CN102276537B - Preparation method of 2-cyan-5-amiopyrimidine - Google Patents
Preparation method of 2-cyan-5-amiopyrimidine Download PDFInfo
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- CN102276537B CN102276537B CN 201110169997 CN201110169997A CN102276537B CN 102276537 B CN102276537 B CN 102276537B CN 201110169997 CN201110169997 CN 201110169997 CN 201110169997 A CN201110169997 A CN 201110169997A CN 102276537 B CN102276537 B CN 102276537B
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- cyan
- pyrimidine
- nitro
- amiopyrimidine
- nitropyrimidine
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Abstract
The invention provides a preparation method of 2-cyan-5-amiopyrimidine. The method comprises the following specific steps: nitrifying 2-hydroxypyrimidine hydrochloride serving as a raw material to prepare 2-hydroxyl-5-nitropyrimidine; performing elimination-addition on the 2-hydroxyl-5-nitro-pyrimidine to prepare 2-chloride-5-nitropyrimidine; substituting the 2-chloride-5-nitropyrimidine with cyan to prepare 2-cyan-5-nitropyrimidine; and reducing the 2-cyan-5-nitropyrimidine under illumination to prepare the 2-cyan-5-amiopyrimidine. The synthesis route adopted in the invention is simple (only 4 steps), the raw materials have low price and are easily available, the reaction condition is mild, the intermediate and product are easily separated, and the yield is higher. The prepared 2-cyan-5-amiopyrimidine medical intermediate has wide application prospects in pharmaceutical chemicals, biological anti-cancer and other aspects.
Description
Technical field
The present invention relates to pyrimidine derivatives, be specifically related to a kind of preparation method of 2-cyan-5-amiopyrimidine.
Technical background
Pyrimidines is the very important heterogeneous ring compound of a class, extensively is present in human body and the life entity.Because of the singularity of its structure, the effect that this compounds has is antimycotic, Promoting plant growth is regulated can be used for preparing Insecticides (tech) ﹠ Herbicides (tech) and sterilant etc.After itself and metal ion form title complex, not only can prolong activity, lasting period and the transformation period of former medicine, and can reduce mammiferous toxicity.In addition, the intermediate of pyrimidines or a lot of medicine, agricultural chemicals, application prospect is boundless.Therefore, it causes people's concern already as new drug molecular designing and synthetic basic building block.The situation that hydrogen atom from pyrimidine ring is replaced by different substituents can be divided into single replacement, two replacement, three replacement and four replacements.Holding at present facile is single the replacement and three replacements, and two replacement and quaternary pyrimidine derivatives are less, and especially the pyrimidine compound of 2,5 replacements still less.Correlative study shows that 2-amino or cyano group substituted pyrimidines compound have good anti-tumor activity, and 5-substituted-amino or cyanopyrimidine compound have stronger antibacterial and anti-inflammation functions.After the pyrimidine ring hydrogen is replaced by amino and cyano group simultaneously, except the function with single substituted pyrimidines separately, can also modify the amino acid that obtains more pyrimidine derivatives and correspondence to active group (amino or cyano group) by relevant reaction.
At present for the preparation of 2-cyan-5-amiopyrimidine, Chem.Pharm.Bull.2000,48,1504-1513 and Collection of Czechoslovak Chemical Communications, 1975,40,1396-402 has carried out study on the synthesis to it, and synthetic route is as follows;
Said synthesis route needed for 6 steps, and operation is complicated, and especially bad control is reacted in final step, and by product is more.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of 2-cyan-5-amiopyrimidine compound, the method technique is simple, cost is lower, is easy to realize industrialization.
The preparation method of a kind of 2-cyan-5-amiopyrimidine provided by the invention comprises the steps:
1), preparation 2-chloro-5-nitro-pyrimidine, can be according to existing document (Patent:WO2007/135350; (2007)) preparation;
2), the DMSO solution that will be dissolved with 2-chloro-5-nitro-pyrimidine splashes among the DMSO and water mixed solvent that contains NaCN and DABCO, stirred overnight at room temperature, reaction solution is used 1mol/L hydrochloric acid, saturated NaHCO successively through ethyl acetate extraction
3, the saturated common salt water washing, drying is revolved to desolventize and is obtained 2-cyano group-5 nitro-pyrimidine; Reaction equation is as follows:
3), under the nitrogen protection, in the acetonitrile solvent, 2-cyano group-5-nitro-pyrimidine and formic acid are reacted 1.5-2.5h under λ=254nm rayed, add a small amount of water and solid Na
2CO
3, stirring, extracted with diethyl ether is separated, and ether-hexanaphthene recrystallization obtains the 2-cyan-5-amiopyrimidine; Reaction equation is as follows:
Step 2) in, the mol ratio of described 2-chloro-5-nitro-pyrimidine, DABCO and NaCN is 7~10: 1: 7~15; Described DMSO and H
2The volume ratio of O is 2-4: 1;
Step 3) in, described H
2O and CH
3The CN volume ratio is 1: 3~6,2-cyano group-5-nitro-pyrimidine, formic acid and Na
2CO
3Mol ratio is 1: 10-15: 15-30;
Compared with prior art advantage of the present invention and effect:
Synthetic route of the present invention simple (only 4 steps), raw material cheaply is easy to get, and reaction conditions is gentle, and intermediate and product are easily separated, and productive rate is higher.The 2-cyan-5-amiopyrimidine medicine intermediate for preparing has broad application prospects at aspects such as medication chemistry and biological anticancers.
Embodiment
Embodiment 1
1) in the there-necked flask of the 500mL that electric mixer is housed, add the 200mL vitriol oil, ice bath cooling and stirring are lower, and 25.92g (0.20mol) 2-hydroxy pyrimidine hydrochloride is added in the sulphuric acid soln in batches.Then by constant pressure funnel 65.0g (0.40mol) nitrosonitric acid is splashed into, be heated to 90 ℃ of stirring reaction 24h.Reaction is poured in a large amount of frozen water after finishing to be cooled to room temperature, the pH=2.5 that neutralizes of the sodium hydroxide solution with 50%.With ethyl acetate (3 * 300mL) extractions three times, merge organic phase, with saturated common salt water washing (2 * 300mL) washed twice, anhydrous sodium sulfate drying, decompression is revolved to desolventize and is obtained thick product 2-hydroxyl-5-nitro-pyrimidine 11.5g, productive rate 42.2% does not need directly next step reaction of purifying.
In the 250mL there-necked flask of magnetic stirring apparatus is housed, add 10.0g (0.071mol) 2-hydroxyl-5-nitro-pyrimidine, after 9.0mL (0.071mol) DMA and the 100mL phosphorus oxychloride, add back flow reaction, the TLC detection reaction finishes.After most of phosphorus oxychloride is removed in underpressure distillation, pour into and stir 30min in the frozen water.(3 * 150mL) extractions three times merge organic phase, and behind anhydrous sodium sulfate drying, decompression is revolved to desolventize and obtained thick product, get product, 2-chloro-5-nitro-pyrimidine 6.29g, productive rate: 55.6% behind the recrystallization with methylene dichloride.
1H?NMR(CDCl
3/400MHz)δ9.38(s,2H);
13C?NMR(CDCl
3/100MHz)δ141.2,153.8,165.9;EI-MS(m/z)158.63[M
+],160.58[M
++2]。
2) in the there-necked flask of the 250mL that magnetic stirring apparatus is housed, add 1.715g (0.035mol) sodium cyanide, 0.54g (5.0mmol) DABCO, 15mL DMSO and 30mL water.The 20mL DMSO solution that then will be dissolved with 5.58g (0.035mol) 2-chloro-5-nitro-pyrimidine splashes in the mentioned solution.Reaction mixture at room temperature stirs and spends the night, reaction solution is poured in the 250mL water, with ethyl acetate extraction three times (3 * 150mL), merge organic phase, after washing with 1N hydrochloric acid, saturated sodium bicarbonate solution and saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, decompression is revolved to desolventize and is obtained white solid, 2-cyano group-5-nitro-pyrimidine 4.73g, productive rate: 90.3%.
1H?NMR(CDCl
3/400MHz)δ9.96(s,2H);
13C?NMR(CDCl
3/100MHz)δ111.2,144.8,151.2,152.9;EI-MS(m/z)151.05[M
++1]。
3) under nitrogen protection, 3.0g (0.02mol) 2-cyano group-5-nitro-pyrimidine in the 100mL there-necked flask adds the formic acid of 10 times of equivalents, the degassed acetonitrile of 40mL.Under the rayed of 254nm, stirring reaction 2h.After reaction finishes, in mixing also, add 10ml water and excessive Na
2CO
3Solid, after stirring 10min, filter, decompression is revolved except behind a large amount of solvents, uses extracted with diethyl ether 3 times (3 * 150mL), merge organic phase, anhydrous sodium sulfate drying, the crude product that desolventizes is revolved in decompression, and crude product gets white solid through ether-normal hexane recrystallization, 2-cyan-5-amiopyrimidine 2.12g, productive rate 88.45%.
1H?NMR(CDCl
3/400MHz)δ4.08(s,2H),8.81(s,2H);
13C?NMR(CDCl
3/100MHz)δ110.9,133.6,145.8,149.2;EI-MS(m/z)121.03[M
++1]。
Embodiment 2
1) with embodiment 1
2) in the there-necked flask of the 250mL that magnetic stirring apparatus is housed, add 2.45g (0.05mol) sodium cyanide, 0.45g (4.17mmol) DABCO, 20mL DMSO and 30mL water.The 20mL DMSO solution that then will be dissolved with 5.58g (0.035mol) 2-chloro-5-nitro-pyrimidine splashes in the mentioned solution.Reaction mixture at room temperature stirs and spends the night, reaction solution is poured in the 250mL water, with ethyl acetate extraction three times (3 * 150mL), merge organic phase, after washing with 1N hydrochloric acid, saturated sodium bicarbonate solution and saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, decompression is revolved to desolventize and is obtained white solid, 2-cyano group-5-nitro-pyrimidine 4.82g, productive rate: 92.1%.
1H?NMR(CDCl
3/400MHz)δ9.96(s,2H);
13C?NMR(CDCl
3/100MHz)δ111.2,144.8,151.2,152.9;EI-MS(m/z)151.05[M
++1]。
3) under nitrogen protection, 3.0g (0.02mol) 2-cyano group-5-nitro-pyrimidine in the 100mL there-necked flask adds the formic acid of 15 times of equivalents, the degassed acetonitrile of 40mL.Under the rayed of 254nm, stirring reaction 2.0h.After reaction finishes, in mixing also, add 10ml water and excessive Na
2CO
3Solid, after stirring 10min, filter, decompression is revolved except behind a large amount of solvents, uses extracted with diethyl ether 3 times (3 * 150mL), merge organic phase, anhydrous sodium sulfate drying, the crude product that desolventizes is revolved in decompression, and crude product gets white solid through ether-normal hexane recrystallization, 2-cyan-5-amiopyrimidine 2.11g, productive rate 87.48%.
1H?NMR(CDCl
3/400MHz)δ4.11(s,2H),8.87(s,2H);
13C?NMR(CDCl
3/100MHz)δ111.7,133.4,145.9,150.9;EI-MS(m/z)121.22[M
++1]。
Embodiment 3
1) with embodiment 1
2) with embodiment 1
3) under nitrogen protection, 3.0g (0.02mol) 2-cyano group-5-nitro-pyrimidine in the 100mL there-necked flask adds the formic acid of 12 times of equivalents, the degassed acetonitrile of 40mL.Under the rayed of 254nm, stirring reaction 1.5h.After reaction finishes, in mixing also, add 10ml water and excessive Na
2CO
3Solid, after stirring 10min, filter, decompression is revolved except behind a large amount of solvents, uses extracted with diethyl ether 3 times (3 * 150mL), merge organic phase, anhydrous sodium sulfate drying, the crude product that desolventizes is revolved in decompression, and crude product gets white solid through ether-normal hexane recrystallization, 2-cyan-5-amiopyrimidine 2.05g, productive rate 85.37%.
1H?NMR(CDCl
3/400MHz)δ4.09(s,2H),8.85(s,2H);
13C?NMR(CDCl
3/100MHz)δ111.3,133.1,145.7,150.1;EI-MS(m/z)121.43[M
++1]。
Claims (1)
1. the preparation method of a 2-cyan-5-amiopyrimidine is characterized in that, comprises the steps:
1), the DMSO solution that will be dissolved with 2-chloro-5-nitro-pyrimidine splashes among the DMSO and water mixed solvent that contains NaCN and DABCO, stirred overnight at room temperature, reaction solution is used 1mol/L hydrochloric acid, saturated NaHCO successively through ethyl acetate extraction
3, the saturated common salt water washing, drying is revolved to desolventize and is obtained 2-cyano group-5 nitro-pyrimidine; Reaction equation is as follows:
2), under the nitrogen protection, in the acetonitrile solvent, 2-cyano group-5-nitro-pyrimidine and formic acid are reacted 1.5-2.5h under λ=254nm rayed, add a small amount of water and solid Na
2CO
3, stirring, extracted with diethyl ether is separated, and ether-hexanaphthene recrystallization obtains the 2-cyan-5-amiopyrimidine; Reaction equation is as follows:
In the step 1), the mol ratio of described 2-chloro-5-nitro-pyrimidine, DABCO and NaCN is 7~10: 1: 7~15; Described DMSO and H
2The volume ratio of O is 2-4: 1;
Step 2) in, described H
2O and CH
3The CN volume ratio is 1:3~6,2-cyano group-5-nitro-pyrimidine, formic acid and Na
2CO
3Mol ratio is 1: 10-15: 15-30.
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