CN106316934A - Synthetic method for gimeracil - Google Patents
Synthetic method for gimeracil Download PDFInfo
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- CN106316934A CN106316934A CN201610674757.8A CN201610674757A CN106316934A CN 106316934 A CN106316934 A CN 106316934A CN 201610674757 A CN201610674757 A CN 201610674757A CN 106316934 A CN106316934 A CN 106316934A
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- pyridone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/69—Two or more oxygen atoms
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Abstract
The invention belongs to the technical field of chemical synthesis and particularly relates to a synthetic method for gimeracil. The method comprises the steps that 3-cyano-4-methoxy-2-H-pyridone and sulfonyl chloride react in glacial acetic acid, and then 3-cyano-4-methoxy-5-chlorine 2-(1H)pyridine is obtained through separation; 3-cyano-4-methoxy-5-chlorine 2-(1H)pyridine then reacts with hydrobromic acid, and gimeracil is obtained. According to the preparing method for gimeracil, the technological operation is simple and convenient, the cycle is short, cost is low, product purity is high, and mass production of the product is easy.
Description
Technical field
The invention belongs to chemosynthesis technical field, being specifically related to is the synthetic method of a kind of gimeracil.
Background technology
Gimeracil, chemical name: 5-chloro-4-hydroxyl-2 (1H)-pyridone, its structural formula of CAS 103766-25-2 is such as
Under:
。
One of PTS tegafur, gimeracil and oteracil potassium constituent, gimeracil can suppress under dihydropyrimidine dehydrogenase effect from replacing
Add the catabolism of the 5-fluorouracil that fluorine discharges, contribute in long-time blood effective with 5-fluorouracil in tumor tissues
The degree of depth, thus obtain the curative effect similar with 5-fluorouracil Intravenous Infusion.
Tegafur, gimeracil and oteracil potassium is that a kind of Fluorouracil derivative is administered orally anticarcinogen, and it includes ftorafur (FT) and two categories below regulation
Agent: gimeracil (CDHP) and oteracil (Oxo).The effect of its three kinds of components is as follows: FT is the precursor medicine of 5-fluorouracil
Thing, has excellent oral administration biaavailability, can in vivo be converted into 5-fluorouracil.CDHP can suppress at dihydro-pyrimidin
The catabolism of the 5-fluorouracil discharged from FT under dehydrogenase effect, contributes in long-time blood and 5-in tumor tissues
Fluorouracil effective depth, thus obtain the curative effect similar with 5-fluorouracil Intravenous Infusion.Oxo can block 5-fluorine urine
The phosphorylation of pyrimidine, after oral administration, Oxo has the highest distributed density in gastrointestinal tissue, thus it is phonetic to affect 5-fluorine urine
Pyridine is distributed at gastrointestinal, and then reduces the effect of 5-Fu toxicity.Tegafur, gimeracil and oteracil potassium has the advantage that compared with 5-fluorouracil
1. can maintain higher blood drug level and improve active anticancer；2. medicine toxicity is significantly reduced；3. convenient drug administration.
In Japan, tegafur, gimeracil and oteracil potassium went through for treating late gastric cancer in 1999, and calendar year 2001 goes through for treating head and neck
Portion's cancer, goes through for treating colorectal cancer for 2003, within 2004, goes through for treating nonsmall-cell lung cancer.Facing for many years
Bed application attestation, tegafur, gimeracil and oteracil potassium is safely and effectively cancer therapy drug.According to statistics, the chemotherapy of Japan's late gastric cancer, there is the disease of more than 80%
Example uses tegafur, gimeracil and oteracil potassium, and treated effect is up to 44.6%.
The synthesis (Shenyang Pharmaceutical University journal Nov2005 vol22 No6 P420-421) of document Gimeracil discloses
A kind of synthetic method of Gimeracil, the method is with 3-cyano group-4-methoxyl group-2(1H)-pyridone is as raw material, and N mono-chloro
Succimide (NCS) reacts in glacial acetic acid and prepares 5-chloro-3-cyano group-4-methoxyl group-2 (1H) pyridone, then at hydrogen bromine
In acid solution, hydrolysis obtains gimeracil.Mol ratio 3-cyano group-4-methoxyl group-2-H-pyridone: NCS=1:1.1 in the method,
Glacial acetic acid solvent amount is 7.5 times of 3-cyano group-4-methoxyl group-2-H-pyridone raw material.Intermediate 3-cyano group-4-in the method
Methoxyl group-5-chlorine 2-(1H) pyridone preparation process needs to use N-chlorosuccinimide (NCS), and glacial acetic acid needs dense
Contracting, acetic acid boiling point is high, concentrates more difficult aborning, needs vacuum equipment, makes generated time extend, and secondary anti-in concentration process
Ying Duo, introduces impurity many, thereby results in finished product gimeracil purity difference, need repeatedly to refine.
Document Heterocycles vol36 No1 1993 145-148 discloses the synthetic method of a kind of gimeracil,
The method is with 3-cyano group-4-methoxyl group-2(1H)-pyridone as raw material, react system in glacial acetic acid with sulfonic acid chloride or chlorine
Obtaining 5-chloro-3-cyano group-4-methoxyl group-2 (1H) pyridone, then in dilute sulfuric acid or hydrobromic acid solution, reaction prepares lucky beautiful
Pyrimidine.Intermediate 3-cyano group-4-methoxyl group-5-chlorine 2-(1H in the method) glacial acetic acid needs also exist for dense in pyridone preparation process
Contracting, in easy course of reaction, side reaction is many, introduces impurity many, thereby results in finished product gimeracil purity difference, need multiple fine
System；It addition, after acetic acid has concentrated, need to use methanol and diisopropyl ether to refine, so other solvent that introduces, one is easy
Causing dissolvent residual in end-product, two is either methanol or ether, its price will than water expensive a lot, considerably increase life
Produce cost.
All there is problems of yield by both the above preparation method low, the cycle is long, and cost is high, is not suitable for industry metaplasia
The shortcomings such as product.
Summary of the invention
In order to solve above-mentioned technical problem, the invention provides the synthetic method of a kind of gimeracil.The method product
Yield is high, and low cost is simple to operate, is particularly well-suited to industrialized production.
The present invention is to be realized by following technical scheme:
S1:3-cyano group-4-methoxyl group-5-chlorine 2-(1H) preparation of pyridone
3-cyano group-4-methoxyl group-2-H-pyridone, glacial acetic acid are joined in reactor, lowers the temperature and stir, treating that temperature is down to 20
Starting to drip sulfonic acid chloride time below DEG C, after dropping, be warming up to 52 ± 2 DEG C, be incubated 50-54 DEG C of reaction, TLC monitoring raw material is anti-
Should be complete, it is cooled to 20 ± 3 DEG C, stirs 2 hours, filter to obtain white solid, dry and obtain 3-cyano group-4-methoxyl group-5-chlorine 2-
(1H) pyridone；
The preparation of S2: gimeracil
By 3-cyano group-4-methoxyl group-5-chlorine 2-(1H) pyridone and hydrobromic acid put in reactor, stirring, is heated to backflow
Reaction 18h, cooling, concentrating under reduced pressure hydrobromic acid, add deionized water stirring and molten add decolorizing with activated carbon clearly to residual solid is whole,
Heat filter, be incubated 50 ± 3 DEG C, starts to drip the sodium hydroxide solution regulation pH value of 40% to pH=4 ± 0.5, separates out a large amount of solid, drop
Temperature, to 10-15 DEG C, stirs 3 hours, and sucking filtration obtains gimeracil.
Synthetic reaction route of the present invention is as follows:
In the synthetic method of above-mentioned gimeracil, 3-cyano group-4-methoxyl group-2-H-pyridone and glacial acetic acid in described step S1
Mass volume ratio be 1:7-10, unit g:ml.
In the synthetic method of above-mentioned gimeracil, 3-cyano group-4-methoxyl group-2-H-pyridone and sulphur in described step S1
The mol ratio of acyl chlorides is 1:1-1.2.
In the synthetic method of above-mentioned gimeracil, in described step S1,50-54 DEG C of response time is 3-5h.
In the synthetic method of above-mentioned gimeracil, in described step S1,50-54 DEG C of response time is 4h.
In the synthetic method of above-mentioned gimeracil, in described step S2, hydrobromic acid mass percent concentration is 48%.
Beneficial effect:
(1) synthetic method of the gimeracil of the present invention, not reconcentration glacial acetic acid, crystallize of lowering the temperature after using reaction completely instead, then
Being filtrated to get intermediate purification product, gained intermediate purity is high；Then in 48% hydrobromic acid solution, hydrolysis obtains product, dissolves
After decolouring, alkali tune crystallize obtains product again, it is not necessary to refined, i.e. can get the gimeracil that purity is higher.
(2) in the preparation method of the gimeracil that the present invention provides, the 3-cyano group-4-methoxyl group-5-chlorine 2-of intermediate
(1H) in the preparation process of pyridone, crystallize of directly lowering the temperature is used, it is not necessary to use methanol and diisopropyl ether to refine, in preparation process
Do not introduce other solvents, on the premise of ensureing product purity, reduce production cost.
(2) preparation method of the gimeracil that the present invention provides, technological operation is easy, and the cycle is short, low cost, product purity
Good, it is easy to the large-scale production of product.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is further described, in order to those skilled in the art knows more about
The present invention, but and it is not so limited the present invention.
Owing to 3-cyano group-4-methoxyl group-2-H-pyridone is easier to buy in the market, this technique all uses this raw material to be
Initiation material.
Embodiment 1
S1:3-cyano group-4-methoxyl group-5-chlorine 2-(1H) preparation of pyridone
By 3-cyano group-4-methoxyl group-2-H-pyridone 6.0g(0.04mol), 45ml glacial acetic acid put into 250 milliliters of there-necked flasks
In, it is cooled to less than 15 DEG C, then drips 6.18g(0.045mol) gram sulfonic acid chloride, solution temperature controls between 10 ~ 15 DEG C,
The speed of dropping can be controlled according to the change of temperature.After dropping, stir half an hour, be warming up to 52 ± 2 DEG C, insulation
50-54 DEG C reaction 4h, TLC(TLC developing solvent: ethyl acetate: methanol=9:1) monitoring raw material reaction complete, reactant liquor is cooled to
20 ± 2 DEG C, stirring 2 hours, filter, filter cake 58ml water washs, and at 80 DEG C, wet product is dried under normal pressure 12h the most dry,
7.01g3-cyano group-4-methoxyl group-5-chlorine 2-(1H) pyridone white powder, yield 95.0%, theoretical yield 7.38g.
The preparation of S2: gimeracil
By 3-cyano group-4-methoxyl group-5-chlorine 2-(1H) pyridone 6.0g(0.033mol) and 163g mass percentage concentration be 48%
Hydrobromic acid solution is put in 500 milliliters of there-necked flasks, is heated to back flow reaction 18h, is cooled to 50 ± 2 DEG C, concentrating under reduced pressure matter
Amount percentage concentration be the hydrobromic acid solution of 48%, add 60ml deionized water stirring to residual solid whole molten clearly, add 0.6g activity
Carbon, 80 DEG C of stirring 15min, heat considers, and filtrate is incubated 50 ± 3 DEG C, starts to drip the sodium hydroxide solution regulation pH value of 40% to pH=4
± 0.5, it is cooled to 10-15 DEG C after having adjusted, stirs 3 hours, sucking filtration 12ml water washs.Wet product is baking material 14h under 80 DEG C of normal pressures,
4.40g gimeracil off-white powder, yield 93%, theoretical yield 4.73g, purity is more than 99.5%, and single impurity is respectively less than
0.1%
Embodiment 2
S1:3-cyano group-4-methoxyl group-5-chlorine 2-(1H) preparation of pyridone
By 3-cyano group-4-methoxyl group-2-H-pyridone 6.0g(0.04mol), 42ml glacial acetic acid put into 250 milliliters of there-necked flasks
In, it is cooled to less than 15 DEG C, then drips 5.40g(0.040mol) gram sulfonic acid chloride, solution temperature controls between 10 ~ 15 DEG C,
The speed of dropping can be controlled according to the change of temperature.After dropping, stir half an hour, be warming up to 52 ± 2 DEG C, insulation
50-54 DEG C reaction 3h, TLC(TLC developing solvent: ethyl acetate: methanol=9:1) monitoring raw material reaction complete, reactant liquor is cooled to
20 ± 2 DEG C, stirring 2 hours, filter, filter cake 58ml water washs, and at 80 DEG C, wet product is dried under normal pressure 12h the most dry,
6.91g3-cyano group-4-methoxyl group-5-chlorine 2-(1H) pyridone white powder, yield 93.6%, theoretical yield 7.38g.
The preparation of S2: gimeracil
By 3-cyano group-4-methoxyl group-5-chlorine 2-(1H) pyridone 6.0g(0.033mol) and 163g mass percentage concentration be 48%
Hydrobromic acid solution is put in 500 milliliters of there-necked flasks, is heated to back flow reaction 18h, is cooled to 50 ± 2 DEG C, concentrating under reduced pressure matter
Amount percentage concentration be the hydrobromic acid solution of 48%, add 60ml deionized water stirring to residual solid whole molten clearly, add 0.6g activity
Carbon, 80 DEG C of stirring 15min, heat considers, and filtrate is incubated 50 ± 3 DEG C, starts to drip the sodium hydroxide solution regulation pH value of 40% to pH=4
± 0.5, it is cooled to 10-15 DEG C after having adjusted, stirs 3 hours, sucking filtration 12ml water washs.Wet product is baking material 14h under 80 DEG C of normal pressures,
4.39g gimeracil off-white powder, yield 92.8%, theoretical yield 4.73g, purity is more than 99.5%, and single impurity is respectively less than
0.1%。
Embodiment 3
S1:3-cyano group-4-methoxyl group-5-chlorine 2-(1H) preparation of pyridone
By 3-cyano group-4-methoxyl group-2-H-pyridone 6.0g(0.04mol), 60ml glacial acetic acid put into 250 milliliters of there-necked flasks
In, it is cooled to less than 15 DEG C, then drips 6.48g(0.048mol) gram sulfonic acid chloride, solution temperature controls between 10 ~ 15 DEG C,
The speed of dropping can be controlled according to the change of temperature.After dropping, stir half an hour, be warming up to 52 ± 2 DEG C, insulation
50-54 DEG C reaction 5h, TLC(TLC developing solvent: ethyl acetate: methanol=9:1) monitoring raw material reaction complete, reactant liquor is cooled to
20 ± 2 DEG C, stirring 2 hours, filter, filter cake 58ml water washs, and at 80 DEG C, wet product is dried under normal pressure 12h the most dry,
6.95g3-cyano group-4-methoxyl group-5-chlorine 2-(1H) pyridone white powder, yield 94.2%, theoretical yield 7.38g..
The preparation of S2: gimeracil
By 3-cyano group-4-methoxyl group-5-chlorine 2-(1H) pyridone 6.0g(0.033mol) and 163g mass percentage concentration be 48%
Hydrobromic acid solution is put in 500 milliliters of there-necked flasks, is heated to back flow reaction 18h, is cooled to 50 ± 2 DEG C, concentrating under reduced pressure matter
Amount percentage concentration be the hydrobromic acid solution of 48%, add 60ml deionized water stirring to residual solid whole molten clearly, add 0.6g activity
Carbon, 80 DEG C of stirring 15min, heat considers, and filtrate is incubated 50 ± 3 DEG C, starts to drip the sodium hydroxide solution regulation pH value of 40% to pH=4
± 0.5, it is cooled to 10-15 DEG C after having adjusted, stirs 3 hours, sucking filtration 12ml water washs.Wet product is baking material 14h under 80 DEG C of normal pressures,
4.41g gimeracil off-white powder, yield 93.2%, theoretical yield 4.73g, purity is more than 99.5%, and single impurity is respectively less than
0.1%。
Comparative example 1 is prepared with reference to the method described in Shenyang Pharmaceutical University journal Nov2005vol22No6P420-421
The preparation of S1:5-chloro-3-cyano group-4-methoxyl group-2 (1H) pyridone
By 3-cyano group-4-methoxyl group-2 (1H) pyridone 400.0g (2.66mo1) and N-chlorosuccinimide (NCS) 390.6g
(2.93mo1) join in 3000mL glacial acetic acid, 45 DEG C of stirring 8h, remove solvent under reduced pressure, add methanol and the mixing of diisopropyl ether
Solvent (volume ratio is 1:1) 100mL, separates out white solid, sucking filtration, is joined by filter cake in 500mI water, by volume fraction be
The NaOH regulation pH value of 10%, to 9, stirs 1h, stands, sucking filtration, be dried, obtain solid 452.9g, yield 92.3%
The preparation of S2: gimeracil
Chloro-for 5-3-itrile group-4-methoxyl group-2 (1H) pyridone (4) 184.5g (1.0mo1) is joined 922.5mL mass fraction
It is in the hydrobromic acid of 48%, is heated to 125 DEG C, be stirred at reflux 24h, obtain white solid after concentrating under reduced pressure, add 800mI water-soluble
Solve, be that 10%NaQH aqueous solution is neutralized to pH value and is about 4 by volume fraction, separate out white solid, sucking filtration, be dried, gained solid
It is the ethyl alcohol recrystallization of 95% by volume fraction, obtains Gimeracil 126.5g, yield 86.9%, after testing purity 91.5%,
Big single miscellaneous 0.54%.
Prepared by comparative example 2 list of references Heterocycles vol36 No1 1993 145-148
The preparation of S1:5-chloro-3-cyano group-4-methoxyl group-2 (1H) pyridone
By 3-cyano group-4-methoxyl group-2-H-pyridone 20.0g(0.133 mol), join in 200ml glacial acetic acid, then drip
Sulfonic acid chloride 128ml(0.160mol), drip at ambient temperature, after dropping, stir 4 hours at 50 DEG C, be concentrated in vacuo, to
Residue adds 15ml methanol and 15ml diisopropyl ether, collect solid be filtrated to get the 5-chloro-3-cyano group-4-methoxyl group of 22.3g-
2 (1H) pyridone product, yield 91%；
The preparation of S2: gimeracil
Chloro-for 5-3-itrile group-4-methoxyl group-2 (1H) pyridone 5.0g (27.1mm o1) is put in the hydrobromic acid of 47%, return
Stream reaction 24 hours, is concentrated in vacuo, and residue is soluble in water, neutralizes with 10% sodium hydrate aqueous solution, then adjusts pH with 5% hydrochloric acid
To 4.0-4.5, filter, washing, obtain 13.6g gimeracil, yield 93%.After testing, purity is more than 92.4%, and maximum list is miscellaneous
0.45%。
Claims (6)
1. a synthetic method for gimeracil, comprises the steps:
S1:3-cyano group-4-methoxyl group-5-chlorine 2-(1H) preparation of pyridone
3-cyano group-4-methoxyl group-2-H-pyridone, glacial acetic acid are joined in reactor, lowers the temperature and stir, treating that temperature is down to 20
Starting to drip sulfonic acid chloride time below DEG C, after dropping, be warming up to 52 ± 2 DEG C, be incubated 50-54 DEG C of reaction, TLC monitoring raw material is anti-
Should be complete, it is cooled to 20 ± 3 DEG C, stirs 2 hours, filter to obtain white solid, dry and obtain 3-cyano group-4-methoxyl group-5-chlorine 2-
(1H) pyridone；
The preparation of S2: gimeracil
By 3-cyano group-4-methoxyl group-5-chlorine 2-(1H) pyridone and hydrobromic acid put in reactor, stirring, is heated to backflow
Reaction 18h, cooling, concentrating under reduced pressure hydrobromic acid, add deionized water stirring and molten add decolorizing with activated carbon clearly to residual solid is whole,
Heat filter, be incubated 50 ± 3 DEG C, starts to drip the sodium hydroxide solution regulation pH value of 40% to pH=4 ± 0.5, separates out a large amount of solid, drop
Temperature, to 10-15 DEG C, stirs 3 hours, and sucking filtration obtains gimeracil.
The synthetic method of gimeracil the most according to claim 1, it is characterised in that 3-cyano group-4-in described step S1
Methoxyl group-2-H-pyridone is 1:7-10 with the mass volume ratio of glacial acetic acid.
The synthetic method of gimeracil the most according to claim 1, it is characterised in that 3-cyano group-4-in described step S1
Methoxyl group-2-H-pyridone is 1:1-1.2 with the mol ratio of sulfonic acid chloride.
The synthetic method of gimeracil the most according to claim 1, it is characterised in that in described step S1 50-54 DEG C anti-
It is 3-5h between Ying Shi.
The synthetic method of gimeracil the most according to claim 4, it is characterised in that in described step S1 50-54 DEG C anti-
It is 4h between Ying Shi.
The synthetic method of gimeracil the most according to claim 1, it is characterised in that hydrobromic acid quality in described step S2
Percent concentration is 48%.
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| CN113861106A (en) * | 2021-10-26 | 2021-12-31 | 山东安舜制药有限公司 | Production process of high-purity medicinal gimeracil |
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Application publication date: 20170111 |