CN103360307A - Preparation method of 5-chloro-2,4-dihydroxypyridine - Google Patents
Preparation method of 5-chloro-2,4-dihydroxypyridine Download PDFInfo
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Abstract
The invention relates to a method for synthesizing 5-chloro-2,4-dihydroxypyridine. The method comprises the single-step reaction for enabling a compound G-1 to selectively remove three chlorine atoms to prepare a compound G-2. The method has the advantages of short synthesis route, simplicity and convenience in operation, high yield and easiness in industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of dihydropyridine dehydrogenase inhibitor 5-chloro-2,4-dihydroxypyridine.
Background technology
5-chloro-2,4-dihydroxypyridine is one of the component of the oral anti-tumor compound medicine " for lucky difficult to understand " of listing Japanese Taiho pharmaceutical industries Co., Ltd. in March, 1999.The constitutive molar ratio of Tegafur, Gimeracil and oteracil potassium is 1: 0.4: 1 in the compound.The active metabolite 5 FU 5 fluorouracil of Tegafur is extremely unstable in vivo, easily by dihydropyrimidine dehydrogenase (DPD) the fast degradation inactivation of tumor tissues and normal organ generation.And 5-chloro-2, the 4-dihydroxy-pyridine is the reversibly-competitive inhibitor of a kind of DPD, can efficiently suppress DPD in the tumor tissues, thereby the decomposition rate of the 5 FU 5 fluorouracil that slows down, prolong the acting duration of 5 FU 5 fluorouracil, so 5-chloro-2,4-dihydroxypyridine and Tegafur coupling can obviously be improved curative effect of medication.
At present, the preparation of 5-chloro-2,4-dihydroxypyridine mainly contains following several method:
1, take 4-nitropyridine-N-oxide compound as raw material, gets 5-chloro-2,4-dihydroxypyridine (KOLDER C R, DEN H H J. Rec.Tray.Chim.1953.72 (2): 285-295) through the reaction of 7 steps.This synthetic route is tediously long, and total recovery is low, and only 12%, be unfavorable for suitability for industrialized production.
2, by 3-chloro-2, obtain 3 after the chlorination of 4-dihydroxy-pyridine, 5-two chloro-2, the 4-dihydroxy-pyridine again with hydrogen bromide, sodium bisulfite in tube sealing through 200 ℃ of reactions, selectivity is sloughed 3 chlorine atom and is obtained 5-chloro-2,4-dihydroxypyridine (DEN H H J, KOLDER C R .Rec, Tray.Chim.1953,72 (8): 853-858).This route is used very harsh tube sealing reaction condition, and used Hydrogen bromide is the reagent of perishable experimental installation, so that this route is difficult to realize suitability for industrialized production.
3, by 2,4-dihydroxy-pyridine and SULPHURYL CHLORIDE reaction obtain 3,5-two chloro-2, the 4-dihydroxy-pyridine, use at last hydrogen bromide, the chlorine of sloughing 3 through tube sealing reaction obtains product (DEN H H J, COMBE W P again, KOLDER C R .Rec.Tray.Chim.1953,73 (4): 704-708.).This route also relates to very harsh tube sealing reaction condition, and used Hydrogen bromide is the reagent of perishable experimental installation, so that this route is difficult to realize suitability for industrialized production.
4, propane dinitrile and trimethyl orthoacetate etc. are raw material, react to get 5-chloro-2,4-dihydroxypyridine (MITTELBACH M etc. Arch.Pharm.1985,31:481-486) through 5 steps.The purity of this route end product is not high, can not satisfy 5-chloro-2,4-dihydroxypyridine as the required purity of medicine, thereby limits the industrial application of this route yet.
5, with 2, the 4-dimethoxy-pyridine is through being the synthetic 5-chloro-2 of raw material, the 4-dihydroxy-pyridine, disclose compound G-4 under acidic conditions, slough this reactions steps of methyl on 2 and 4 methoxyl groups (Journal of the Chemical Society, 1912, vol. 101, p. 1947), but the method for the document need to remove methyl with hydrogenchloride under the condition of 175 ℃ of high temperature and autoclave, and reaction conditions is very harsh, is difficult to realize suitability for industrialized production.
Summary of the invention
For the technical problem that present preparation 5-chloro-2,4-dihydroxypyridine exists, the invention provides a kind of method of synthetic 5-chloro-2,4-dihydroxypyridine, the method has advantages of that synthetic route is brief, easy and simple to handle, productive rate is high, be easy to suitability for industrialized production.
To achieve these goals, the technical solution used in the present invention is:
A kind of preparation method of 5-chloro-2,4-dihydroxypyridine comprises that making compound G-1 selectivity slough 3 chlorine atoms obtains compound G-2:
It is characterized by: compound G-1 and iodine negative ion react under the slightly acidic solvent and obtain G-2.
Wherein, described iodine negative ion is potassiumiodide or sodium iodide, used weak acid is acetic acid or ammonium chloride or ammonium sulfate, described solvent is ethanol, methyl alcohol, Virahol, acetonitrile or N, a kind of in the dinethylformamide, described temperature of reaction is 50 ℃～80 ℃, and the mol ratio of described compound G-1 and iodide ion is 1: 2～3.
Preparation method according to above-mentioned 5-chloro-2,4-dihydroxypyridine is characterized by: also comprise following reactions steps, after dechlorination reaction finishes, add hypo solution or sodium sulfite solution in the reaction solution until reaction solution is clarified, leave standstill, separate out white solid, filter drying.
Preferably, adopt recrystallization to purify the gained white solid, the selected solvent of recrystallization is water or methyl alcohol or ethanol.
According to above-mentioned 5-chloro-2, the preparation method of 4-dihydroxy-pyridine, it is characterized by: also comprise following reactions steps: G-3 compound 2, chlorinations occur with the N-chlorosuccinimide 3 and 5 and obtain compound G-4 in the 4-dimethoxy-pyridine under suitable solvent, compound G-4 sloughs the methyl on 2 and 4 methoxyl groups under acidic conditions:
Wherein, the chlorination reagent of described chlorination is the N-chlorosuccinimide, described solvent is acetonitrile, N, dinethylformamide, N, a kind of in N-N,N-DIMETHYLACETAMIDE, methylene dichloride or the chloroform, described temperature of reaction is 38 ℃～80 ℃, and the mol ratio of described compound G-3 and N-chlorosuccinimide is 1: 2～3.5, and described compound G-3 and the N-chlorosuccinimide reaction times in solvent is 1～5 hour.
Preferably, further comprising the steps of: as after described chlorination is finished, to steam behind the described solvent of part and add entry, separate out and filter the gained solid and be compound G-4.
Wherein, in described G-4-G-1 reactions steps, temperature of reaction is 50 ℃～70 ℃, and used acid is hydrochloric acid, and used reaction system is that concentration is the aqueous hydrochloric acid system of 3～5 mol/L.
Preferably, further comprising the steps of: as after described G-4-the G-1 reactions steps is finished, white solid to be separated out in the reaction solution cooling, filter out white solid and use cold water washing, drying.
Raw material 2 used in the present invention, 4-dimethoxy-pyridine are the reagent that is easy to get, and beneficial effect of the present invention is as follows:
1, to adopt 2,4-dimethoxy-pyridine be that raw material obtains the compound 5-chloro-2,4-dihydroxypyridine through chlorination, demethylation, dechlorination three-step reaction in the present invention, synthetic route is brief, and is easy and simple to handle, and condition is easily controlled, total recovery high (75%～90%), product purity high (purity is greater than 99.8%).
2, the present invention does not relate to the dangerous reaction conditionss such as pyroreaction still, has avoided the use of the stronger HBr of corrodibility yet, and the route feasibility is stronger.
3, the aftertreatment of synthetic method of the present invention is not only simple to operate, and product purity is high, is easy to suitability for industrialized production.
Embodiment
In order more clearly to understand technology contents of the present invention, now further specify in conjunction with the embodiments as follows:
Embodiment 1
1.1 compound G-4 i.e. 3,5-, two chloro-2, the preparation of 4-dihydroxy-pyridine
With raw material G-3(Suzhou Highfine Biotech Co., Ltd.) (10 g; 71 mmol) be dissolved in acetonitrile (Solution on Chemical Reagents in Shanghai company of traditional Chinese medicines group; chemical pure) in (70 mL); stir the lower N-chlorosuccinimide (Solution on Chemical Reagents in Shanghai company of traditional Chinese medicines group, chemical pure) (25.0 g, 187 mmol) that adds; slowly be warming up to 50 ℃ of reactions; solution becomes clarification by muddiness, reacts after 3 hours, and rotary evaporation is removed the solvent of 2/3 volume; in reaction solution, add 50mL water; ice bath leaves standstill, and separates out white crystalline solid, filters out white solid; the flushing of filter cake water; be drying to obtain compound G-4,13 g that weigh, yield 86.7%.
1H NMR (CDCl3, 500MHz): δ = 8.0 (s , 1H), 4.0 (s , 3H), 3.9 (s , 3H)。
MS (EI): m/e = 207
M.p.= 50℃
1.2 compound G-4 i.e. 3,5-, two chloro-2, the preparation of 4-dihydroxy-pyridine
With raw material G-3(Suzhou Highfine Biotech Co., Ltd.) (10 g; 71 mmol) be dissolved in chloroform (Solution on Chemical Reagents in Shanghai company of traditional Chinese medicines group; chemical pure) in (70 mL); stir the lower N-chlorosuccinimide (Solution on Chemical Reagents in Shanghai company of traditional Chinese medicines group, chemical pure) (18.9 g, 142 mmol) that adds; slowly be warming up to 55 ℃ of reactions; solution becomes clarification by muddiness, reacts after 5 hours the rotary evaporation desolventizing; in reaction solution, add 50mL water; ice bath leaves standstill, and separates out white crystalline solid, filters out white solid; the flushing of filter cake water; be drying to obtain compound G-4,11.7 g that weigh, yield 78.0%.
1H NMR (CDCl3, 500MHz): δ= 8.0 (s , 1H), 4.0 (s , 3H), 3.9 (s , 3H)。
MS(EI): m/e = 207
M.p.=50℃
1.3 compound G-4 i.e. 3,5-, two chloro-2, the preparation of 4-dihydroxy-pyridine
With raw material G-3(Suzhou Highfine Biotech Co., Ltd.) (10 g; 71 mmol) be dissolved in N; dinethylformamide (Solution on Chemical Reagents in Shanghai company of traditional Chinese medicines group; chemical pure) in (70 mL); stir the lower N-chlorosuccinimide (Solution on Chemical Reagents in Shanghai company of traditional Chinese medicines group, chemical pure) (33.0 g, 248 mmo l) that adds; slowly be warming up to 65 ℃ of reactions, solution becomes clarification by muddiness.React after 1 hour, add 250mL water in reaction solution, ice bath leaves standstill, and separates out white crystalline solid, filters out white solid, and the flushing of filter cake water is drying to obtain compound G-4,10.5 g that weigh, yield 70.0%.
1H NMR (CDCl3, 500MHz): δ = 8.0 (s , 1H), 4.0 (s , 3H), 3.9 (s , 3H )。
MS (EI): m/e = 207
M.p.=50℃
1.4 compound G-4 i.e. 3,5-, two chloro-2, the preparation of 4-dihydroxy-pyridine
With raw material G-3(Suzhou Highfine Biotech Co., Ltd.) (10 g; 71 mmol) be dissolved in N; N-N,N-DIMETHYLACETAMIDE (Solution on Chemical Reagents in Shanghai company of traditional Chinese medicines group; chemical pure) in (60 mL); stir the lower N-chlorosuccinimide (Solution on Chemical Reagents in Shanghai company of traditional Chinese medicines group, chemical pure) (28.3 g, 213 mmo l) that adds; slowly be warming up to 80 ℃ of reactions, solution becomes clarification by muddiness.React after 2 hours, add 250mL water in reaction solution, ice bath leaves standstill, and separates out white crystalline solid, filters out white solid, and the flushing of filter cake water is drying to obtain compound G-4,10.0 g that weigh, yield 67.0%.
1H NMR (CDCl
3, 500MHz): δ = 8.0 (s , 1H), 4.0 (s , 3H), 3.9 (s , 3H )。
MS (EI): m/e = 207
M.p.=50℃
1.5 compound G-4 i.e. 3,5-, two chloro-2, the preparation of 4-dihydroxy-pyridine
With raw material G-3(Suzhou Highfine Biotech Co., Ltd.) (10 g; 71 mmol) be dissolved in methylene dichloride (Solution on Chemical Reagents in Shanghai company of traditional Chinese medicines group; chemical pure) in (60 mL); add N-chlorosuccinimide (Solution on Chemical Reagents in Shanghai company of traditional Chinese medicines group under stirring; chemical pure) (28.3 g; 213 mmol); slowly be warming up to 38 ℃ of reactions; react after 4 hours, steam solvent, add 250mL water; separate out white crystalline solid; namely get compound G-4, dry 12.1 g that weigh, yield 81.0%.
1H NMR (CDCl
3, 500MHz): δ = 8.0 (s , 1H), 4.0 (s , 3H), 3.9 (s , 3H )。
MS (EI): m/e = 207
M.p.=50℃
Embodiment 2
2.1 compound G-1 i.e. 3,5-, two chloro-2, the preparation of 4-dihydroxy-pyridine
Raw material G-4 (10 g, 48 mmol) is suspended in the aqueous hydrochloric acid (50 mL) of 3N, is warming up to 70 ℃ of reactions, the solution becomes clarification, behind 6 h, white solid is separated out in cooling, filters out white solid, wash filter cake with water, drying 7.5 g that weigh to get, yield 86.3%.
1H NMR (DMSO-
d 6 , 500MHz): δ = 11.9 (s, 1H), 11.5 (br, 1H), 7.6 (s, 1H)MS (EI): m/e = 179
2.2 compound G-1 i.e. 3,5-, two chloro-2, the preparation of 4-dihydroxy-pyridine
Raw material G-4 (10 g, 48mmol) is suspended in the aqueous hydrochloric acid (40 mL) of 5N, is warming up to 50 ℃ of reactions, the solution becomes clarification, behind the 5h, white solid is separated out in cooling, filters out white solid, wash filter cake with water, drying 6.5 g that weigh to get, yield 75%.
1H NMR (DMSO-
d 6 , 500MHz): δ=11.9 (s, 1H), 11.5 (br, 1H), 7.6 (s, 1H)
MS (EI): m/e = 179
2.3 compound G-1 i.e. 3,5-, two chloro-2, the preparation of 4-dihydroxy-pyridine
Raw material G-4 (10 g, 48mmol) is suspended in the aqueous hydrochloric acid (45 mL) of 4N, is warming up to 60 ℃ of reactions, the solution becomes clarification, 5.5 behind the h, white solid is separated out in cooling, filters out white solid, wash filter cake with water, drying 7.0 g that weigh to get, yield 81%.
1H NMR (DMSO-
d 6 , 500MHz): δ=11.9 (s, 1H), 11.5 (br, 1H), 7.6 (s, 1H)
MS (EI): m/e = 179
Embodiment 3
3.1 compound G-2 is the preparation of 5-chloro-2,4-dihydroxypyridine
With raw material G-1(8 g, 44 mmol) mix with acetonitrile (100 mL), add HOAc 3 mL, NaI 13.2 g(88 mmol), being warmed up to 80 ℃ of reactions, to brown again to dark-brown, 8 h afterreactions are complete by white opacity flavescence look for solution colour.In reaction solution, add 10%Na
2S
2O
3Aqueous solution 200mL leaves standstill to solution decolourization, separates out white solid, filters washing filter cake, drying, the 5.5 g. yields 84.6% of weighing.Purity is greater than 99.9% behind the water recrystallization.
1H NMR (DMSO-d6, 500MHz): δ = 11.2 (br , 2H) , 7.4 (s , 1H) , 5.7 (s, 1H).
MS (EI): m/e = 145
3.2 compound G-2 is the preparation of 5-chloro-2,4-dihydroxypyridine
With raw material G-1(8 g, 44mmol) mix with 80 mL DMFs, add HOAc 3mL, NaI (16.5 g, 110 mmol), be warmed up to 50 ℃ of reactions, to brown again to dark-brown, 6 h afterreactions are complete by white opacity flavescence look for solution colour.In reaction solution, add 10%Na
2S
2O
3The aqueous solution (200 mL) to solution decolourization, leaves standstill, and separates out white solid, filters washing filter cake, drying, 5.7 g that weigh, yield 88%.With purity behind the ethyl alcohol recrystallization greater than 99.8%.
1H NMR (DMSO-d6, 500MHz): δ = 11.2 (br , 2H), 7.4 (s , 1H), 5.7 (s, 1H).
MS (EI): m/e = 145
3.3 compound G-2 is the preparation of 5-chloro-2,4-dihydroxypyridine
Raw material G-1 (8 g, 44 mmol) is mixed with ethanol (100 mL), add ammonium chloride (5 g), KI(18.3 g, 110 mmol), be warmed up to 70 ℃ of reactions, to brown again to dark-brown, 8 h afterreactions are complete by white opacity flavescence look for solution colour.Add 10% sodium sulfite aqueous solution (260mL) sodium sulfite aqueous solution in the reaction solution and leave standstill to solution decolourization, separate out white solid, filter, washing filter cake, drying, the 5.5 g. yields 85% of weighing.With purity behind the ethyl alcohol recrystallization greater than 99.8%.
1H NMR (DMSO-d6, 500MHz): δ = 11.2 (br , 2H), 7.4 (s, 1H), 5.7 (s, 1H).
MS (EI): m/e = 145
3.4 compound G-2 is the preparation of 5-chloro-2,4-dihydroxypyridine
Raw material G-1 (8 g, 44 mmol) is mixed with Virahol (100 mL), add ammonium sulfate (5.8g), NaI(18.3 g, 110 mmol), be warmed up to 65 ℃ of reactions, to brown again to dark-brown, 7 h afterreactions are complete by white opacity flavescence look for solution colour.In reaction solution, add 10% sodium sulfite aqueous solution (260mL) to solution decolourization, leave standstill, separate out white solid, filter, washing filter cake, drying, the 5.1 g. yields 80% of weighing.With purity after the recrystallizing methanol greater than 99.8%.
1H NMR (DMSO-
d 6 , 500MHz): δ = 11.2 (br , 2H), 7.4 (s, 1H), 5.7 (s, 1H).
MS (EI): m/e = 145
3.5 compound G-2 is the preparation of 5-chloro-2,4-dihydroxypyridine
Raw material G-1 (8 g, 44 mmol) is mixed with methyl alcohol (90 mL), adds HOAc(3 mL), KI(14.6 g, 88 mmol), being warmed up to 60 ℃ of reactions, to brown again to dark-brown, 7 h afterreactions are complete by white opacity flavescence look for solution colour.In reaction solution, add 10%Na
2S
2O
3The aqueous solution (260 mL) to solution decolourization, leaves standstill, and separates out white solid, filters washing filter cake, drying, the 5.0 g. yields 77% of weighing.With purity after the recrystallizing methanol greater than 99.8%.
1H NMR (DMSO-
d 6 , 500MHz): δ = 11.2 (br , 2H), 7.4 (s, 1H), 5.7 (s, 1H).
MS (EI): m/e = 145
In sum, the method for the synthetic 5-chloro-2,4-dihydroxypyridine of the present invention has advantages of that synthetic route is brief, easy and simple to handle, productive rate is high, be easy to suitability for industrialized production.
Claims (9)
1. the preparation method of a 5-chloro-2,4-dihydroxypyridine comprises that making compound G-1 selectivity slough 3 chlorine atoms obtains compound G-2:
It is characterized by: compound G-1 and iodine negative ion react under the slightly acidic solvent and obtain G-2.
2. preparation method according to claim 1, it is characterized by: described iodine negative ion is potassiumiodide or sodium iodide, used weak acid is acetic acid or ammonium chloride or ammonium sulfate, described solvent is ethanol, methyl alcohol, Virahol, acetonitrile or N, a kind of in the dinethylformamide, described temperature of reaction is 50 ℃～80 ℃, and the mol ratio of described compound G-1 and iodide ion is 1: 2～3.
3. preparation method according to claim 1 is characterized by: further comprising the steps of, after dechlorination reaction finishes, add hypo solution or sodium sulfite solution in the reaction solution until the reaction solution clarification is left standstill, separate out white solid, filter drying.
4. preparation method according to claim 3 is characterized by: described white solid carries out recrystallization purifies, and the selected solvent of recrystallization is water or methyl alcohol or ethanol.
5. arbitrary described preparation method according to claim 1 ~ 4, it is characterized by: also comprise following reactions steps: G-3 compound 2, chlorinations occur with the N-chlorosuccinimide 3 and 5 and obtain compound G-4 in the 4-dimethoxy-pyridine under suitable solvent, compound G-4 sloughs the methyl on 2 and 4 methoxyl groups under acidic conditions:
6. preparation method according to claim 5, it is characterized by: the chlorination reagent of described chlorination is the N-chlorosuccinimide, described solvent is acetonitrile, N, dinethylformamide, N, a kind of in N-N,N-DIMETHYLACETAMIDE, methylene dichloride or the chloroform, described temperature of reaction is 38 ℃～80 ℃, and the mol ratio of described compound G-3 and N-chlorosuccinimide is 1: 2～3.5, and described compound G-3 and the N-chlorosuccinimide reaction times in solvent is 1～5 hour.
7. preparation method according to claim 5 is characterized by: further comprising the steps of: steam the described solvent of part and add entry after described chlorination is finished, separate out and filter the gained solid and namely get compound G-4.
8. preparation method according to claim 5, it is characterized by: in described G-4-G-1 reactions steps, temperature of reaction is 50 ℃～70 ℃, and used acid is hydrochloric acid, used reaction system is that concentration is the aqueous hydrochloric acid system of 3～5 mol/L.
9. preparation method according to claim 5 is characterized by: further comprising the steps of: after described G-4-the G-1 reactions steps is finished, white solid is separated out in the reaction solution cooling, filter out white solid and use cold water washing, drying.
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| CN106854177A (en) * | 2017-01-04 | 2017-06-16 | 苏州健雄职业技术学院 | A kind of preparation method of the formaldehyde of 6 chlorine, 4 pyridone 3 |
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Non-Patent Citations (2)
| Title |
|---|
| H. J. DEN HERTOG, ET AL.: "The reactivity of halogen atoms occupying positions 3 and 5 in 2,4-dihydroxypyridine", 《RECUEIL》 * |
| KAZUMASA FUNABIKI, ET AL.: "Ring-fluorinated fluoresceins as an organic photosensitizer for dye-sensitized solar cells using nanocrystalline zinc oxide", 《JOURNAL OF FLUORINE CHEMISTRY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106854177A (en) * | 2017-01-04 | 2017-06-16 | 苏州健雄职业技术学院 | A kind of preparation method of the formaldehyde of 6 chlorine, 4 pyridone 3 |
| CN106854177B (en) * | 2017-01-04 | 2019-10-11 | 苏州健雄职业技术学院 | A kind of preparation method of 6- chloro-4-hydroxyl pyridine -3- formaldehyde |
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Address after: 210061 Jiangsu Province, Nanjing city high tech Development Zone of High Road No. 28 Patentee after: NANJING LVYE PHARMA CO., LTD. Patentee after: East China Normal University Address before: 210061 Jiangsu Province, Nanjing city high tech Development Zone of High Road No. 28 Patentee before: Nanjing Luye Pharmaceutical Co., Ltd. Patentee before: East China Normal University |