CN102952084A - Synthesis method of 4, 6-dichloro-2-methylthio-5-nitro pyrimidine - Google Patents
Synthesis method of 4, 6-dichloro-2-methylthio-5-nitro pyrimidine Download PDFInfo
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Abstract
The invention discloses a synthesis method of 4, 6-dichloro-2-methylthio-5-nitro pyrimidine, belonging to synthesis of pyridine compounds. According to the synthesis method of the 4, 6-dichloro-2-methylthio-5-nitro pyrimidine, the 4, 6-dichloro-2-methylthio-5-nitro pyrimidine is synthesized through four-step reaction such as nitrification, cyclization, methylation and chlorination from diethyl malonate, wherein a nitrification reagent in the first step is concentrated nitric acid or fuming nitric acid; a pyrimidine heterocyclic compound is formed with thiourea in the second step under the action of sodium alcoholate; a methylation reagent in the third step is dimethyl sulfate; a chlorination reagent in the fourth step is phosphorus oxychloride; and meanwhile, a small amount of N, N-dimethylaniline is used as a catalyst. The technical route is rational, easy and convenient to select, the synthesis method is easy to operate, and the target compound is successfully synthesized.
Description
Technical field
The present invention relates to a kind ofly 4, the synthetic method of 6-two chloro-2-methylthio group-5-nitro-pyrimidines belongs to the synthetic of pyrimidines.
Background technology
Pyrimidines is the intermediate of many medicine, agricultural chemicals, and application prospect is boundless.Do not have ready-made total synthesis method in the synthetic document of 4,6-, two chloro-2-methylthio group-5-nitro-pyrimidines, it is more meaningful and valuable therefore studying the synthetic of this compound.
Summary of the invention
The invention provides a kind of 4, the synthetic method of 6-two chloro-2-methylthio group-5-nitro-pyrimidines.
Technical scheme of the present invention is: a kind of 4, the operation steps of the synthetic method of 6-two chloro-2-methylthio group-5-nitro-pyrimidines is:
(1) the first step is nitrated
Diethyl malonate is nitrated at excessive concentrated nitric acid or nitrosonitric acid, hydrolysis, organic solvent extraction, drying, precipitation, underpressure distillation, get a step product 2-nitro diethyl malonate, 0～30 ℃ of temperature of reaction, nitric acid is 4.0-10.0 with respect to the molar equivalent ratio of diethyl malonate; Organic solvent is common solvent, preferred toluene, ethyl acetate;
(2) second step cyclisation
Thiocarbamide is heating for dissolving in methyl alcohol or alcohol solvent, under the effect of corresponding sodium alkoxide, generates 4,6-dihydroxyl-2-sulfydryl-5-nitro-pyrimidine with 2-nitro diethyl malonate ring closure reaction; The cyclization temperature is at 40-80 ℃, and thiocarbamide is 1.0-1.05 with respect to the molar equivalent of 2-nitro diethyl malonate, and sodium alkoxide is 2.0-2.5 with respect to the molar equivalent of 2-nitro diethyl malonate;
(3) the 3rd steps methylated
4,6-dihydroxyl-2-sulfydryl-5-nitro-pyrimidine dissolves in aqueous sodium hydroxide solution, methylate with methyl-sulfate and to generate three step products 4,6-dihydroxyl-2-methylthio group-5-nitro-pyrimidine, temperature of reaction 10-40 ℃, sodium hydroxide is 3-6 with respect to the molar equivalent of 4,6-dihydroxyl-2-sulfydryl-5-nitro-pyrimidine, methyl-sulfate is 1.0-1.5 with respect to the molar equivalent of 4,6-dihydroxyl-2-sulfydryl-5-nitro-pyrimidine;
(4) the 4th one-step chlorinations
Three step products 4, the chlorination in excessive phosphorus oxychloride (both as reactant, again as solvent) of 6-dihydroxyl-2-methylthio group-5-nitro-pyrimidine, hydrolysis, ethyl acetate extraction, drying, precipitation, purifying get the finished product 4,6-two chloro-2-methylthio group-5-nitro-pyrimidines; Temperature of reaction is 100-110 ℃ of back flow reaction temperature, yield 40-80%; Chlorination process adds a small amount of N, and N-xylidine is made catalyzer.
Adopt above-mentioned technical scheme, from basic material diethyl malonate and thiocarbamide, through nitrated, cyclisation methylates and chlorination generates target product.
Reaction equation:
The invention has the beneficial effects as follows: this 4, the synthetic method of 6-two chloro-2-methylthio group-5-nitro-pyrimidines, from diethyl malonate, through nitrated, cyclisation methylates, and the chlorination four-step reaction is synthetic.
The first step nitrating agent is concentrated nitric acid or nitrosonitric acid, second step and thiocarbamide form pyrimidine heterocyclic compound under the effect of sodium alkoxide, the methylating reagent in the 3rd step is methyl-sulfate, and the chlorination reagent in the 4th step is phosphorus oxychloride, use simultaneously a small amount of N, N-xylidine is made catalyzer.The selection of this technological line is reasonable, easy, easily operation, success synthesized target compound.
Embodiment
Below the present invention is further illustrated with specific embodiment.
Embodiment 1
The first step is nitrated:
To 500ml with adding diethyl malonate 80g(0.5mol in the churned mechanically four-hole reaction flask, 1.0eq), stir and be down to 10-12 ℃, drip 20% nitrosonitric acid 184ml (4.3mol, 8.6eq), warm at 15-20 ℃ in the control in the dropping process, reacted 2-3 hour at 15 ℃ after dripping, after reaction solution slowly poured in the beaker that fills the 200g frozen water stir hydrolysis, layering.Water layer extracts with toluene, merges organic layer, uses successively 5% aqueous solution of urea, 10%Na
2CO
3The aqueous solution is washed organic layer to slightly acidic, anhydrous MgSO
4Dry.Precipitation, underpressure distillation get a step product 2-nitro diethyl malonate.Yield 83%.
The second step cyclization:
To with adding ethanol 200ml in the churned mechanically 500ml four-hole reaction flask, add metal Na 23g(1.0mol, 2.0eq in batches) reflux.Dissolve rear adding thiocarbamide 38g (0.5mol, 1.0eq) fully until Na.Be warming up to 50-60 ℃ and be stirred to whole dissolvings, drip 2-nitro diethyl malonate 108g(95%, 0.5mol, 1.0eq), drip afterreaction stopped reaction after 3 hours, be down to normal temperature, precipitation, add 300 gram water dissolution, hydrochloric acid is transferred PH 5-6, separates out solid, suction filtration, vacuum drying gets secondary product 4,6-dihydroxyl-2-sulfydryl-5-nitro-pyrimidine 57.7g, content 95%; Yield 58 %.
The 3rd step methylated:
With secondary product 4, in NaOH (2.5mol, the 5.0eq) aqueous solution of 6-dihydroxyl-2-sulfydryl-5-nitro-pyrimidine 99.6g (95%, 0.5mol, 1.0eq) adding 20%,
Stirring and dissolving is cooled to 10 ℃, drips methyl-sulfate 63.6g(99%, 0.5mol, 1.0eq), dropwise 10-20 ℃ of reaction of rear maintenance temperature 4 hours, hydrochloric acid is transferred PH 2-3, there is solid to separate out, filters drying, get three step products 4,6-dihydroxyl-2-methylthio group-5-nitro-pyrimidine 84.7g, content 97%, yield 81%.
The 4th one-step chlorination:
With three step products 4,6-dihydroxyl-2-methylthio group-5-nitro-pyrimidine 21g(97%, 0.1mol, 1.0eq) add in the 100ml phosphorus oxychloride, and add 5ml N, N-xylidine (being called for short DMA) is made catalyzer, be heated to back flow reaction 8 hours, and distilled out excessive phosphorus oxychloride, be hydrolyzed in the adding frozen water, use ethyl acetate extraction, anhydrous sodium sulfate drying filters, precipitation, purifying gets the finished product 17.5 grams, content 96%, yield 70%.
Embodiment 2
The first step is nitrated:
To 500ml with adding diethyl malonate 80g(0.5mol in the churned mechanically four-hole reaction flask, 1.0eq), stirring is cooled to 0-5 ℃, drip 20% nitrosonitric acid 90ml (2.1mol, 4.2eq), warm at 0-10 ℃ in the control in the dropping process, reacted 5-6 hour at 10 ℃ after dripping, after reaction solution slowly poured in the beaker that fills the 200g frozen water stir hydrolysis, layering.Water layer extracts with toluene, merges organic layer, uses successively 5% aqueous solution of urea, 10%Na
2CO
3The aqueous solution is washed organic layer to slightly acidic, anhydrous MgSO
4Dry.Precipitation, underpressure distillation get a step product 2-nitro diethyl malonate.Yield 67%.
The second step cyclization:
To with adding ethanol 200ml in the churned mechanically 500ml four-hole reaction flask, add metal Na 28.8g(1.25mol, 2.5eq in batches) reflux.Dissolve rear adding thiocarbamide 40g (0.525mol, 1.05eq) fully until Na.Be warming up to 40-50 ℃ and be stirred to whole dissolvings, drip 2-nitro diethyl malonate 105.8g(97%, 0.5mol, 1.0eq), drip afterreaction stopped reaction after 6 hours, be down to normal temperature, precipitation, add 300 gram water dissolution, hydrochloric acid is transferred PH 5-6, separates out solid, suction filtration, vacuum drying gets secondary product 4,6-dihydroxyl-2-sulfydryl-5-nitro-pyrimidine 80.8g, content 96%; Yield 82 %.
The 3rd step methylated:
With secondary product 4, in NaOH (1.5mol, the 3.0eq) aqueous solution of 6-dihydroxyl-2-sulfydryl-5-nitro-pyrimidine 98.6g (96%, 0.5mol, 1.0eq) adding 20%,
Stirring and dissolving is cooled to 10 ℃, drips methyl-sulfate 76.4g(99%, 0.6mol, 1.2eq), dropwise 20-30 ℃ of reaction of rear maintenance temperature 6 hours, hydrochloric acid is transferred PH 2-3, there is solid to separate out, filters drying, get three step products 4,6-dihydroxyl-2-methylthio group-5-nitro-pyrimidine 81.3g, content 96%, yield 77%.
The 4th one-step chlorination:
With three step products 4,6-dihydroxyl-2-methylthio group-5-nitro-pyrimidine 21g(97%, 0.1mol, 1.0eq) add in the 80ml phosphorus oxychloride, and add 5ml N, N-xylidine (being called for short DMA) is made catalyzer, be heated to back flow reaction 10 hours, and distilled out excessive phosphorus oxychloride, be hydrolyzed in the adding frozen water, use ethyl acetate extraction, anhydrous sodium sulfate drying filters, precipitation, purifying gets the finished product 20.2 grams, content 95%, yield 80%.
Embodiment 3
The first step is nitrated:
To 500ml with adding diethyl malonate 80g(0.5mol in the churned mechanically four-hole reaction flask, 1.0eq), stir and be down to 10-12 ℃, drip 98% concentrated nitric acid 128ml (3.0mol, 6eq), warm at 20-30 ℃ in the control in the dropping process, reacted 8 hours at 25 ℃ after dripping, after reaction solution slowly poured in the beaker that fills the 200g frozen water stir hydrolysis, layering.The water layer ethyl acetate extraction merges organic layer, uses successively 5% aqueous solution of urea, 10%Na
2CO
3The aqueous solution is washed organic layer to slightly acidic, anhydrous MgSO
4Dry.Precipitation, one step of underpressure distillation product 2-nitro diethyl malonate.Yield 53%.
The second step cyclization:
To with adding ethanol 200ml in the churned mechanically 500ml four-hole reaction flask, add metal Na 26.5g(1.15mol, 2.3eq in batches) reflux.Dissolve rear adding thiocarbamide 38g (0.5mol, 1.0eq) fully until Na.Be warming up to 70 ℃ and be stirred to whole dissolvings, drip 2-nitro diethyl malonate 110g(93%, 0.5mol, 1.0eq), drip rear back flow reaction stopped reaction after 5 hours, be down to normal temperature, precipitation, add 300 gram water dissolution, hydrochloric acid is transferred PH 5-6, separates out solid, suction filtration, vacuum drying gets secondary product 4,6-dihydroxyl-2-sulfydryl-5-nitro-pyrimidine 69.4g, content 98%; Yield 72 %.
The 3rd step methylated:
With secondary product 4, in NaOH (2.5mol, the 5.0eq) aqueous solution of 6-dihydroxyl-2-sulfydryl-5-nitro-pyrimidine 99.6g (95%, 0.5mol, 1.0eq) adding 10%,
Stirring and dissolving is cooled to 10 ℃, drips methyl-sulfate 95.5g(99%, 0.5mol, 1.5eq), dropwise 10-20 ℃ of reaction of rear maintenance temperature 4 hours, hydrochloric acid is transferred PH 2-3, there is solid to separate out, filters drying, get three step products 4,6-dihydroxyl-2-methylthio group-5-nitro-pyrimidine 84.7g, content 97%, yield 81%.
The 4th one-step chlorination:
With three step products 4,6-dihydroxyl-2-methylthio group-5-nitro-pyrimidine 21g(97%, 0.1mol, 1.0eq) add in the 100ml phosphorus oxychloride, and add 5ml N, N-xylidine (being called for short DMA) is made catalyzer, be heated to back flow reaction 6 hours, distill out excessive phosphorus oxychloride, be hydrolyzed in the adding frozen water, use ethyl acetate extraction, anhydrous sodium sulfate drying, filter, precipitation, purifying get the finished product 11.6 grams.
Claims (1)
1. one kind 4, the synthetic method of 6-two chloro-2-methylthio group-5-nitro-pyrimidines, it is characterized in that: the operation steps of described synthetic method is:
(1) the first step is nitrated
Diethyl malonate is nitrated in excessive concentrated nitric acid or nitrosonitric acid, hydrolysis, and organic solvent extraction, drying, precipitation, underpressure distillation gets a step product 2-nitro diethyl malonate; 0～30 ℃ of temperature of reaction, nitric acid is 4.0-10.0 with respect to the molar equivalent ratio of diethyl malonate, organic solvent is toluene, ethyl acetate;
(2) second step cyclisation
Thiocarbamide is heating for dissolving in methyl alcohol or alcohol solvent, under the effect of corresponding sodium alkoxide, generates 4,6-dihydroxyl-2-sulfydryl-5-nitro-pyrimidine with 2-nitro diethyl malonate ring closure reaction; The cyclization temperature is at 40-80 ℃, and thiocarbamide is 1.0-1.05 with respect to the molar equivalent of 2-nitro diethyl malonate, and sodium alkoxide is 2.0-2.5 with respect to the molar equivalent of 2-nitro diethyl malonate;
(3) the 3rd steps methylated
4,6-dihydroxyl-2-sulfydryl-5-nitro-pyrimidine dissolves in aqueous sodium hydroxide solution, methylate with methyl-sulfate and to generate three step products 4,6-dihydroxyl-2-methylthio group-5-nitro-pyrimidine, temperature of reaction 10-40 ℃, sodium hydroxide is 3-6 with respect to the molar equivalent of 4,6-dihydroxyl-2-sulfydryl-5-nitro-pyrimidine, methyl-sulfate is 1.0-1.5 with respect to the molar equivalent of 4,6-dihydroxyl-2-sulfydryl-5-nitro-pyrimidine;
(4) the 4th one-step chlorinations
Three step products 4,6-dihydroxyl-2-methylthio group-5-nitro-pyrimidine chlorination in excessive phosphorus oxychloride, hydrolysis, ethyl acetate extraction, drying, precipitation, purifying get the finished product 4,6-two chloro-2-methylthio group-5-nitro-pyrimidines; Temperature of reaction is 100-110 ℃ of back flow reaction temperature, yield 40-80%; Chlorination process adds a small amount of N, and N-xylidine is made catalyzer.
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| CN103333117A (en) * | 2013-05-18 | 2013-10-02 | 嘉兴中科化学有限公司 | Preparation method of 4[(4-chloro-2-pyrmidyl)amino]cyanophenyl |
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| CN106496133A (en) * | 2016-10-19 | 2017-03-15 | 青岛云天生物技术有限公司 | The preparation method of ticagrelor midbody |
| CN110372605A (en) * | 2019-06-24 | 2019-10-25 | 南京普锐达医药科技有限公司 | Synthesis method of 2-methylthio-4, 6-dichloro-5-nitropyrimidine |
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Application publication date: 20130306 |