CN108586360A - A kind of preparation method of the chloro- 3- methyluracils of 6- - Google Patents
A kind of preparation method of the chloro- 3- methyluracils of 6- Download PDFInfo
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- CN108586360A CN108586360A CN201810609634.5A CN201810609634A CN108586360A CN 108586360 A CN108586360 A CN 108586360A CN 201810609634 A CN201810609634 A CN 201810609634A CN 108586360 A CN108586360 A CN 108586360A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
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Abstract
A kind of preparation method of 6 chlorine, 3 methyluracil, uses dimethyl malenate, with N methylurea in the case where sodium methoxide is as alkaline condition, cyclization, then obtain 1 methylbarbituric acid of intermediate by being acidified purification；Again product is obtained through phosphorus oxychloride chlorination.Advantageous effect is：Reaction process is more environmentally-friendly, and by-product is few, and without using the reagent of pollution weight；Reaction process is simple, and safety is good, is conducive to industrialized production；The yield higher of end product.
Description
Technical field
The invention belongs to field of biological pharmacy more particularly to a kind of preparation methods of the chloro- 3- methyluracils of 6-.
Background technology
The chloro- 3- methyluracils of 6- are the key intermediates of Egelieting, and Egelieting is Japanese Takeda companies research and development
Serine protease inhibitors of dipeptidyl IV, primary treatment diabetes B.In November, 2013 is approved to list in China,
It is a kind of novel diabetes medication.
Currently, main production uses malonic acid and N- methylurea to obtain target product through cyclization, chlorination for raw material, but
It is that the synthesis technology yield is low, especially cyclization step, whole yield is less than 60%.
Or, target product, but the iodomethane for using environmental pollution larger are synthesized to obtain with iodomethane using 6- chlorouracils,
And cost is costly.
Invention content
To solve the above-mentioned problems, the present invention adopts the following technical scheme that：
A kind of preparation method of the chloro- 3- methyluracils of 6-, specifically includes following steps,
（a）Sodium methoxide shown in methylurea, formula III shown in formula II is added in methanol solution, temperature adjustment is to 40-50 DEG C；It [uses
Sodium methoxide come make reaction solution in alkalinity]
（b）It is 40-50 DEG C to keep temperature, and dimethyl malenate shown in formula I is slowly added dropwise；After being added dropwise, temperature rising reflux is anti-
It answers, 1- methylbarbituric acids shown in production IV；
[slowly dimethyl malenate I is added in methylurea II under alkaline condition, can effectively avoid dimethyl malenate
Again with methanol esterification after I hydrolysis, it is also avoided that generation acid-base neutralization reaction；When dimethyl malenate I is slowly added dropwise, the third two
It after dimethyl phthalate I is hydrolyzed into malonic acid, is preferentially reacted with methylurea II, avoids malonic acid and reacted with methanol, improve yield；
If malonic acid is directly added dropwise, with alkaline matter neutralization reaction occurs for malonic acid, causes by-product to generate, also reduces yield]
（c）Reactant is cooled to 20-30 DEG C, and IV crystal of 1- methylbarbituric acids is precipitated, filters, dry；
（d）Controlled at 10-20 DEG C, in step（c）Hydrochloric acid, crystal is added in IV crude product of 1- methylbarbituric acids after drying
Mass ratio with hydrochloric acid is 1：2；[sodium methoxide is in step（a）In make solution be alkalinity, ensure that the hydrolysis of lipid；Wherein plus
Enter hydrochloric acid, neutralization reaction occurs for the two, generates methanol and sodium chloride so that the sodium methoxide of relative risk is removed, two products
And hydrochloric acid is soluble easily in water, easily facilitates removing]
（e）It is 10-20 DEG C to keep temperature, is stirred, centrifugation, dry IV solid of 1- methylbarbituric acids；
（f）By step（e）The solid of dry gained is mixed with phosphorus oxychloride shown in formula V, and H is added dropwise at 18-23 DEG C2O；H2O
With step（e）The solid masses ratio of dry gained is 1：（5-5.5）；
Phosphorus oxychloride（V）
（g）H2After O is added dropwise to complete, it is slowly warming up to 70-75 DEG C, constant temperature stirs, and the chloro- 3- methyl urine of 6- shown in production VI is phonetic
Pyridine；
（h）Reactant is cooled to 20-30 DEG C, is then slowly added into H2O；H2O and step（f）Dry added 1- Methyl barbiturates
Sour IV solid masses ratio is（4.5-5.5）：1；Stirring filters, obtains solid；
（i）To step（h）The solid of gained is recrystallized, and chloro- VI solids of 3- methyluracils of 6- are obtained.
Preferably, step（c）During precipitating crystal, methanol is concentrated, it is step to make the concentration of methanol total amount（a）Middle addition
The 60-80% of total amount.[method of concentration methanol is known technology, does not add to repeat]
Preferably, step（i）Recrystallizing specific step is：
The first step, by step（h）Obtained solid dissolves in sodium hydroxide solution, adjusts the temperature to 45-55 DEG C, keeps solid complete
Dissolving；
Second step, it is 6-7 that hydrochloric acid, which is added dropwise, and adjusts PH, is precipitated crystal, and it is 10-20 DEG C to adjust temperature, keeps the temperature crystallization；
Third walks, and liquid is centrifuged, by centrifugation obtained solid drying.
Preferably, in the first step, the mass ratio of concentration of sodium hydroxide solution 5%, sodium hydroxide solution and solid is（5-
5.5）：1.
Preferably, step（b）The temperature of temperature rising reflux is 55-60 DEG C；Step（b）Middle dimethyl malenate I is at the uniform velocity to drip
Add, time for adding 1-2h.
Preferably, step（h）Be incorporated slowly as be added dropwise, 0.5-1h is added.
The beneficial effects of the invention are as follows：
1. reaction process is more environmentally-friendly, by-product is few, and without using the reagent of pollution weight；
2. reaction process is simple, safety is good, is conducive to industrialized production；
3. the yield and purity higher of end product.
Description of the drawings
Fig. 1 is the reaction equation of the present invention；
Fig. 2 is the mass spectrogram of 1 final product of the embodiment of the present invention；
Fig. 3-5 is embodiment 1-3 liquid chromatograms.
The Roman number mark of compound in attached drawing referring to identifying in the present invention.
Specific implementation mode
With reference to embodiment, invention is further explained：
Embodiment 1
It is prepared by 1- methylbarbituric acid solids：15g methylurea II, 11g sodium methoxides III, temperature adjustment are added in 500ml methanol solutions
To 50 DEG C；Keep temperature, 2h that 24ml dimethyl malenates I are slowly added dropwise；After being added dropwise, 60 DEG C of back flow reactions are warming up to, it is raw
At 1- methylbarbituric acids IV；Reactant is cooled to 30 DEG C, concentrates methanol, makes the concentration of methanol total amount to be initially added total amount
60%, IV crystal of 1- methylbarbituric acids solid is precipitated, filters, it is dry；
1- Methyl barbiturate acid crystals purify：Controlled at 20 DEG C, the 1- methylbarbituric acids solid IV after aforementioned drying
It is added hydrochloric acid in crude product, the mass ratio of crystal and hydrochloric acid is 1：2.5；It is 20 DEG C to keep temperature, is stirred, centrifugation, dry 1- first
IV solid of base barbiturates；Yield is 89%, purity 98%.
It is prepared by the chloro- 3- methyluracils of 6-：By IV solid of 1- methylbarbituric acids and three of dry gained after aforementioned proposition
Chlorethoxyfos V mix, and H is added dropwise at 23 DEG C2O, 1h are added, H2The IV solid masses ratio of 1- methylbarbituric acids of O and dry gained
It is 1：5.5；H2After O is added dropwise to complete, it is slowly warming up to 75 DEG C（Heating-up time is 1.5 hours or so）, constant temperature stirring, generation 6-
Chloro- 3- methyluracils VI；Reactant is cooled to 30 DEG C, is then slowly added into H2O, H2The quality of O and aforementioned added 1- methyl
IV mass ratio of barbiturates is 5.5：1；Stirring filters, obtains solid, which is chloro- VI crude products of 3- methyluracils of 6-；
The chloro- 3- methyluracils purification recrystallizations of 6-：Chloro- VI crude products of 3- methyluracils of the 6- of aforementioned gained are dissolved in into 5% hydrogen-oxygen
Change in sodium solution, the mass ratio of sodium hydroxide solution and chloro- VI crude products of 3- methyluracils of 6- is 5.5：1；Adjust the temperature to 55
DEG C, so that solid is completely dissolved；Hydrochloric acid is added dropwise and adjusts PH between 6-7, precipitates crystal, it is 20 DEG C to adjust temperature, keeps the temperature crystallization；It will
Liquid centrifuges, and dries centrifugation obtained solid to obtain the chloro- 3- methyluracils of 6-；Yield is 83%, purity 98.5%, liquid phase color
Spectrogram is as shown in Figure 3.
Embodiment 2
It is prepared by 1- methylbarbituric acid solids：15g methylurea II, 11g sodium methoxides III, temperature adjustment are added in 500ml methanol solutions
To 40 DEG C；Keep temperature, 1h that 24ml dimethyl malenates I are slowly added dropwise；After being added dropwise, 60 DEG C of back flow reactions are warming up to, it is raw
At 1- methylbarbituric acids IV；Reactant is cooled to 20 DEG C, concentrates methanol, makes the concentration of methanol total amount to be initially added total amount
80%, IV crystal of 1- methylbarbituric acids solid is precipitated, filters, it is dry；
1- Methyl barbiturate acid crystals purify：Controlled at 10 DEG C, the 1- methylbarbituric acids solid IV after aforementioned drying
It is added hydrochloric acid in crude product, the mass ratio of crystal and hydrochloric acid is 1：1.5；It is 10 DEG C to keep temperature, is stirred, centrifugation, dry 1- first
IV solid of base barbiturates；Yield is 89%, purity 96%.
It is prepared by the chloro- 3- methyluracils of 6-：By IV solid of 1- methylbarbituric acids and three of dry gained after aforementioned proposition
Chlorethoxyfos V mix, and H is added dropwise at 20 DEG C2O, 1h are added, H2The IV solid masses ratio of 1- methylbarbituric acids of O and dry gained
It is 1：4.5；H2After O is added dropwise to complete, it is slowly warming up to 70 DEG C（Heating-up time is 1.5 hours or so）, constant temperature stirring, generation 6-
Chloro- 3- methyluracils VI；Reactant is cooled to 20 DEG C, is then slowly added into H2O, H2The quality of O and aforementioned added 1- methyl
IV mass ratio of barbiturates is 5：1；Stirring filters, obtains solid, which is chloro- VI crude products of 3- methyluracils of 6-；
The chloro- 3- methyluracils purification recrystallizations of 6-：Chloro- VI crude products of 3- methyluracils of the 6- of aforementioned gained are dissolved in into 5% hydrogen-oxygen
Change in sodium solution, the mass ratio of sodium hydroxide solution and chloro- VI crude products of 3- methyluracils of 6- is 5：1；55 DEG C are adjusted the temperature to,
Solid is set to be completely dissolved；It is 6 that hydrochloric acid, which is added dropwise, and adjusts PH, is precipitated crystal, and it is 20 DEG C to adjust temperature, keeps the temperature crystallization；Liquid is centrifuged,
It dries centrifugation obtained solid to obtain the chloro- 3- methyluracils of 6-；Yield is 82%, purity 98%, liquid chromatogram such as Fig. 4 institutes
Show.
Embodiment 3
It is prepared by 1- methylbarbituric acid solids：15g methylurea II, 11g sodium methoxides III, temperature adjustment are added in 500ml methanol solutions
To 45 DEG C；Keep temperature, 1.5h that 24ml dimethyl malenates I are slowly added dropwise；After being added dropwise, 60 DEG C of back flow reactions are warming up to,
Generate 1- methylbarbituric acids IV；Reactant is cooled to 25 DEG C, concentrates methanol, makes the concentration of methanol total amount to be initially added total amount
70%, IV crystal of 1- methylbarbituric acids solid is precipitated, filters, it is dry；
1- Methyl barbiturate acid crystals purify：Controlled at 15 DEG C, the 1- methylbarbituric acids solid IV after aforementioned drying
It is added hydrochloric acid in crude product, the mass ratio of crystal and hydrochloric acid is 1：2；It is 15 DEG C to keep temperature, is stirred, centrifugation, dry 1- methyl
IV solid of barbiturates；Yield is 90%, purity 98%.
It is prepared by the chloro- 3- methyluracils of 6-：By IV solid of 1- methylbarbituric acids and three of dry gained after aforementioned proposition
Chlorethoxyfos V mix, and H is added dropwise at 20 DEG C2O, 1h are added, H2The IV solid masses ratio of 1- methylbarbituric acids of O and dry gained
It is 1：5；H2After O is added dropwise to complete, it is slowly warming up to 70 DEG C（Heating-up time is 1.5 hours or so）, constant temperature stirring, generate 6- it is chloro-
3- methyluracils VI；Reactant is cooled to 20 DEG C, is then slowly added into H2O, H2The quality of O and aforementioned added 1- methyl bar
It is 5 than appropriate sour IV mass ratio：1；Stirring filters, obtains solid, which is chloro- VI crude products of 3- methyluracils of 6-；
The chloro- 3- methyluracils purification recrystallizations of 6-：Chloro- VI crude products of 3- methyluracils of the 6- of aforementioned gained are dissolved in into 5% hydrogen-oxygen
Change in sodium solution, the mass ratio of sodium hydroxide solution and chloro- VI crude products of 3- methyluracils of 6- is 5：1；55 DEG C are adjusted the temperature to,
Solid is set to be completely dissolved；It is 7 that hydrochloric acid, which is added dropwise, and adjusts PH, is precipitated crystal, and it is 15 DEG C to adjust temperature, keeps the temperature crystallization；Liquid is centrifuged,
It dries centrifugation obtained solid to obtain the chloro- 3- methyluracils of 6-；Yield is 85%, purity 99.5%, liquid chromatogram such as Fig. 5
It is shown.
Embodiment 4
It is prepared by 1- methylbarbituric acid solids：15g methylurea II, 11g sodium methoxides III is added in 500ml methanol solutions at 45 DEG C
With 24ml dimethyl malenates I；5min is stirred, 60 DEG C of back flow reactions are warming up to, generates 1- methylbarbituric acids IV；Reactant drops
Temperature concentrates methanol to 25 DEG C, makes the concentration of methanol total amount to be initially added the 60% of total amount, 1- methylbarbituric acids solid IV is precipitated
Crystal filters, dry；
1- Methyl barbiturate acid crystals purify：Controlled at 15 DEG C, the 1- methylbarbituric acids solid IV after aforementioned drying
It is added hydrochloric acid in crude product, the mass ratio of crystal and hydrochloric acid is 1：2；It is 15 DEG C to keep temperature, is stirred, centrifugation, dry 1- methyl
IV solid of barbiturates；Yield is 72%, purity 89%.
It is prepared by the chloro- 3- methyluracils of 6-：By IV solid of 1- methylbarbituric acids and three of dry gained after aforementioned proposition
Chlorethoxyfos V mix, and H is added dropwise at 20 DEG C2O, 1h are added, H2The IV solid masses ratio of 1- methylbarbituric acids of O and dry gained
It is 1：5；H2After O is added dropwise to complete, it is slowly warming up to 70 DEG C, constant temperature stirring generates the chloro- 3- methyluracils of 6- VI；Reactant drops
Temperature is then slowly added into H to 20 DEG C2O, H2The quality of O is 5 with aforementioned added IV mass ratio of 1- methylbarbituric acids：1；It stirs
It mixes, filters, obtain solid, which is chloro- VI crude products of 3- methyluracils of 6-；
The chloro- 3- methyluracils purification recrystallizations of 6-：Chloro- VI crude products of 3- methyluracils of the 6- of aforementioned gained are dissolved in into 5% hydrogen-oxygen
Change in sodium solution, the mass ratio of sodium hydroxide solution and chloro- VI crude products of 3- methyluracils of 6- is 5：1；55 DEG C are adjusted the temperature to,
Solid is set to be completely dissolved；It is 7 that hydrochloric acid, which is added dropwise, and adjusts PH, is precipitated crystal, and it is 15 DEG C to adjust temperature, keeps the temperature crystallization；Liquid is centrifuged,
It dries centrifugation obtained solid to obtain the chloro- 3- methyluracils of 6-；Yield is 67%, purity 87%.
Embodiment 5
It is prepared by 1- methylbarbituric acid solids：15g methylurea II, 11g sodium methoxides III, temperature adjustment are added in 500ml methanol solutions
To 45 DEG C；Keep temperature, 1.5h that 24ml dimethyl malenates I are slowly added dropwise；After being added dropwise, 60 DEG C of back flow reactions are warming up to,
Generate 1- methylbarbituric acids IV；Reactant is cooled to 25 DEG C, concentrates methanol, makes the concentration of methanol total amount to be initially added total amount
70%, IV crystal of 1- methylbarbituric acids solid is precipitated, filters, it is dry；
1- Methyl barbiturate acid crystals purify：Controlled at 15 DEG C, the 1- methylbarbituric acids solid IV after aforementioned drying
It is added hydrochloric acid in crude product, the mass ratio of crystal and hydrochloric acid is 1：0.5；It is 15 DEG C to keep temperature, is stirred, centrifugation, dry 1- first
IV solid of base barbiturates；Yield is 91%, purity 89%.
It is prepared by the chloro- 3- methyluracils of 6-：By IV solid of 1- methylbarbituric acids and three of dry gained after aforementioned proposition
Chlorethoxyfos V mix, and H is added dropwise at 20 DEG C2O, 1h are added, H2The IV solid masses ratio of 1- methylbarbituric acids of O and dry gained
It is 1：5；H2After O is added dropwise to complete, it is slowly warming up to 70 DEG C（Heating-up time is 1.5 hours or so）, constant temperature stirring, generate 6- it is chloro-
3- methyluracils VI；Reactant is cooled to 20 DEG C, is then slowly added into H2O, H2The quality of O and aforementioned added 1- methyl bar
It is 5 than appropriate sour IV mass ratio：1；Stirring filters, obtains solid, which is chloro- VI crude products of 3- methyluracils of 6-；
The chloro- 3- methyluracils purification recrystallizations of 6-：Chloro- VI crude products of 3- methyluracils of the 6- of aforementioned gained are dissolved in into 5% hydrogen-oxygen
Change in sodium solution, the mass ratio of sodium hydroxide solution and chloro- VI crude products of 3- methyluracils of 6- is 5：1；55 DEG C are adjusted the temperature to,
Solid is set to be completely dissolved；It is 7 that hydrochloric acid, which is added dropwise, and adjusts PH, is precipitated crystal, and it is 15 DEG C to adjust temperature, keeps the temperature crystallization；Liquid is centrifuged,
It dries centrifugation obtained solid to obtain the chloro- 3- methyluracils of 6-；Yield is 85%, purity 97%.
Embodiment 6
It is prepared by 1- methylbarbituric acid solids：15g methylurea II, 11g sodium methoxides III, temperature adjustment are added in 500ml methanol solutions
To 45 DEG C；Keep temperature, 1.5h that 24ml dimethyl malenates I are slowly added dropwise；After being added dropwise, 60 DEG C of back flow reactions are warming up to,
Generate 1- methylbarbituric acids IV；Reactant is cooled to 25 DEG C, concentrates methanol, makes the concentration of methanol total amount to be initially added total amount
70%, IV crystal of 1- methylbarbituric acids solid is precipitated, filters, it is dry；
1- Methyl barbiturate acid crystals purify：Controlled at 15 DEG C, the 1- methylbarbituric acids solid IV after aforementioned drying
It is added hydrochloric acid in crude product, the mass ratio of crystal and hydrochloric acid is 1：2；It is 15 DEG C to keep temperature, is stirred, centrifugation, dry 1- methyl
IV solid of barbiturates；Yield is 90%, purity 98%.
It is prepared by the chloro- 3- methyluracils of 6-：By IV solid of 1- methylbarbituric acids and three of dry gained after aforementioned proposition
Chlorethoxyfos V mix, and H is added dropwise at 20 DEG C2O, 1h are added, H2The IV solid masses ratio of 1- methylbarbituric acids of O and dry gained
It is 1：5；H2After O is added dropwise to complete, it is rapidly heated to 70 DEG C（Heating-up time is 10min or so）, constant temperature stirring, the chloro- 3- of generation 6-
Methyluracil VI；Reactant is cooled to 20 DEG C, is then slowly added into H2O, H2The quality of O compares with aforementioned added 1- methyl bar
Appropriate sour IV mass ratio is 5：1；Stirring filters, obtains solid, which is chloro- VI crude products of 3- methyluracils of 6-；
The chloro- 3- methyluracils purification recrystallizations of 6-：Chloro- VI crude products of 3- methyluracils of the 6- of aforementioned gained are dissolved in into 5% hydrogen-oxygen
Change in sodium solution, the mass ratio of sodium hydroxide solution and chloro- VI crude products of 3- methyluracils of 6- is 5：1；55 DEG C are adjusted the temperature to,
Solid is set to be completely dissolved；It is 7 that hydrochloric acid, which is added dropwise, and adjusts PH, is precipitated crystal, and it is 15 DEG C to adjust temperature, keeps the temperature crystallization；Liquid is centrifuged,
It dries centrifugation obtained solid to obtain the chloro- 3- methyluracils of 6-；Yield is 85%, purity 91%.
Embodiment 7
It is prepared by 1- methylbarbituric acid solids：15g methylurea II, 11g sodium methoxides III, temperature adjustment are added in 500ml methanol solutions
To 45 DEG C；Keep temperature, 1.5h that 24ml dimethyl malenates I are slowly added dropwise；After being added dropwise, 60 DEG C of back flow reactions are warming up to,
Generate 1- methylbarbituric acids IV；Reactant is cooled to 25 DEG C, concentrates methanol, makes the concentration of methanol total amount to be initially added total amount
70%, IV crystal of 1- methylbarbituric acids solid is precipitated, filters, it is dry；
1- Methyl barbiturate acid crystals purify：Controlled at 15 DEG C, the 1- methylbarbituric acids solid IV after aforementioned drying
It is added hydrochloric acid in crude product, the mass ratio of crystal and hydrochloric acid is 1：2；It is 15 DEG C to keep temperature, is stirred, centrifugation, dry 1- methyl
IV solid of barbiturates；Yield is 90%, purity 98%.
It is prepared by the chloro- 3- methyluracils of 6-：By IV solid of 1- methylbarbituric acids and three of dry gained after aforementioned proposition
Chlorethoxyfos V mix, and H is added dropwise at 20 DEG C2O, 1h are added, H2The IV solid masses ratio of 1- methylbarbituric acids of O and dry gained
It is 1：10；H2After O is added dropwise to complete, it is slowly warming up to 70 DEG C（1.5h left and right）, constant temperature stirring, the generation chloro- 3- methyluracils of 6-
Ⅵ；Reactant is cooled to 20 DEG C, is then slowly added into H2O, H2The quality of O and aforementioned added IV mass of 1- methylbarbituric acids
Than being 10：1；Stirring filters, obtains solid, which is chloro- VI crude products of 3- methyluracils of 6-；
The chloro- 3- methyluracils purification recrystallizations of 6-：Chloro- VI crude products of 3- methyluracils of the 6- of aforementioned gained are dissolved in into 5% hydrogen-oxygen
Change in sodium solution, the mass ratio of sodium hydroxide solution and chloro- VI crude products of 3- methyluracils of 6- is 20：1；Adjust the temperature to 55
DEG C, so that solid is completely dissolved；It is 7 that hydrochloric acid, which is added dropwise, and adjusts PH, is precipitated crystal, and it is 15 DEG C to adjust temperature, keeps the temperature crystallization；By liquid from
The heart dries centrifugation obtained solid to obtain the chloro- 3- methyluracils of 6-；Yield is 82%, purity 89%.
Embodiment 8
It is prepared by 1- methylbarbituric acid solids：15g methylurea II, 8.2gNaOH, temperature adjustment to 45 are added in 500ml methanol solutions
℃；Keep temperature, 1.5h that 24ml dimethyl malenates I are slowly added dropwise；After being added dropwise, 60 DEG C of back flow reactions are warming up to, are generated
1- methylbarbituric acids IV；Reactant is cooled to 25 DEG C, concentrates methanol, makes the concentration of methanol total amount to be initially added the 70% of total amount,
IV crystal of 1- methylbarbituric acids solid is precipitated, filters, it is dry；
1- Methyl barbiturate acid crystals purify：Controlled at 15 DEG C, the 1- methylbarbituric acids solid IV after aforementioned drying
It is added hydrochloric acid in crude product, the mass ratio of crystal and hydrochloric acid is 1：2；It is 15 DEG C to keep temperature, is stirred, centrifugation, dry 1- methyl
IV solid of barbiturates；Yield is 47%, purity 62%.
Embodiment 9
It is prepared by 1- methylbarbituric acid solids：15g methylurea II, 11g sodium methoxides III, temperature adjustment are added in 500ml methanol solutions
To 45 DEG C；Keep temperature, 10min that 24ml dimethyl malenates I are slowly added dropwise；After being added dropwise, 60 DEG C of back flow reactions are warming up to,
Generate 1- methylbarbituric acids IV；Reactant is cooled to 25 DEG C, concentrates methanol, makes the concentration of methanol total amount to be initially added total amount
70%, IV crystal of 1- methylbarbituric acids solid is precipitated, filters, it is dry；
1- Methyl barbiturate acid crystals purify：Controlled at 15 DEG C, the 1- methylbarbituric acids solid IV after aforementioned drying
It is added hydrochloric acid in crude product, the mass ratio of crystal and hydrochloric acid is 1：2；It is 15 DEG C to keep temperature, is stirred, centrifugation, dry 1- methyl
IV solid of barbiturates；Yield is 85%, purity 88%.
Embodiment 10
It is prepared by 1- methylbarbituric acid solids：15g methylurea II, 11g sodium methoxides III, temperature adjustment are added in 500ml methanol solutions
To 45 DEG C；Keep temperature, 8h that 24ml dimethyl malenates I are slowly added dropwise；After being added dropwise, 60 DEG C of back flow reactions are warming up to, it is raw
At 1- methylbarbituric acids IV；Reactant is cooled to 25 DEG C, concentrates methanol, makes the concentration of methanol total amount to be initially added total amount
60%, IV crystal of 1- methylbarbituric acids solid is precipitated, filters, it is dry；
1- Methyl barbiturate acid crystals purify：Controlled at 15 DEG C, the 1- methylbarbituric acids solid IV after aforementioned drying
It is added hydrochloric acid in crude product, the mass ratio of crystal and hydrochloric acid is 1：2；It is 15 DEG C to keep temperature, is stirred, centrifugation, dry 1- methyl
IV solid of barbiturates；Yield is 90%, purity 98.5%.
Dropwise addition described herein, generally all referring to being at the uniform velocity added dropwise, however, in practical operation, it may be right as needed
Flow is regulated and controled, and above-described embodiment ignores the error of regulating flow generation.
In addition, the invention is not limited in the above embodiments, as long as it reaches the present invention's with essentially identical means
Technique effect should all belong to the scope of protection of the present invention.
Claims (7)
1. a kind of preparation method of the chloro- 3- methyluracils of 6-, it is characterised in that：Specifically include following steps,
Formula is added in methanol solution（Ⅱ）Shown in methylurea, formula（Ⅲ）Shown in sodium methoxide, temperature adjustment is to 40-50 DEG C；
It is 40-50 DEG C to keep temperature, and formula is slowly added dropwise（Ⅰ）Shown in dimethyl malenate；After being added dropwise, temperature rising reflux is anti-
It answers, production（Ⅳ）Shown in 1- methylbarbituric acids；
Reactant is cooled to 20-30 DEG C, and 1- methylbarbituric acid solids are precipitated（Ⅳ）Crystal filters, dry；
Controlled at 10-20 DEG C, in step（c）1- methylbarbituric acid solids after drying（Ⅳ）Hydrochloric acid is added in crude product,
The mass ratio of crystal and hydrochloric acid is 1：（1.5-2.5）；
It is 10-20 DEG C to keep temperature, is stirred, centrifugation, dry 1- methylbarbituric acids（Ⅳ）Solid；
By step（e）The 1- methylbarbituric acids of dry gained（Ⅳ）Solid and formula（Ⅴ）Shown in phosphorus oxychloride mixing, in 18-
H is added dropwise at 23 DEG C2O；H2O and step（e）The solid masses ratio of dry gained is 1：（5-5.5）；
H2After O is added dropwise to complete, it is slowly warming up to 70-75 DEG C, constant temperature stirs, production（Ⅵ）Shown in 6- chloro- 3- methyl urine it is phonetic
Pyridine；
Reactant is cooled to 20-30 DEG C, is then slowly added into H2O；Stirring filters, obtains solid；
To step（h）The solid of gained is recrystallized, and the chloro- 3- methyluracils of 6- are obtained（Ⅵ）Solid.
2. a kind of preparation method of the chloro- 3- methyluracils of 6- according to claim 1, it is characterised in that：Step（c）
During precipitating crystal, methanol is concentrated, it is step to make the concentration of methanol total amount（a）The middle 60-80% that total amount is added.
3. a kind of preparation method of the chloro- 3- methyluracils of 6- according to claim 1, it is characterised in that：Step（i）Weight
Crystallizing specific step is：
The first step, by step（h）Obtained solid dissolves in sodium hydroxide solution, adjusts the temperature to 45-55 DEG C, keeps solid complete
Dissolving；
Second step, it is 6-7 that hydrochloric acid, which is added dropwise, and adjusts PH, is precipitated crystal, and it is 10-20 DEG C to adjust temperature, keeps the temperature crystallization；
Third walks, and liquid is centrifuged, by centrifugation obtained solid drying.
4. a kind of preparation method of the chloro- 3- methyluracils of 6- according to claim 3, it is characterised in that：In the first step,
Concentration of sodium hydroxide solution is 5%, and the mass ratio of sodium hydroxide solution and solid is（5-5.5）：1.
5. a kind of preparation method of the chloro- 3- methyluracils of 6- according to claim 1, it is characterised in that：Step（b）It rises
The temperature of temperature reflux is 55-60 DEG C；Step（b）Middle dimethyl malenate（Ⅰ）To be at the uniform velocity added dropwise, time for adding 1-2h.
6. a kind of preparation method of the chloro- 3- methyluracils of 6- according to claim 1, it is characterised in that：Step（h）'s
It is incorporated slowly as being added dropwise, 0.5-1h is added.
7. a kind of preparation method of the chloro- 3- methyluracils of 6- according to claim 1, it is characterised in that：Step（h）In
H is added2The quality and step of O（f）Added 1- methylbarbituric acids（Ⅳ）Solid masses ratio is（4.5-5.5）：1.
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