CN106083745B - The synthetic method of 6-fluoro-3-hydroxy-2-pyrazinamide - Google Patents
The synthetic method of 6-fluoro-3-hydroxy-2-pyrazinamide Download PDFInfo
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- 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
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Abstract
The present invention relates to a kind of synthetic methods of 3 hydroxyl of 6 fluorine of compound, 2 pyrazinamide, include the following steps：By formula（Ⅳ）Compound passes through amine transesterification formula（Ⅲ）Compound, by formula（Ⅲ）Compound passes through fluoro-reaction formula（Ⅱ）Compound, reaction equation are； Wherein：Substituent R is C1‑4Alkoxy, X, Y are Cl or Br, and substituent X, Y can be identical or differs.6 bromine of starting material needed for present invention synthesis（Chlorine）The preparation method of 3 Aminopyrazine formic acid esters is simple, and cost is relatively low；Synthetic route is brief, and method is simple, only four-step reaction is needed to can be prepared by critical product；Each step reaction condition is more mild, avoids, using strong corrosive, highly toxic reagent, reducing the pollution to environment.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to a kind of synthetic method of 6-fluoro-3-hydroxy-2-pyrazinamide.
Background technology
Favipiravir（Favipiravir）It is a kind for the treatment of of influenza drug, by Japan folic hill, chemical industrial company develops, and makees
It is granted in Japan's manufacture sale in 2014 for novel antiviral drug.It is different from many Tamiflu mechanism of action, Tamiflu
Equal drugs are to prevent infection from aggravating by preventing the virus of proliferation from getting into extracellularly, and Favipiravir is by block cell
Gene duplication, to contain the viral proliferation of itself.Its entitled 6-fluoro-3-hydroxy-2-pyrazinamide of chemistry, chemical structural formula
It is as follows：
Currently, include in the prior art CN99809897.3 about the synthetic method Patents documents of Favipiravir,
WO2010087117A1, CN201110316778.X, CN201210301602.1, US2013245264A1,13th
International Electronic Conference on Synthetic Organic Chemistry, Nov.1-30,
2009, Chinese Journal of Pharmaceuticals 2013,44 (9), these existing patent documents such as 841-843 disclose a variety of Favipiravirs
Synthetic method and technique, are specifically expressed as follows：
Synthetic route 1（CN99809897.3, WO0010569）
The compound patent CN99809897.3 of Fushan Mountain chemical industrial company of Yuan Yan companies（WO0010569）In disclose method
Draw Wei synthetic route.With the bromo- 3- Aminopyrazines -2- methyl formates of 6- through diazotising alcoholysis, transition metal palladium chtalyst hexichol
Imino group substitution, deamination protection, amine transesterification, through the graceful reaction of seat（Balz-Schiemann Reaction）React fluoro, most
Demethylation obtains Favipiravir target product under sodium iodide and trim,ethylchlorosilane collective effect afterwards.
The reaction step of palladium chtalyst containing transition metal in the synthetic route, wherein catalyst Pd2(dba)3With ligand (S)-(-)-
2,2'- is bis-（Diphenyl phosphine）- 1,1'- dinaphthalenes are expensive；Xi Man reaction amino turns Euler's reagent used in fluorine step（Fluorine
Change pyridinium hydroxide）With strong corrosive and toxicity, and yield is relatively low；In addition sodium iodide and trimethylchloro-silicane are used in final step reaction
Alkane demethylation, reaction are difficult to control, and yield is also very low, and it is extremely low to ultimately cause total recovery.So the synthetic route is of high cost, it 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 chemical synthetic organic chemistry meeting article is disclosed with 3- hydroxyl -6- nitro pyrazine -2- formamides
For starting material, through chlorination, amido bond is dehydrated to obtain bis- chloro- 2- cyanogen of 3,6- simultaneously under phosphorus oxychloride/pyridine reaction system
Base pyrazine intermediate product, the intermediate product hydrolyze to obtain using fluoro-reaction, cyan-hydrolysis finally by selective fluorine atom
Favipiravir target product.
During repeating the experiment of the route, it is found that intermediate 3, bis- chloro- 2 cyano pyrazines of 6- have strong sensitization
Effect, easily causes serious injury to experimenter, another intermediate 3, is easily risen in bis- fluoro- 2 cyano pyrazine last handling processes of 6-
China, property is unstable and equally has strong sensitization, and there are greater risks in synthesis amplification process.
Synthetic route 3（WO2010087117A1）
World patent WO2010087117A1 discloses to pass through as starting material using 3- hydroxypyrazine -2- formamides to be led to first
It crosses bromo and obtains the bromo- 3- hydroxyls of 6--pyrazine -2- formamides, be then obtained by the reaction 3,6- under phosphorus oxychloride/pyridine reaction system
Two chloro- 2 cyano pyrazine intermediates, the intermediate further across fluoro-reaction, cyan-hydrolysis, finally by selective hydrolysis
Fluorine atom obtains Favipiravir target product.
The synthetic route and route 2 are substantially similar, and only former nitro substitution intermediate replaces with Bromo-intermediates, so and
Route 2 there is a problem of identical.
Synthetic route 4（CN201110316778.X）
Patent CN201110316778.X is disclosed using the bromo- 3- Aminopyrazines -2- methyl formates of 6- as starting material, is passed through
After Boc protects amino, be further advanced by fluoro, de- Boc protections, diazotising hydrolysis and etc. obtain the production of Favipiravir target
Object.
Amino and pyridine ring are increased the cloud density of pyridine ring, can not be passed through by p- п conjugations in the route
Nucleophilic substitution directly replaces bromine atom to obtain fluoro product, after Boc protections on amino, although can weaken amino
In frared spectra, but Boc protection amino still plays the effect of supplied for electronic, therefore polarity upset cannot be brought it about to living
Change contraposition bromine atom reaction site, the production of pyrazine fluoro still can not be theoretically obtained by the direct nucleophilic displacement of fluorine of fluorine-containing nucleopilic reagent
Object.We carry out fluoro experiment according to the condition of the patent route and do not obtain fluoro product by repeatedly attempting, into one
Step demonstrates the possible outcome of above-mentioned theory analysis.
Synthetic route 5（CN201210301602.1）
Patent CN201210301602.1 disclose using -2 pyrazine carboxylic acid of 3- hydroxyls as starting material by diazotising hydrolysis,
The series reactions such as esterification, amine transesterification, nitrification, reduction, diazotising fluoro synthesize the route of Favipiravir.
It is similar that the patent route and 1 original of route grind patent, relates generally to Schiemann reaction amino and turns used in fluorine step
Euler's reagent（Hydrogen fluoride pyridine）With strong corrosive and toxicity, and the problem that yield is relatively low；Additionally, due to lacking for pyridine ring
Electronic effect is unfavorable for electrophilic substitution reaction, therefore nitro substitution reaction need to use the concentrated sulfuric acid/concentrated nitric acid etc. by force in the route
The harshness reaction condition such as acid highly corrosive, equally causes larger difficulty to industrialized production.
Synthetic route 6（US2013245264A1）
Patent US2013245264A1 disclose it is a kind of it is novel synthesis Favipiravir synthetic route, the route use from
Head synthetic method prepares 5- amino -4- using ethyl diethoxyacetate as starting material by multistep reaction first（2,
2- diethoxy acetylaminos）Isoxazole -3- methyl formate intermediates, it is different which by intramolecular cyclization obtains 5- hydroxyls
Oxazole simultaneously [4,5-b] pyrazine -3- methyl formates, further across chloro, fluoro, oxazole hydrolysis, cyan-hydrolysis
Obtain Favipiravir target product.
This method synthetic route step is tediously long, the fluoro- isoxazoles of intermediate 5- simultaneously fluorine in [4,5-b] pyrazine -3- methyl formates
Atom active is higher, is easily hydrolyzed into hydroxyl again in hydrolytic process, causes process overall yields relatively low.
Invention content
The purpose of the present invention is overcoming above-mentioned deficiency existing in the prior art, a kind of novel formula is provided（Ⅰ）Compound
The synthetic method of 6-fluoro-3-hydroxy-2-pyrazinamide.
Embodiment of the present invention is as follows：
A kind of synthetic method of the fluoro- 3 hydroxyl -2- pyrazinamides of compound 6-, includes the following steps：
(a) by formula（Ⅳ）Compound passes through amine transesterification formula（Ⅲ）Compound, reaction equation are；
(b) by formula（Ⅲ）Compound passes through fluoro-reaction formula（Ⅱ）Compound, reaction equation are；
Wherein：Substituent R is C1-4Alkoxy, X, Y are Cl or Br, and substituent X, Y can be identical or differs.
Specifically substituent R can be following groups：Methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutyl
Oxygroup or tert-butoxy, preferably R are methoxy or ethoxy；Substituent X, Y are preferably Br simultaneously.
Specifically, step（b）In, the fluoro-reaction, fluoro reagent is selected from tetrabutyl ammonium fluoride, potassium fluoride, fluorine
Change one or more of caesium and silver fluoride, preferred fluorinated potassium；Fluoro reagent and formula（Ⅲ）The molar ratio of compound is（2~6）：
1, preferably（3~5）：1；
Step（b）In, fluoro-reaction temperature is 80~150 DEG C, preferably 80~100 DEG C；
Step（b）In, the fluoro-reaction to improve fluoro-reaction rate needs that phase transfer catalyst is added, described
Phase transfer catalyst be tetrabutylammonium bromide；
Step（b）In, the fluoro-reaction carries out in a solvent, and solvent is selected from tetrahydrofuran, acetonitrile, Isosorbide-5-Nitrae-dioxy six
One or more of ring, n,N-Dimethylformamide, n,N-dimethylacetamide, dimethyl sulfoxide (DMSO) and 2- butanone, preferably N,
Dinethylformamide or dimethyl sulfoxide.
Further, by formula（Ⅱ）Formula is made by hydrolysis in compound（Ⅰ）Compound, reaction equation are；
Specifically, the hydrolysis carries out under alkaline condition, alkali be 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.
Further, above-mentioned formula（Ⅳ）Formula（Ⅴ）Compound passes through Sandmeyer chloros or bromo-reaction
It obtains, reaction equation is；
Wherein：Substituent X, Y are Cl or Br, can be identical or be differed.
In a preferred experimental program of the invention, the present invention prepares the following institute of method complete path of Favipiravir
Show：
The advantages of present invention is relative to existing synthetic route：
1）Starting material 6- bromines needed for synthesis（Chlorine）The preparation method of -3- Aminopyrazine formic acid esters is simple, and cost is relatively low；
2）Synthetic route is brief, and method is simple, only four-step reaction is needed to can be prepared by critical product；
3）It is more mild that the present invention respectively walks reaction condition, avoids, using strong corrosive, highly toxic reagent, reducing to environment
Pollution.
Specific implementation mode
Further illustrated the present invention below by embodiment, for a person skilled in the art, should not will under
Row embodiment is interpreted as limitation of the present invention, instructs according to prior art, is modified or improved to it and belongs to the present invention's
In protection domain.
Embodiment 1：The preparation of bis- bromo- 2- pyrazine carboxylic acids methyl esters of 3,6-
In 600ml n,N-Dimethylformamide, the bromo- 3- Aminopyrazines methyl formates of 120g (0.52mol) 6- are added,
181g copper bromides（0.78mol）, mixing is stirred at room temperature, 90.87g is added dropwise to system（0.78mol）Isoamyl nitrite drips
Finish, is warming up to 65 DEG C of 2~3h of reaction.Reaction finishes, and is down to room temperature, and 200ml water and the extraction of 1L ethyl acetate is added, and liquid separation has
Machine is mutually washed with saturated salt solution and saturated sodium bicarbonate solution successively, dry, is decolourized, and vacuum distillation obtains 150.3g brown
Oily liquids, the grease are beaten to obtain 124g off-white powders with petroleum ether.Yield：81.5%.MS:295 [M+H]
Following table compound is prepared using same procedure：
Embodiment 2：The preparation of bis- bromo- 2- pyrazinamides of 3,6-
In 850ml methanol, bis- bromo- 2- pyrazine carboxylic acids methyl esters of 85g (0.29mol) 3,6- is added, 1.7L ammonium hydroxide is added,
2~3h of reaction is stirred at room temperature.Filtering, filter cake are eluted with methanol, dry to obtain 75g faint yellow solids.Yield：92%.MS:280 [M+
H]
Following table compound is prepared using same procedure：
Embodiment 3：The preparation method 1 of bis- fluoro- 2- pyrazinamides of 3,6-
In 50ml dimethyl sulfoxide (DMSO)s, bis- bromo- 2- pyrazinamides of 5g (17.8mmol) 3,6-, 6.2g is added
（106.8mmol）Potassium fluoride, 1.2g (3.56mmol) tetrabutylammonium bromide are warming up to 150 DEG C of reaction 3h.Reaction finishes, and is down to
50ml water and the extraction of 150ml ethyl acetate is added in room temperature, and liquid separation, organic phase saturated common salt water washing is dry, decolourizes, decompression
It is concentrated to give crude oil product, the faint yellow target products of 1.2g are obtained with recrystallisation from isopropanol.Yield：43%.MS:160 [M+H]
Embodiment 4：The preparation method 2 of bis- fluoro- 2- pyrazinamides of 3,6-
In 80ml n,N-Dimethylformamide, bis- chloro- 2- pyrazinamides of 8g (41.7mmol) 3,6-, 14.3g is added
（94.2mmol）Cesium fluoride, 2.7g (8.3mmol) tetrabutylammonium bromide are warming up to 80 DEG C of reaction 6h.Reaction finishes, and is down to room
80ml water and the extraction of 240ml ethyl acetate is added in temperature, and liquid separation, organic phase saturated common salt water washing is dry, decoloration, and decompression is dense
Contracting obtains crude oil product, and the faint yellow target products of 2.1g are obtained with recrystallisation from isopropanol.Yield：32%.
Embodiment 5：The preparation method 3 of bis- fluoro- 2- pyrazinamides of 3,6-
In 100ml dimethyl sulfoxide (DMSO)s, the chloro- 2- pyrazinamides of the bromo- 3- of 10g (42.3mmol) 6-, 9.8g is added
（169.2mmol）Potassium fluoride, 2.7g (8.5mmol) tetrabutylammonium bromide are warming up to 100 DEG C of reaction 5h.Reaction finishes, and is down to room
100ml water and the extraction of 300ml ethyl acetate is added in temperature, and liquid separation, organic phase saturated common salt water washing is dry, decolourizes, decompression
It is concentrated to give crude oil product, the faint yellow target products of 2.7g are obtained with recrystallisation from isopropanol.Yield：40%.
Embodiment 6：The preparation method 4 of bis- fluoro- 2- pyrazinamides of 3,6-
In 50ml dimethyl sulfoxide (DMSO)s, bis- bromo- 2- pyrazinamides of 5g (17.8mmol) 3,6-, 18.6g is added
（71.2mmol）Tetrabutyl ammonium fluoride is warming up to 120 DEG C of reaction 5h.Reaction finishes, and is down to room temperature, and 50ml water and 150ml is added
Ethyl acetate extracts, liquid separation, organic phase saturated common salt water washing, dry, and decoloration is concentrated under reduced pressure to give crude oil product,
The faint yellow target products of 0.8g are obtained with recrystallisation from isopropanol.Yield：30%.
Embodiment 7：The preparation method 5 of bis- fluoro- 2- pyrazinamides of 3,6-
In 100ml dimethyl sulfoxide (DMSO)s, the chloro- 2- pyrazinamides of the bromo- 3- of 10g (42.3mmol) 6-, 16g is added
（126.9mmol）Silver fluoride, 2.7g (8.5mmol) tetrabutylammonium bromide are warming up to 100 DEG C of reaction 4h.Reaction finishes, and is down to room
100ml water and the extraction of 300ml ethyl acetate is added in temperature, and liquid separation, organic phase saturated common salt water washing is dry, decolourizes, decompression
It is concentrated to give crude oil product, the faint yellow target products of 2.8g are obtained with recrystallisation from isopropanol.Yield：42%.
Embodiment 8：The preparation method 1 of 6-fluoro-3-hydroxy-2-pyrazinamide
Bis- fluoro- 2- pyrazines of 5g (31.4mmol) 3,6- are added in 25ml water and 25ml 1,4- dioxane in the mixed solvents
Amide and 5.1g（62.8mmol）Sodium acetate is warming up to 60 DEG C of reaction 6h.Reaction solution is added in 50ml water, 2 mol/L salt are added
Acid is adjusted to pH 2.5, is extracted with ethyl acetate, liquid separation, is filtered after dry, and solvent is evaporated off in filtrate decompression, obtains faint yellow solid production
Object obtains the faint yellow target products of 2.9g with ethyl alcohol recrystallization.Yield：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)
Embodiment 9：The preparation method 2 of 6-fluoro-3-hydroxy-2-pyrazinamide
Bis- fluoro- 2- pyrazinamides of 8g (50.3mmol) 3,6- are added in 80ml water and 80ml dimethyl sulfoxide (DMSO) in the mixed solvents
And 8.4g（100.6mmol）Sodium bicarbonate is warming up to 80 DEG C of reaction 4h.Reaction solution is added in 80ml water, 2 mol/L salt are added
Acid is adjusted to pH 2.5, is extracted with ethyl acetate, liquid separation, is filtered after dry, and solvent is evaporated off in filtrate decompression, obtains faint yellow solid production
Object obtains the faint yellow target products of 4.1g with ethyl alcohol recrystallization.Yield：52%.
Claims (11)
1. a kind of synthetic method of 6-fluoro-3-hydroxy-2-pyrazinamide, which is characterized in that include the following steps：
(a) by formula（Ⅳ）Compound passes through amine transesterification formula（Ⅲ）Compound, reaction equation are：
(b) by formula（Ⅲ）Compound passes through fluoro-reaction formula（Ⅱ）Compound, reaction equation are：
(c) by formula（Ⅱ）Formula is made by hydrolysis in compound（Ⅰ）Compound, reaction equation are；
Wherein：Substituent R is C1-4Alkoxy, X, Y are Cl or Br, and substituent X, Y can be identical or differs；
Step（a）In, reaction is stirred at room temperature in ammonium hydroxide and methanol solvate and prepares；
Step（b）In, the fluoro-reaction, fluoro reagent is in tetrabutyl ammonium fluoride, potassium fluoride, cesium fluoride and silver fluoride
One or more；Fluoro reagent with（Ⅲ）The molar ratio of compound is（2~6）：1；Fluoro-reaction temperature is 80 ~ 150 DEG C；Add
Enter phase transfer catalyst tetrabutylammonium bromide.
2. synthetic method 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.
3. synthetic method according to claim 2, it is characterised in that：Substituent R is methoxy or ethoxy.
4. synthetic method according to claim 1, it is characterised in that：Substituent X, Y are Br simultaneously.
5. synthetic method according to claim 1, it is characterised in that：Step（b）Described in fluoro-reaction, fluoro reagent
And formula（Ⅲ）The molar ratio of compound is（3~5）：1.
6. synthetic method according to claim 1, it is characterised in that：Step（b）Middle fluoro-reaction temperature is 80~100
℃。
7. synthetic method according to claim 1, it is characterised in that：Step（b）In, the fluoro-reaction is in a solvent
It carries out, solvent is selected from tetrahydrofuran, acetonitrile, Isosorbide-5-Nitrae-dioxane, n,N-Dimethylformamide, n,N-dimethylacetamide, two
One or more of first sulfoxide and 2- butanone.
8. synthetic method according to claim 7, it is characterised in that：Solvent is that N,N-dimethylformamide or diformazan are sub-
Sulfone.
9. synthetic method according to claim 1, it is characterised in that：Step（c）Described in hydrolysis in alkaline item
Carried out under part, alkali be selected from potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium phosphate, sodium phosphate, sodium hydroxide or
Potassium hydroxide.
10. synthetic method according to claim 9, it is characterised in that：The alkali is sodium acetate or sodium bicarbonate.
11. synthetic method 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 are Cl or Br, can be identical or be differed.
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| CN106866553B (en) * | 2017-03-28 | 2020-02-04 | 中南大学 | Synthesis method of Favipiravir |
| CN111592499B (en) * | 2020-06-29 | 2022-01-07 | 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 |
| CN113072507B (en) * | 2021-03-18 | 2022-09-13 | 中国科学院上海有机化学研究所 | Preparation method of fluoropyrazine compound |
| 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 |
| 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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