CN102276537A - Preparation method of 2-cyan-5-amiopyrimidine - Google Patents

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

The preparation method of 2-cyano group-5-aminopyrimidine

Technical field

The present invention relates to pyrimidine derivatives, be specifically related to the preparation method of a kind of 2-cyano group-5-aminopyrimidine.

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, that this compounds has is antimycotic, promote the effect of plant growth regulating, 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, pyrimidines still is the intermediate of many medicine, agricultural chemicals, and application prospect is boundless.Therefore, it causes people's attention already as new drug molecular designing and the basic building block of synthetic.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.What obtain easily at present replaces and three replacements for single, 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 antitumor 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 function, can also modify the amino acid that obtains more pyrimidine derivatives and correspondence by relevant reaction pair active group (amino or cyano group) with single substituted pyrimidines separately.

At present for 2-cyano group-5-aminopyrimidine preparation, 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-cyano group-5-aminopyrimidine compounds, this method technology is simple, cost is lower, is easy to realize industrialization.

The preparation method of a kind of 2-cyano group provided by the invention-5-aminopyrimidine 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 less water and solid Na ₂CO ₃, stirring, extracted with diethyl ether is separated, and ether-hexanaphthene recrystallization obtains 2-cyano group-5-aminopyrimidine; 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;

In the step 3), 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;

Advantage compared with prior art of the present invention and effect:

Synthetic route of the present invention simple (only 4 steps), raw material cheaply is easy to get, the reaction conditions gentleness, intermediate and product are easily separated, and productive rate is higher.The 2-cyano group for preparing-5-aminopyrimidine medicine intermediate 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, the ice bath cooling is also stirred down, and 25.92g (0.20mol) 2-hydroxy pyrimidine hydrochloride is added in the sulphuric acid soln in batches.By constant pressure funnel 65.0g (0.40mol) nitrosonitric acid is splashed into then, 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%.(3 * 300mL) extractions three times merge organic phase, with saturated common salt water washing (2 * 300mL) washed twice with ethyl acetate, anhydrous sodium sulfate drying, decompression is revolved to desolventize and is obtained thick product 2-hydroxyl-5-nitro-pyrimidine 11.5g, and 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, 9.0mL (0.071mol) N after accelerine and the 100mL phosphorus oxychloride, adds back flow reaction, and 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 will be dissolved with 5.58g (0.035mol) 2-chloro-5-nitro-pyrimidine then splashes in the above-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 in the 100mL there-necked flask (0.02mol) 2-cyano group-5-nitro-pyrimidine adds 10 times of normal formic acid, the 40mL acetonitrile that outgases.Under the rayed of 254nm, stirring reaction 2h.After reaction finishes, in mixing also, add 10ml water and excessive N a ₂CO ₃Solid, after stirring 10min, filter, decompression is used extracted with diethyl ether 3 times (3 * 150mL) after revolving and removing a large amount of solvents, 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-cyano group-5-aminopyrimidine 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 will be dissolved with 5.58g (0.035mol) 2-chloro-5-nitro-pyrimidine then splashes in the above-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 in the 100mL there-necked flask (0.02mol) 2-cyano group-5-nitro-pyrimidine adds 15 times of normal formic acid, the 40mL acetonitrile that outgases.Under the rayed of 254nm, stirring reaction 2.0h.After reaction finishes, in mixing also, add 10ml water and excessive N a ₂CO ₃Solid, after stirring 10min, filter, decompression is used extracted with diethyl ether 3 times (3 * 150mL) after revolving and removing a large amount of solvents, 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-cyano group-5-aminopyrimidine 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 in the 100mL there-necked flask (0.02mol) 2-cyano group-5-nitro-pyrimidine adds 12 times of normal formic acid, the 40mL acetonitrile that outgases.Under the rayed of 254nm, stirring reaction 1.5h.After reaction finishes, in mixing also, add 10ml water and excessive N a ₂CO ₃Solid, after stirring 10min, filter, decompression is used extracted with diethyl ether 3 times (3 * 150mL) after revolving and removing a large amount of solvents, 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-cyano group-5-aminopyrimidine 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 2-cyano group-5-aminopyrimidine is characterized in that, comprises the steps:

1), preparation 2-chloro-5-nitro-pyrimidine;

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 less water and solid Na ₂CO ₃, stirring, extracted with diethyl ether is separated, and ether-hexanaphthene recrystallization obtains 2-cyano group-5-aminopyrimidine; 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;

In the step 3), 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.