CN103086962A - Synthetic method for 5-chlorine-2,4-dyhydroxyl pyridine - Google Patents
Synthetic method for 5-chlorine-2,4-dyhydroxyl pyridine Download PDFInfo
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Abstract
The invention provides a preparation method for 5-chlorine-2,4-dyhydroxyl pyridine (gimeracil). The preparation method comprises the following steps of: (a), enabling a compound in a formula (I) and a chloride agent to carry out chlorination in an organic solvent at 40 DEG C to 70 DEG C to obtain a compound in a formula (II); (b), enabling the compound in the formula (I) to carry out hydrolysis reaction, decarboxylic reaction as well as dealkylation reaction in an acid reaction system at 70 DEG C to 90 DEG C to obtain the compound 5-chlorine-2,4-dyhydroxyl pyridine in a formula (III), wherein R and R' in the formula (I) and the formula (II) are independently selected from C1-C4 alkyl, preferably methyl or ethyl. The synthetic method for the gimeracil disclosed by the invention is short in route, simple to operate, high in yield, good in product purity, and easy to realize industrial production.
Description
Technical field
The present invention relates to the chemicals field, relate more specifically to a kind of synthetic method of the 5-chloro-2,4-dihydroxypyridine (Gimeracil) as dihydropyridine desaturase (DPD) inhibitor.
Background technology
5-chloro-2,4-dihydroxypyridine (Gimeracil) be Japanese Taiho pharmaceutical industries Co., Ltd. in the oral anti-tumor compound medicine of in March, 1999 listing " for lucky difficult to understand " one of component.In compound, the constitutive molar ratio of Tegafur, Gimeracil and oteracil potassium is 1: 0.4: 1.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 Gimeracil is the reversibly-competitive inhibitor of a kind of DPD, can efficiently suppress DPD in tumor tissues, thus the decomposition rate of the 5 FU 5 fluorouracil that slows down, the acting duration of prolongation 5 FU 5 fluorouracil.So just can improve curative effect of medication when Gimeracil and Tegafur coupling.
At present, the synthetic route of Gimeracil mainly contains following several:
(1) take 4-nitropyridine-N-oxide compound as raw material, get Gimeracil (KOLDERCR, DENHHJ.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, is only 12%, is unfavorable for suitability for industrialized production.
(2) 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 relates to very harsh tube sealing reaction condition, and Hydrogen bromide used is the reagent of perishable experimental installation, makes this route be difficult to realize suitability for industrialized production.
(3) 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 the chlorine atom of 3 and is obtained Gimeracil (DEN H H J, KOLDER C R.Rec, Tray.Chim.1953,72 (8): 853-858).This route is also used very harsh tube sealing reaction condition, and Hydrogen bromide used is the reagent of perishable experimental installation, makes this route be difficult to realize suitability for industrialized production.
(4) be that reaction obtains Gimeracil to raw material through 3 steps by malonyl chloride, this route is due at intermediate α, also there are more or less some problems on the operation of the synthesis material of alpha, beta-unsaturated ketone acid ester derivant and reaction conditions, make this route be difficult to realize suitability for industrialized production.
(5) propane dinitrile and trimethyl orthoacetate etc. are raw material, react to get Gimeracil, (MITTELBACH, M etc.Arch.Pharm.1985,31:481-486) through 5 steps.This route final step reaction needed hydrolysis cyano group, and decarboxylation.Because cyan-hydrolysis is more difficult, the dense Hydrogen bromide backflow that this step reaction uses or 40% sulfuric acid are 130 ℃ of reactions.Dense Hydrogen bromide is very large to the corrodibility of experimental installation, and 40% sulfuric acid is also very harsh at 130 ℃ of reaction conditionss.Therefore the purity of product is not high, needs repeatedly recrystallization just can obtain qualified product.This route is difficult to satisfy Gimeracil as the required purity of medicine, thereby also limits the industrial application of this route.
Summary of the invention
For overcoming the problems referred to above of the prior art, the invention provides the synthetic method of a kind of 5-chloro-2,4-dihydroxypyridine (Gimeracil), 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.
The technical solution used in the present invention is: a kind of 5-chloro-2, the synthetic method of 4-dihydroxy-pyridine, comprise the following steps: (a) make formula (I) compound and chlorination reagent under 40 ℃～70 ℃, chlorination occur in organic solvent, obtain formula (II) compound; (b) make in step (a) resulting formula (II) compound in the reaction system of acidic conditions, issue the reaction of unboiled water solution, decarboxylic reaction and dealkylation at 70 ℃～90 ℃, obtain formula (III) compound 5-chloro-2,4-dihydroxypyridine, i.e. Gimeracil;
Formula (I) formula (II) formula (III)
Wherein, R, the R ' in formula (I) and formula (II) compound is independently selected from C
1-C
4Alkyl.
Preferably, R, R ' are independently selected from methyl or ethyl, can certainly be selected from other alkyl.
Preferably, in step (a), chlorination reagent is the N-chlorosuccinimide.
Preferably, in step (a), organic solvent is selected from one or more in acetonitrile, methylene dichloride, tetrahydrofuran (THF), dioxane or trichloromethane.Also can use other similar organic solvents herein.
Preferably, in step (a), the molar feed ratio of formula (I) compound and N-chlorosuccinimide is 1: 1.5～1: 2.5.
Further, in step (a), the reaction times of chlorination is 1-5 hour.
Further, the chlorination in step (a) also comprises following post-processing step after finishing: add entry after steaming partial solvent, crystallize out filters, and obtains formula (II) compound.
Preferably, in step (b), the acid of using in the reaction system of acidic conditions is hydrochloric acid.
More preferably, in step (b), the reaction system of acidic conditions is that concentration is the aqueous hydrochloric acid of 3-10 mol/L.
Further, in step (b), after hydrolysis reaction, decarboxylic reaction and dealkylation, also comprise following post-processing step: reaction solution is cooling, separate out white solid, filter out white solid, and with cold water washing, drying.
Compared with prior art, the present invention has following advantages:
1, raw material formula used in the present invention (I) compound be the reagent that is easy to prepare (Angew.Chem.Int.Ed.2011,50,4222-4226).It is raw material that the present invention adopts formula (I) compound, obtains formula (II) compound 5-chloro-2,4-dihydroxypyridine (Gimeracil) through chlorination, hydrolysis ester group and decarboxylation, dealkylation.Synthetic route is brief, and is easy and simple to handle, and condition is easily controlled, total recovery high (40%-70%), 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, and has avoided the stronger hydrobromic use of corrodibility, and the route feasibility is stronger.
3, not only post-processing operation is simple for synthetic method of the present invention, 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 in conjunction with specific embodiments the present invention is described in further detail.
Embodiment 1
Preparation compound 2-hydrogen-4-chloro-5-methoxyl-6-group-4 ethyl formate pyridone
Raw material 2-hydrogen-5-methoxyl group-6 group-4 ethyl formate pyridone (10g, 50.7mmol) is dissolved in acetonitrile (70mL), under agitation adds the NCS(N-chlorosuccinimide, 17.2g, 126.75mmol), slowly being warming up to 45 ℃ of reactions, solution becomes clarification by muddiness.After 6h, the TLC detection reaction is complete, and rotary evaporation remove portion solvent adds 50mL water, and ice bath is standing, separate out white crystalline solid, filter out white solid, the filter cake water rinses, be drying to obtain compound 2-hydrogen-4-chloro-5-methoxyl-6-group-4 ethyl formate pyridone, the 8.9g that weighs, yield 76.0%.
1H?NMR(CDCl
3，400MHz)：δ=13.41(s，1H)，7.43(s，1H)，4.39(q，J=7.4Hz，2H)，3.89(s，3H)，1.37(t，J=7.1Hz，3H)，MS(EI)：m/e=216
Embodiment 2
Preparation compound 2-hydrogen-4-chloro-5-methoxyl-6-group-4 ethyl formate pyridone
Raw material 2-hydrogen-5-methoxyl group-6 group-4 ethyl formate pyridone (10g, 50.7mmol) is dissolved in acetonitrile (70mL), under agitation adds NCS(17.2g, 126.75mmol), slowly be warming up to 55 ℃ of reactions, solution becomes clarification by muddiness.After 6h, the TLC detection reaction is complete, rotary evaporation remove portion solvent, add 50mL water in reaction solution, ice bath is standing, separates out white crystalline solid, filters out white solid, the filter cake water rinses, be drying to obtain compound 2-hydrogen-4-chloro-5-methoxyl-6-group-4 ethyl formate pyridone, the 7.9g that weighs, yield 67.5%.
1H?NMR(CDCl
3，400MHz)：δ=13.41(s，1H)，7.43(s，1H)，4.39(q，?J=7.4Hz，2H)，3.89(s，3H)，1.37(t，J=7.1Hz，3H)，MS(EI)：m/e=216。
Embodiment 3
Preparation compound 2-hydrogen-4-chloro-5-oxyethyl group-6-group-4 ethyl formate pyridone
Raw material 2-hydrogen-5-oxyethyl group-6-group-4 ethyl formate pyridone (10g, 47.4mmol) is dissolved in acetonitrile (70mL), adds the NCS(N-chlorosuccinimide under stirring, 17.2g, 126.75mmol), slowly being warming up to 65 ℃ of reactions, solution becomes clarification by muddiness.After 4h, the TLC detection reaction is complete, rotary evaporation remove portion solvent, add 50mL water in reaction solution, ice bath is standing, separates out white crystalline solid, filters out white solid, the filter cake water rinses, be drying to obtain compound 2-hydrogen-4-chloro-5-oxyethyl group-6-group-4 ethyl formate pyridone, the 8.1g that weighs, yield 70.5%.
1H?NMR(CDCl
3，400MHz)：δ=13.41(s，1H)，7.43(s，1H)，4.39(q，J=7.4Hz，2H)，3.59(q，J=7.3Hz，2H)，1.37(t，J=7.1Hz，3H)，1.11(t，J=7.2Hz，3H)，MS(EI)：m/e=230。
Embodiment 4
Preparation formula (III) compound 5-chloro-2,4-dihydroxypyridine (Gimeracil)
With the raw material 2-hydrogen of above-described embodiment preparation-4-chloro-5-methoxyl-6-group-4 ethyl formate pyridone (10g, 43.3mmol) be suspended in the aqueous hydrochloric acid (50mL) of 3N, be warming up to 90 ℃ of reactions, solution becomes clarification, after 6-7h, the cooling white solid of separating out, filter out white solid, wash filter cake with water, the drying 4.9g that weighs to get, be Gimeracil, yield 78.0%.
1H?NMR(DMSO-d
6，500MHz)：δ=11.2(br，2H)，7.4(s，1H)，5.7(s，1H)。
MS(EI)：m/e=145。
Embodiment 5
Preparation formula (III) compound is 5-chloro-2,4-dihydroxypyridine (Gimeracil)
With the raw material 2-hydrogen of above-described embodiment preparation-4-chloro-5-methoxyl-6-group-4 ethyl formate pyridone (10g, 43.3mmol) be suspended in the aqueous hydrochloric acid (50mL) of 6N, be warming up to 80 ℃ of reactions, solution becomes clarification, after 6-7h, the cooling white solid of separating out, filter out white solid, wash filter cake with water, 5.0g weighs after drying to get, be Gimeracil, yield 79.6%.
1H?NMR(DMSO-d
6，500MHz)：δ=11.2(br，2H)，7.4(s，1H)，5.7(s，1H)。
MS(EI)：m/e=145。
Embodiment 6
Preparation formula (III) compound, i.e. 5-chloro-2,4-dihydroxypyridine (Gimeracil)
With raw material 2-hydrogen-4-chloro-5-oxyethyl group-6-group-4 ethyl formate pyridone (10g, 40.8mmol) be suspended in the aqueous hydrochloric acid (50mL) of 10N, be warming up to 70 ℃ of reactions, solution becomes clarification, after 6-7h, the cooling white solid of separating out, filter out white solid, wash filter cake with water, 4.5g weighs after drying to get, be Gimeracil, yield 76.0%.
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 Gimeracil 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.
Above specific embodiment of the present invention is illustrated; but protection content of the present invention is not only limited to above embodiment; in technical field, the common knowledge of a GPRS just can be carried out diversified change in its technology main idea scope under of the present invention.
Claims (10)
1. the synthetic method of a 5-chloro-2,4-dihydroxypyridine, is characterized in that, comprises the following steps:
(a) make formula (
) chlorination occurs in compound and chlorination reagent under 40 ℃ ~ 70 ℃ in organic solvent, obtain formula (
) compound;
(b) make resulting formula in step (a) (
) compound in the reaction system of acidic conditions, issue the reaction of unboiled water solution, decarboxylic reaction and dealkylation at 70 ℃ ~ 90 ℃, obtain formula (
) the compound 5-chloro-2,4-dihydroxypyridine;
Wherein, formula (
) and formula (
) R, R ' in compound be independently selected from C
1-C
4Alkyl.
2. the synthetic method of 5-chloro-2,4-dihydroxypyridine according to claim 1, it is characterized in that: R, R ' are independently selected from methyl or ethyl.
3. the synthetic method of 5-chloro-2,4-dihydroxypyridine according to claim 1 and 2, it is characterized in that: in step (a), described chlorination reagent is the N-chlorosuccinimide.
4. the synthetic method of 5-chloro-2,4-dihydroxypyridine according to claim 1, it is characterized in that: in step (a), described organic solvent is selected from one or more in acetonitrile, methylene dichloride, tetrahydrofuran (THF), dioxane or trichloromethane.
5. the synthetic method of 5-chloro-2,4-dihydroxypyridine according to claim 3 is characterized in that: in step (a), described formula (
) molar feed ratio of compound and N-chlorosuccinimide is 1:1.5 ~ 1:2.5.
6. the synthetic method of 5-chloro-2,4-dihydroxypyridine according to claim 1, it is characterized in that: in step (a), the reaction times of described chlorination is 1-5 hour.
7. the synthetic method of 5-chloro-2,4-dihydroxypyridine according to claim 1, is characterized in that, chlorination in step (a) also comprises following post-processing step after finishing: add entry after steaming partial solvent, crystallize out filters, obtain formula (
) compound.
8. the synthetic method of 5-chloro-2,4-dihydroxypyridine according to claim 1, is characterized in that, in step (b), the acid of using in the reaction system of described acidic conditions is hydrochloric acid.
9. the synthetic method of 5-chloro-2,4-dihydroxypyridine according to claim 8, is characterized in that, in step (b), the reaction system of described acidic conditions is that concentration is the aqueous hydrochloric acid of 3-10 mol/L.
10. 5-chloro-2 according to claim 1, the synthetic method of 4-dihydroxy-pyridine, it is characterized in that, after hydrolysis reaction, decarboxylic reaction and dealkylation in step (b), also comprise following post-processing step: reaction solution is cooling, separate out white solid, filter out white solid, and with cold water washing, drying.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664772A (en) * | 2013-11-29 | 2014-03-26 | 山东永泰化工有限公司 | Synthesis method of 5-chloro-3-cyano-4-methony-2-(1H)-pyridinone |
| CN106316934A (en) * | 2016-08-17 | 2017-01-11 | 济南川成医药科技开发有限公司 | Synthetic method for gimeracil |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0578324A (en) * | 1991-09-19 | 1993-03-30 | Taiho Yakuhin Kogyo Kk | 3-substituted-5-halogenopyridine derivative |
| WO2006080339A1 (en) * | 2005-01-26 | 2006-08-03 | Taiho Pharmaceutical Co., Ltd. | Process for production of 5-chloro-2,4-dihydroxypyridine |
| CN102432530A (en) * | 2011-11-17 | 2012-05-02 | 深圳海王药业有限公司 | Method for preparing high-purity gimeracil |
-
2013
- 2013-01-25 CN CN2013100297583A patent/CN103086962A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0578324A (en) * | 1991-09-19 | 1993-03-30 | Taiho Yakuhin Kogyo Kk | 3-substituted-5-halogenopyridine derivative |
| WO2006080339A1 (en) * | 2005-01-26 | 2006-08-03 | Taiho Pharmaceutical Co., Ltd. | Process for production of 5-chloro-2,4-dihydroxypyridine |
| CN102432530A (en) * | 2011-11-17 | 2012-05-02 | 深圳海王药业有限公司 | Method for preparing high-purity gimeracil |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664772A (en) * | 2013-11-29 | 2014-03-26 | 山东永泰化工有限公司 | Synthesis method of 5-chloro-3-cyano-4-methony-2-(1H)-pyridinone |
| CN106316934A (en) * | 2016-08-17 | 2017-01-11 | 济南川成医药科技开发有限公司 | Synthetic method for gimeracil |
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