (Bn), substituted benzyl, benzyloxycarbonyl (Cbz), triphenylmethyl, t-butyldimethylsilyl (TBDMS), trimethylsilyl (TMS), t-butyldiphenylsilyl (TBDPS), triethylsilyl (TES), triisopropylsilyl (DIPS), 2- (trisilyl) ethoxymethyl, dihydropyranyl, bromopropenyl, ethylformyl, acetyl or benzoyl, and the like.
Reference to "substituted benzyl" or "substituted benzyl" means that the phenyl ring of the benzyl group is substituted with one or more methyl, methoxy, or halogen; benzyl substituted on the benzene ring with 1-2 methyl groups, methoxy groups, or halogen groups; including but not limited to p-methoxybenzyl and 2, 4-dimethoxybenzyl.
The "organic solvent" mentioned may be selected from one or more of lower alkane solvents, halogenated lower alkane solvents, ether solvents, nitrile solvents, ketone solvents, ester solvents, amide solvents or sulfoxide solvents; the lower alkane solvent can be selected from cyclohexane, n-hexane, n-heptane, n-pentane, isopentane, petroleum ether, isooctane, cyclopentane and the like; the halogenated lower alkane solvent can be selected from dichloromethane or chloroform; the ether solvent can be selected from tetrahydrofuran, dioxane, isopropyl ether or methyl tertiary butyl ether; the nitrile solvent can be selected from acetonitrile or propionitrile; the ketone solvent can be selected from acetone, methyl ethyl ketone or butanone; the ester solvent can be selected from methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, n-pentyl acetate, isopentyl acetate or neopentyl acetate; the amide-based solvent may be selected from N, N-Dimethylformamide (DMF) or N-methylpyrrolidone (NMP); the sulfoxide solvent is selected from dimethyl sulfoxide (DMSO).
In describing the results of HPLC, specific values are given for retention time. However, it will be appreciated by those skilled in the art that the specific values of these retention times are merely references and that the retention time values may fluctuate during the actual detection. This change in retention time is reflected when the retention time is denoted by "about".
Example 1
At room temperature, the compound of formula (II) (20.0 g,61 mmol) and the compound of formula (III) (21.1 g,67 mmol) were dissolved in 140mL of n-butyl acetate (BuOAc), after complete dissolution, the reaction system was cooled to 0-10℃and trifluoromethanesulfonic acid (TfOH, 9.2g,61 mmol) was slowly added dropwise, and after completion of the dropwise addition, the temperature was raised to room temperature to give a suspension. Continuously dripping 38.9g of ethyl acetate solution of propyl phosphoric anhydride (T3P) with the weight ratio of 50 percent into the reaction solution, wherein the content of T3P is 19.45g (61 mmol); methanesulfonic acid (17.6 g,183 mmol) was added dropwise, and after completion of the addition, the reaction system was warmed to 60℃to continue the reaction. At 23 hours after the reaction, HPLC monitoring was performed, wherein the content of the compound of formula (II) was 4.99%, the content of the compound of formula (I) was 76.62%, and the content of the compound of formula (I-A) was 3.23%, and the specific analysis results were shown in FIG. 1. After the reaction was completed, the mixture was cooled to room temperature. Filtering to obtain a filter cake, washing with BuOAc, dissolving the filter cake in acetonitrile with 4 times of volume, dripping methyl tert-butyl ether (MTBE) until all solids are separated out, filtering, washing with MTBE and water, drying to obtain the compound shown as the formula (I), wherein the yield is 64.9%, the purity is 98.56%, and the content of the compound shown as the formula (I-A) is 0.42%. The specific analysis results are shown in figure 2.
Structural identification of formula (I): 1 H NMR(300MHz,DMSO)δ11.80(s,1H),7.45–7.28(m,2H),7.24 (d,J＝7.0Hz,1H),7.17(d,J＝7.7Hz,1H),7.14–7.02(m,2H),6.90(dd,J＝10.7,4.1Hz,1H),5.80(s,1H),5.55(d,J＝7.7Hz,1H),5.29(dd,J＝12.7,2.2Hz,1H),4.59(dd,J＝9.9,2.9Hz, 1H),4.43(d,J＝12.1Hz,1H),4.19–3.94(m,2H),3.66(t,J＝10.6Hz,2H),3.43(dd,J＝11.6,9.3Hz,1H),3.15–2.97(m,1H).
MS experiment value 532 ([ M+H)] + )。
Example 2
The compound of formula (II) (2.0 kg,1.0 eq) and the compound of formula (III) (2.1 kg,1.1 eq) were dissolved in 14L of n-butyl acetate (BuOAc) at room temperature, after complete dissolution, the reaction system was cooled to 0-10℃and trifluoromethanesulfonic acid (TfOH, 918g,1.0 eq) was slowly added dropwise, and after completion of the addition, the mixture was warmed to room temperature to give a suspension. Continuously dripping 97.4g of ethyl acetate solution of propyl phosphoric anhydride (T3P) with the weight ratio of 50 percent into the reaction solution, wherein the T3P content is 3895g (1.0 eq); methanesulfonic acid (1764 g,3.0 eq) was added dropwise, and after the completion of the addition, the reaction system was warmed to 55-60 ℃ and the reaction was continued. At 38 hours of the reaction, HPLC monitoring was performed, wherein the compound of formula (II) was 4.25%, the compound of formula (I) was 78.80%, and the compound of formula (I-A) was 3.35%, and the specific analysis results are shown in FIG. 3. After the completion of the reaction, the compound of formula (I) was obtained in a yield of 66.0% and a purity of 99.68% by a method similar to that of example 1, wherein the content of formula (I-A) was 0.27%. The specific analysis results are shown in figure 4.
Claims (16)
1. A process for the preparation of a compound of formula (I) comprising: the pyridotriazine dione derivative shown in the formula (II) and the dihydrodibenzoseleno flat derivative shown in the formula (III) generate a compound shown in the formula (I) in the presence of a coupling reagent, and the reaction route is shown as follows:
wherein R is 1 、R 2 、R 3 And R is 4 Each independently selected from hydrogen or halogen; p is a hydroxyl protecting group;
the coupling reagent is a phosphoric anhydride reagent, and the phosphoric anhydride reagent is alkyl phosphoric anhydride; and is also provided with
The preparation method further comprises the following steps:
step 1: dissolving a compound of the formula (II) and a compound of the formula (III) in an organic solvent 1 at 15-35 ℃, cooling the reaction liquid to-10 ℃, dropwise adding an acidic reagent 1, and heating the reaction liquid to 15-35 ℃ until the reaction liquid becomes turbid from clarification;
step 2: dropwise adding a coupling reagent solution and an acidic reagent 2 into the turbid solution obtained in the step 1, heating to 40-100 ℃, and continuing to react for 12-48 hours;
step 3: after monitoring the completion of the reaction, carrying out post-treatment to obtain the compound of the formula (I),
wherein the hydroxyl protecting group is selected from benzyl, substituted benzyl, benzyloxycarbonyl, triphenylmethyl, tert-butyldimethylsilyl, trimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl, triisopropylsilyl, 2- (trisilyl) ethoxymethyl, dihydropyranyl or bromopropenyl, and the substituted benzyl is benzyl substituted with 1-2 methyl, methoxy, or halogen on the benzene ring of the benzyl.
2. The method of claim 1, wherein the phosphoric anhydride reagent is propyl phosphoric anhydride.
3. The method of claim 1, wherein R is 1 、R 2 、R 3 And R is 4 One or both of which are halogen.
4. The process of claim 1, wherein R is 1 And R is 2 Is hydrogen, R 3 And R is 4 Is fluorine.
5. The preparation method according to claim 1, wherein the hydroxyl protecting group is a benzyl group, or a benzyl group substituted with 1 to 2 methyl groups, methoxy groups, or halogen groups on the benzene ring of the benzyl group.
6. The preparation method according to claim 1, wherein the organic solvent 1 in the step 1 is an ester solvent.
7. The method according to claim 6, wherein the ester solvent is one or more selected from the group consisting of methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, n-pentyl acetate, isopentyl acetate and neopentyl acetate.
8. The method according to claim 6, wherein the acidic reagent 1 in step 1 and the acidic reagent 2 in step 2 are the same or different and are inorganic or organic acids.
9. The method according to claim 6, wherein the acidic reagent 1 and the acidic reagent 2 are each independently selected from one or more of benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid and ethanesulfonic acid.
10. The method according to claim 6, wherein the coupling reagent solution is produced by dissolving propyl phosphoric anhydride T3P in an ester solvent selected from one or more of methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, n-pentyl acetate, isopentyl acetate, and neopentyl acetate; the coupling reagent is in a liquid state, can be insoluble in other solvents and can be directly added into a reaction system in a dropwise manner.
11. The process according to claim 6, wherein the molar equivalent ratio of the compound of formula (II) to the compound of formula (III) is from 1:1 to 1:1.5.
12. The process according to claim 6, wherein the molar equivalent ratio of the compound of formula (II) to the compound of formula (III) is from 1:1 to 1:1.2.
13. The process according to claim 6, wherein the molar equivalent ratio of the compound of formula (II) to the acidic reagent 1 is from 1:1 to 1:2.
14. The process according to claim 6, wherein the molar equivalent ratio of the compound of formula (II) to the acidic reagent 1 is from 1:1 to 1:1.5.
15. The process according to claim 6, wherein the molar equivalent ratio of the compound of formula (II) to the acidic reagent 2 is from 1:1 to 1:5.
16. The process according to claim 6, wherein the molar equivalent ratio of the compound of formula (II) to the acidic reagent 2 is from 1:2 to 1:5.
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| CN112521386A (en) * | 2019-09-19 | 2021-03-19 | 周雨恬 | Polycyclic pyridone compound with antiviral effect and pharmaceutical composition and application thereof |
| CN113226327A (en) * | 2019-07-11 | 2021-08-06 | 南京征祥医药有限公司 | Compounds useful for the treatment of influenza virus infections |
| CN113286793A (en) * | 2018-09-10 | 2021-08-20 | 共结晶制药公司 | Pyrrolopyrazine and pyridotriazine influenza virus replication inhibitors |
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| CN113286793A (en) * | 2018-09-10 | 2021-08-20 | 共结晶制药公司 | Pyrrolopyrazine and pyridotriazine influenza virus replication inhibitors |
| CN113226327A (en) * | 2019-07-11 | 2021-08-06 | 南京征祥医药有限公司 | Compounds useful for the treatment of influenza virus infections |
| CN112521386A (en) * | 2019-09-19 | 2021-03-19 | 周雨恬 | Polycyclic pyridone compound with antiviral effect and pharmaceutical composition and application thereof |
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