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CN106083745A - The synthetic method of 6 fluorine 3 hydroxyl 2 pyrazinamide - Google Patents

The synthetic method of 6 fluorine 3 hydroxyl 2 pyrazinamide Download PDF

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CN106083745A
CN106083745A CN201610666191.4A CN201610666191A CN106083745A CN 106083745 A CN106083745 A CN 106083745A CN 201610666191 A CN201610666191 A CN 201610666191A CN 106083745 A CN106083745 A CN 106083745A
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reaction
fluoro
synthetic method
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formula
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CN106083745B (en
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张志强
甄宜战
于阳
赵巧丽
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Shandong Bestcomm Pharmaceutical Co Ltd
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Shandong Bestcomm Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention relates to the synthetic method of a kind of compound 6 fluorine 3 hydroxyl 2 pyrazinamide, comprise the steps: to be prepared formula III compound by formula IV compound by amine ester exchange, being prepared formula II compound by formula III compound by fluoro-reaction, reaction equation is； Wherein: substituent R is C1‑4Alkoxyl, X, Y are Cl or Br, substituent X, and Y can be identical or differ.The preparation method that the present invention synthesizes required initiation material 6 bromine (chlorine) 3 Aminopyrazine formic acid esters is simple, and cost is relatively low；Synthetic route is brief, and method is simple, only needs four-step reaction to can be prepared by critical product；Each step reaction condition is the gentleest, it is to avoid uses severe corrosive, highly toxic reagent, reduces the pollution to environment.

Description

The synthetic method of QD-Z0212
Technical field
The invention belongs to medicinal chemistry art, be specifically related to the synthetic method of a kind of QD-Z0212.
Background technology
Favipiravir (Favipiravir) is a kind for the treatment of of influenza medicine, and by Japan folic hill, chemical industrial company develops, and makees Sale is manufactured in Japan for novel antiviral drug is granted in 2014.They are different from a lot of Tamiflu mechanism of action, oseltamivir phosphate capsule It is that the virus bred by prevention gets into that cell is external prevents infection from increasing the weight of Deng medicine, and Favipiravir is by block cell Gene replication, thus contain propagation of virus itself.Its chemical entitled QD-Z0212, chemical structural formula As follows:
At present, in prior art, the synthetic method Patents document about Favipiravir includes CN99809897.3, WO2010087117A1, CN201110316778.X, CN201210301602.1, US2013245264A1,13th International Electronic Conference on Synthetic Organic Chemistry, Nov.1-30, 2009, Chinese Journal of Pharmaceuticals 2013, these existing patent documentations such as 44 (9), 841-843 disclose multiple Favipiravir Synthetic method and technique, be specifically expressed as follows:
Synthetic route 1(CN99809897.3, WO0010569)
Compound patent CN99809897.3(WO0010569 of Fushan Mountain chemical industrial company of Yuan Yan company) in disclose method and draw The synthetic route of Wei.With 6-bromo-3-Aminopyrazine-2-methyl formate through diazotising alcoholysis, transition metal palladium chtalyst hexichol imido Base replacement, deaminizating protection, amine ester exchange, react fluoro through the graceful reaction of seat (Balz-Schiemann Reaction), finally exist Sodium iodide and trim,ethylchlorosilane jointly act on lower demethylation and obtain Favipiravir target product.
The palladium-catalyzed reaction step Han transition metal in this synthetic route, wherein catalyst Pd2(dba)3With part (S)-(-)- Double (the diphenyl phosphine)-1,1'-dinaphthalene of 2,2'-is expensive；Xi Man reaction amino turns Euler's reagent (fluorine used in fluorine step Change pyridinium hydroxide) there is severe corrosive and toxicity, and yield is relatively low；Additionally with sodium iodide and trimethylchloro-silicane in final step reaction Alkane demethylation, reaction is difficult to control to, and yield is the lowest, ultimately causes total recovery extremely low.So, this synthetic route cost is high, can Operability is poor, easily causes environmental pollution, is unfavorable for industrialized production.
Synthetic route 2(13th International Electronic Conference on Synthetic Organic Chemistry, Nov.1-30,2009)
13rd international chemistry synthetic organic chemistry meeting article discloses with 3-hydroxyl-6-nitro pyrazine-2-Methanamide for rising Beginning raw material obtains 3,6-bis-chloro-2-cyano group pyrrole through chlorination amido link dehydration simultaneously under phosphorus oxychloride/pyridine reaction system Piperazine intermediate product, this intermediate product through fluoro-reaction, cyan-hydrolysis, obtains method finally by the hydrolysis of selectivity fluorine atom again Draw Wei target product.
In the process of the test repeating this route, finding intermediate 3, the chloro-2 cyano pyrazine of 6-bis-has strong sensitization Effect, easily causes serious injury to experimenter, and another intermediate 3 easily rises in 6-bis-fluoro-2 cyano pyrazine last handling process China, character is unstable and has strong sensitization equally, there is greater risk in synthesis amplification process.
Synthetic route 3 (WO2010087117A1)
World patent WO2010087117A1 discloses with 3-HYDROXYPYRAZINE-2-Methanamide for initiation material by first passing through bromine In generation, obtains 6-bromo-3-hydroxyl-pyrazine-2-Methanamide, and then under phosphorus oxychloride/pyridine reaction system, reaction obtains 3,6-bis- Chloro-2 cyano pyrazine intermediate, this intermediate further across fluoro-reaction, cyan-hydrolysis, finally by selective hydrolysis fluorine Atom obtains Favipiravir target product.
This synthetic route and route 2 are substantially similar, and the most former nitro replaces intermediate and replaces with Bromo-intermediates, so and There is identical problem in route 2.
Synthetic route 4(CN201110316778.X)
Patent CN201110316778.X discloses with 6-bromo-3-Aminopyrazine-2-methyl formate as initiation material, passes through Boc After protection amino, it is further advanced by the step such as fluoro, de-Boc protection, diazotising hydrolysis and obtains Favipiravir target product.
In this route, amino and pyrazine ring are by p-п conjugation, increase the cloud density of pyrazine ring, it is impossible to pass through The direct substitution bromine atoms of nucleophilic substitution obtains fluoro product, after being protected by Boc on amino, although can weaken amino In frared spectra, but Boc protection amino still plays the effect of supplied for electronic, therefore can not bring it about polarity upset thus live Change para-position bromine atoms reaction site, the most still cannot obtain pyrazine fluoro by the direct nucleophilic displacement of fluorine of fluorine-containing nucleopilic reagent and produce Thing.We carry out fluoro test according to the condition of this patent route, through repeatedly attempting, the most do not obtain fluoro product, enter one Step demonstrates the possible outcome that above-mentioned theory is analyzed.
Synthetic route 5(CN201210301602.1)
Patent CN201210301602.1 discloses with 3-hydroxyl-2 pyrazine carboxylic acid for initiation material through diazotising hydrolysis, ester The route of the series reaction synthesis Favipiravirs such as change, amine ester exchange, nitrification, reduction, diazotising fluoro.
This patent route grind patent former with route 1 is similar, relates generally to Schiemann reaction amino and turns used in fluorine step Euler's reagent (hydrogen fluoride pyridine) there is severe corrosive and toxicity, and the problem that yield is relatively low；Lacking additionally, due to pyrazine ring Electronic effect, is unfavorable for that electrophilic substitution reaction occurs, thus in this route nitro substitution reaction need to use concentrated sulphuric acid/concentrated nitric acid etc. strong The harsh reaction condition such as acid highly corrosive, causes bigger difficulty to industrialized production equally.
Synthetic route 6(US2013245264A1)
Patent US2013245264A1 discloses the synthetic route of the synthesis Favipiravir of a kind of novelty, and this route uses and from the beginning closes First the method become prepares 5-amino-4-(2,2-two for initiation material by multistep reaction with ethyl diethoxyacetate Ethoxyacetyl amino) isoxazole-3-methyl formate intermediate, this intermediate obtains 5-hydroxyl isoxazole by intramolecular cyclization And [4,5-b] pyrazine-3-methyl formate, obtain further across steps such as chloro, fluoro, oxazole hydrolysis, cyan-hydrolysis Favipiravir target product.
The method synthetic route step is tediously long, fluorine in the fluoro-isoxazole of intermediate 5-also [4,5-b] pyrazine-3-methyl formate Atom active is higher, is the most again hydrolyzed into hydroxyl in hydrolytic process, causes process overall yields ratio relatively low.
Summary of the invention
It is an object of the invention to overcome above-mentioned deficiency present in prior art, it is provided that the formula I compound of a kind of novelty The synthetic method of QD-Z0212.
Embodiment of the present invention is as follows:
The synthetic method of the fluoro-3 hydroxyl-2-pyrazinamide of a kind of compound 6-, comprises the steps:
A () is prepared formula III compound by formula IV compound by amine ester exchange, reaction equation is；
B () is prepared formula II compound by formula III compound by fluoro-reaction, reaction equation is；
Wherein: substituent R is C1-4Alkoxyl, X, Y are Cl or Br, substituent X, and Y can be identical or differ.
Specifically substituent R can be following groups: methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutyl Epoxide or tert-butoxy, preferably R are methoxy or ethoxy；Substituent X, Y is Br the most simultaneously.
Specifically, in step (b), described fluoro-reaction, fluoro reagent is selected from tetrabutyl ammonium fluoride, potassium fluoride, fluorine Change one or more in caesium and Argentous fluoride, preferred fluorinated potassium；The mol ratio of fluoro reagent and formula III compound is (2～6): 1, preferably (3～5): 1；
In step (b), fluoro-reaction temperature is 80～150 DEG C, preferably 80～100 DEG C；
In step (b), described fluoro-reaction, for improving fluoro-reaction speed, need to add phase transfer catalyst, described phase Transfer catalyst is tetrabutyl ammonium bromide；
In step (b), described fluoro-reaction is carried out in a solvent, solvent selected from oxolane, acetonitrile, Isosorbide-5-Nitrae-dioxane, One or more in DMF, N,N-dimethylacetamide, dimethyl sulfoxide and 2-butanone, preferably N, N-bis- Methylformamide or dimethyl sulfoxide.
Further, formula II compound preparing formula I compound by hydrolysis, reaction equation is；
Specifically, described hydrolysis is carried out in the basic conditions, and alkali is selected from potassium acetate, sodium acetate, sodium bicarbonate, carbonic acid Sodium, potassium carbonate, potassium phosphate, sodium phosphate, sodium hydroxide or potassium hydroxide, preferably sodium acetate or sodium bicarbonate.
Further, above-mentioned formula IV formula (V) compound passes through Sandmeyer chloro or bromo-reaction Obtaining, reaction equation is；
Wherein: substituent X, Y is Cl or Br, can be identical or differ.
In one preferred experimental program of the present invention, the present invention prepares the following institute of method complete path of Favipiravir Show:
The present invention is relative to the advantage of existing synthetic route:
1) preparation method of initiation material 6-bromine (the chlorine)-3-Aminopyrazine formic acid esters needed for synthesis is simple, and cost is relatively low；
2) synthetic route is brief, and method is simple, only needs four-step reaction to can be prepared by critical product；
3) respectively to walk reaction condition the gentleest for the present invention, it is to avoid uses severe corrosive, highly toxic reagent, reduces the dirt to environment Dye.
Detailed description of the invention
Further illustrate the present invention below by embodiment, for a person skilled in the art, not should by under Row embodiment is interpreted as limitation of the present invention, according to the teaching of prior art, its amendment or improvement is broadly fallen into the present invention's In protection domain.
The preparation of embodiment 1:3,6-bis-bromo-2-pyrazine carboxylic acid methyl ester
In 600ml DMF, add 120g (0.52mol) 6-bromo-3-Aminopyrazine methyl formate, 181g Copper bromide (0.78mol), is stirred at room temperature mixing, drips 90.87g(0.78mol to system) amyl nitrite, drip complete, It is warming up to 65 DEG C of reactions 2～3h.React complete, be down to room temperature, add 200ml water and the extraction of 1L ethyl acetate, separatory, organic facies Successively with saturated aqueous common salt and saturated sodium bicarbonate solution washing, it is dried, decolouring, decompression distillation, obtains 150.3g brown oil Liquid, this grease petroleum ether is pulled an oar to obtain 124g off-white color solid.Productivity: 81.5%.MS:295 [M+H]
Same procedure is used to prepare following table compound:
The preparation of embodiment 2:3,6-bis-bromo-2-pyrazinamide
In 850ml methanol, add 85g (0.29mol) 3,6-bis-bromo-2-pyrazine carboxylic acid methyl ester, add 1.7L ammonia, room temperature Stirring reaction 2～3h.Filter, filter cake methanol drip washing, dry to obtain 75g faint yellow solid.Yield: 92%.MS:280 [M+H]
Same procedure is used to prepare following table compound:
The preparation method 1 of embodiment 3:3,6-bis-fluoro-2-pyrazinamide
In 50ml dimethyl sulfoxide, add 5g (17.8mmol) 3,6-bis-bromo-2-pyrazinamide, 6.2g(106.8mmol) fluorine Change potassium, 1.2g (3.56mmol) tetrabutyl ammonium bromide, be warming up to 150 DEG C of reaction 3h.React complete, be down to room temperature, add 50ml Water and the extraction of 150ml ethyl acetate, separatory, organic facies saturated aqueous common salt washs, and is dried, and decolouring is concentrated under reduced pressure to give oily Crude material, obtains the faint yellow target product of 1.2g with recrystallisation from isopropanol.Productivity: 43%.MS:160 [M+H]
The preparation method 2 of embodiment 4:3,6-bis-fluoro-2-pyrazinamide
In 80ml DMF, add 8g (41.7mmol) 3,6-bis-chloro-2-pyrazinamide, 14.3g (94.2mmol) cesium fluoride, 2.7g (8.3mmol) tetrabutyl ammonium bromide, it is warming up to 80 DEG C of reaction 6h.React complete, be down to room Temperature, adds 80ml water and the extraction of 240ml ethyl acetate, separatory, and organic facies saturated aqueous common salt washs, and is dried, and decolouring is reduced pressure dense Contracting obtains crude oil product, obtains the faint yellow target product of 2.1g with recrystallisation from isopropanol.Productivity: 32%.
The preparation method 3 of embodiment 5:3,6-bis-fluoro-2-pyrazinamide
In 100ml dimethyl sulfoxide, add the bromo-3-of 10g (42.3mmol) 6-chloro-2-pyrazinamide, 9.8g (169.2mmol) potassium fluoride, 2.7g (8.5mmol) tetrabutyl ammonium bromide, it is warming up to 100 DEG C of reaction 5h.React complete, be down to room Temperature, adds 100ml water and the extraction of 300ml ethyl acetate, separatory, and organic facies saturated aqueous common salt washs, and is dried, decolouring, decompression It is concentrated to give crude oil product, obtains the faint yellow target product of 2.7g with recrystallisation from isopropanol.Productivity: 40%.
The preparation method 4 of embodiment 6:3,6-bis-fluoro-2-pyrazinamide
In 50ml dimethyl sulfoxide, add 5g (17.8mmol) 3,6-bis-bromo-2-pyrazinamide, 18.6g(71.2mmol) four Butyl ammonium fluoride, is warming up to 120 DEG C of reaction 5h.React complete, be down to room temperature, add 50ml water and the extraction of 150ml ethyl acetate, Separatory, organic facies saturated aqueous common salt washs, and is dried, and decolouring is concentrated under reduced pressure to give crude oil product, uses recrystallisation from isopropanol Obtain the faint yellow target product of 0.8g.Productivity: 30%.
The preparation method 5 of embodiment 7:3,6-bis-fluoro-2-pyrazinamide
In 100ml dimethyl sulfoxide, add the bromo-3-of 10g (42.3mmol) 6-chloro-2-pyrazinamide, 16g (126.9mmol) Argentous fluoride, 2.7g (8.5mmol) tetrabutyl ammonium bromide, it is warming up to 100 DEG C of reaction 4h.React complete, be down to room Temperature, adds 100ml water and the extraction of 300ml ethyl acetate, separatory, and organic facies saturated aqueous common salt washs, and is dried, decolouring, decompression It is concentrated to give crude oil product, obtains the faint yellow target product of 2.8g with recrystallisation from isopropanol.Productivity: 42%.
The preparation method 1 of embodiment 8:6-fluoro-3-hydroxyl-2-pyrazinamide
The fluoro-2-pyrazinamide of 5g (31.4mmol) 3,6-bis-is added in 25ml water and 25ml 1,4-dioxane mixed solvent And 5.1g(62.8mmol) sodium acetate, it is warming up to 60 DEG C of reaction 6h.Reactant liquor is added in 50ml water, adds 2 mol/L hydrochloric acid and adjust To pH 2.5, being extracted with ethyl acetate, separatory, filter after drying, filtrate decompression is evaporated off solvent, obtains faint yellow solid product, uses Ethyl alcohol recrystallization obtains the faint yellow target product of 2.9g.Productivity: 60%.MS:158 [M+H]
1H NMR(400MHz, CDCl3), ppm:5.6～7.9 (m, 2H, NH2), 8.30(d,J=6.2 Hz,1H)
The preparation method 2 of embodiment 9:6-fluoro-3-hydroxyl-2-pyrazinamide
In 80ml water and 80ml dimethyl sulfoxide mixed solvent add the fluoro-2-pyrazinamide of 8g (50.3mmol) 3,6-bis-and 8.4g(100.6mmol) sodium bicarbonate, it is warming up to 80 DEG C of reaction 4h.Reactant liquor is added in 80ml water, adds 2 mol/L hydrochloric acid It is adjusted to pH 2.5, is extracted with ethyl acetate, separatory, filter after drying, filtrate decompression is evaporated off solvent, obtains faint yellow solid product, The faint yellow target product of 4.1g is obtained with ethyl alcohol recrystallization.Productivity: 52%.

Claims (10)

1. the synthetic method of a QD-Z0212, it is characterised in that comprise the steps:
A () is prepared formula III compound by formula IV compound by amine ester exchange, reaction equation is:
B () is prepared formula II compound by formula III compound by fluoro-reaction, reaction equation is:
Wherein: substituent R is C1-4Alkoxyl, X, Y are Cl or Br, substituent X, and Y can be identical or differ.
Synthetic method the most according to claim 1, it is characterised in that: substituent R is methoxyl group, ethyoxyl, propoxyl group, different Propoxyl group, butoxy, isobutoxy or tert-butoxy, preferably R are methoxy or ethoxy；Substituent X, Y is Br the most simultaneously.
Synthetic method the most according to claim 1, it is characterised in that: the fluoro-reaction described in step (b), fluoro reagent Selected from tetrabutyl ammonium fluoride, potassium fluoride, cesium fluoride or Argentous fluoride；The mol ratio of fluoro reagent and formula III compound be (2～ 6): 1, preferably (3～5): 1.
Synthetic method the most according to claim 1, it is characterised in that: in step (b), fluoro-reaction temperature is 80～150 DEG C, preferably 80～100 DEG C.
Synthetic method the most according to claim 1, it is characterised in that: fluoro-reaction in step (b), add phase transfer catalysis Agent, described phase transfer catalyst is tetrabutyl ammonium bromide.
Synthetic method the most according to claim 1, it is characterised in that: in step (b), described fluoro-reaction is in a solvent Carry out, solvent selected from oxolane, acetonitrile, Isosorbide-5-Nitrae-dioxane, DMF, N,N-dimethylacetamide, two One or more in first sulfoxide and 2-butanone.
Synthetic method the most according to claim 6, it is characterised in that: solvent is DMF or diformazan Asia Sulfone.
Synthetic method the most according to claim 1, it is characterised in that: prepared formula by formula II compound by hydrolysis (I) compound, reaction equation is；
。
Synthetic method the most according to claim 8, it is characterised in that: described hydrolysis is carried out in the basic conditions, Alkali is selected from potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium phosphate, sodium phosphate, sodium hydroxide or potassium hydroxide, Preferably sodium acetate or sodium bicarbonate.
Synthetic method the most according to claim 1, it is characterised in that: formula IV formula (V) compound passes through Sandmeyer reaction (Sandmeyer) chloro or bromo-reaction obtain, and reaction equation is；
Wherein: substituent X, Y is Cl or Br, can be identical or differ.
CN201610666191.4A 2016-08-15 2016-08-15 The synthetic method of 6-fluoro-3-hydroxy-2-pyrazinamide Active CN106083745B (en)

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CN106866553A (en) * 2017-03-28 2017-06-20 中南大学 A kind of synthetic method of Favipiravir
CN111592499A (en) * 2020-06-29 2020-08-28 中山奕安泰医药科技有限公司 Preparation method of Favipiravir
CN112979565A (en) * 2021-03-24 2021-06-18 阿里生物新材料（常州）有限公司 Synthetic method of 2-chloro-5- (difluoromethoxy) pyrazine
CN113072507A (en) * 2021-03-18 2021-07-06 中国科学院上海有机化学研究所 Preparation method of fluoropyrazine compound
CN113135862A (en) * 2021-04-30 2021-07-20 宁夏常晟药业有限公司 Synthetic method of 6-fluoro-3-hydroxypyrazine-2-carboxylic acid
CN114656412A (en) * 2020-12-22 2022-06-24 山东特珐曼药业有限公司 Synthesis method of Favipiravir
CN115536599A (en) * 2022-09-26 2022-12-30 合肥利夫生物科技有限公司 Preparation method of Favipiravir intermediate 3,6-difluoro-2-pyrazinecarbonitrile

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106866553A (en) * 2017-03-28 2017-06-20 中南大学 A kind of synthetic method of Favipiravir
CN111592499A (en) * 2020-06-29 2020-08-28 中山奕安泰医药科技有限公司 Preparation method of Favipiravir
CN114656412A (en) * 2020-12-22 2022-06-24 山东特珐曼药业有限公司 Synthesis method of Favipiravir
CN113072507A (en) * 2021-03-18 2021-07-06 中国科学院上海有机化学研究所 Preparation method of fluoropyrazine compound
CN112979565A (en) * 2021-03-24 2021-06-18 阿里生物新材料（常州）有限公司 Synthetic method of 2-chloro-5- (difluoromethoxy) pyrazine
CN112979565B (en) * 2021-03-24 2022-05-13 阿里生物新材料（常州）有限公司 Synthetic method of 2-chloro-5- (difluoromethoxy) pyrazine
CN113135862A (en) * 2021-04-30 2021-07-20 宁夏常晟药业有限公司 Synthetic method of 6-fluoro-3-hydroxypyrazine-2-carboxylic acid
CN115536599A (en) * 2022-09-26 2022-12-30 合肥利夫生物科技有限公司 Preparation method of Favipiravir intermediate 3,6-difluoro-2-pyrazinecarbonitrile
CN115536599B (en) * 2022-09-26 2024-06-25 合肥利夫生物科技有限公司 Preparation method of fampicin intermediate 3, 6-difluoro-2-pyrazinecarbonitrile

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