Synthesis of 5-Substituted 3-Amino-1H-Pyrazole-4- ...

Author: Hou

Sep. 23, 2024

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Synthesis of 5-Substituted 3-Amino-1H-Pyrazole-4- ...

Interest in pyrazolo[1,5-]pyrimidine-3-carbonitrile derivatives has been reviewed [ 1 3 ]. Among them are zaleplon ( Figure 1 ) analogues, that have been classified as sedative/hypnotic drugs, and as such, are expected to possess considerable biological activity [ 4 6 ]. With the aim of obtaining compounds possessing the above properties, we examined the condensation of 5-substituted 3-amino-1-4-pyrazolecarbonitrileswith bidentate electrophiles and investigated if such compounds would facilitate regioselective syntheses of substituted 7-aryl-pyrazolo[1,5-]pyrimidine-3-carbonitriles that are structurally related to compound. Compoundis readily available from the reaction of 3-oxo-3-phenylpropanenitrilewith trichloroacetonitrile followed by condensation with hydrazine hydrate [ 7 ]. This methodology was extended and adapted to the synthesis of several 5-substituted aryl and heteroaryl-pyrazolecarbonitriles using oxoalkanonitriles as precursors. We initially investigated developing a novel route to 3-oxoalkanonitrile derivatives

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Results and Discussion

2 with hydroxylamine hydrochloride gave the aldoximes 3 in good yields. These were converted to oxoalkanonitriles 5

via

treatment with diethyl oxalate in the presence of sodium hydride [5 by addition of a solution of hydroxylamine hydrochloride to enaminones 2a-c in alcoholic KOH. Such a transformation apparently results

via

initial formation of an isoxazole 4 that then undergoes base catalyzed ring opening furnishing 5a-c (cf.

Recently we reported that the reaction of enaminoneswith hydroxylamine hydrochloride gave the aldoximesin good yields. These were converted to oxoalkanonitrilestreatment with diethyl oxalate in the presence of sodium hydride [ 8 ]. We now describe a second more efficient process for the preparation ofby addition of a solution of hydroxylamine hydrochloride to enaminonesin alcoholic KOH. Such a transformation apparently resultsinitial formation of an isoxazolethat then undergoes base catalyzed ring opening furnishing(cf. Scheme 1 ).

Scheme 1. Synthesis of 3-oxo-3-arylpropanenitriles 5a-c from enaminones 2a-c.

5a-c so obtained were reacted with trichloroacetonitrile to yield adducts 6a-c. Condensation of these adducts with hydrazine hydrate afforded 7a-c, that cyclized under reflux in dioxane yielding 8a-c in good yields (cf. 1H-NMR spectra of adducts 6a-c at ca. δH = 10 and 12 ppm indicates a non-equivalence of the amino protons, which is probably related to the involvement of one amino proton in an intramolecular H-bond with the carbonyl moiety. Similar features were observed in 7a-c at ca. δH = 9 and 10 ppm. There are alternative procedures described in the literature for the preparation of 8a,b by treating arylmethylenemalononitrile with hydrazine [

via

transformation of isothiazoles and isoxazoles into pyrazoles 8a,b using hydrazines [

-4-pyrazolecarbonitrile derivatives 8a-c with enaminone 2c and enaminonitrile 9, recently prepared in our laboratory [

The oxoalkanonitrile derivativesso obtained were reacted with trichloroacetonitrile to yield adducts. Condensation of these adducts with hydrazine hydrate afforded, that cyclized under reflux in dioxane yieldingin good yields (cf. Scheme 2 ). The doublet splitting of amino group signals observed in theH-NMR spectra of adductsat ca. δ= 10 and 12 ppm indicates a non-equivalence of the amino protons, which is probably related to the involvement of one amino proton in an intramolecular H-bond with the carbonyl moiety. Similar features were observed inat ca. δ= 9 and 10 ppm. There are alternative procedures described in the literature for the preparation ofby treating arylmethylenemalononitrile with hydrazine [ 9 10 ] ortransformation of isothiazoles and isoxazoles into pyrazolesusing hydrazines [ 11 ]. In the present article, the condensation reaction of 3-amino-1-4-pyrazolecarbonitrile derivativeswith enaminoneand enaminonitrilerecently prepared in our laboratory [ 12 ], is examined.

Scheme 2. Synthesis of 3-amino-5-aryl-1

-4-pyrazolecarbonitrile 8a-c from 3-oxo-3-arylpropanenitrile 5a-c.

Scheme 2. Synthesis of 3-amino-5-aryl-1

-4-pyrazolecarbonitrile 8a-c from 3-oxo-3-arylpropanenitrile 5a-c.

-3-aminopyrazole derivatives has been a subject of considerable debate in the past [

]pyrimidines due to comparable reactivity&#;s of the two electrophilic centers in the initial diketone. Recently, use of 1,3-dimethyluracil as the electrophile was reported to involve the attack on both endocyclic and exocyclic nitrogen affording either the pyrazolo[1,5-

]pyrimidin-5-one or 7-one isomers, depending on the reaction conditions [

-3-aminopyrazole with benzylidenemalononitrile [8a-c with enaminonitrile 2c in acetic acid at reflux temperature over a long period of time resulted in selective formation of pyrazolo[1,5-

]pyrimidines derivatives in good yields (cf.

The site at which nucleophiles attack occurs on 1-3-aminopyrazole derivatives has been a subject of considerable debate in the past [ 13 14 ]. Reactions of unsymmetrical 1,3-diketones with 3(5)-aminopyrazoles often lead to the formation of inseparable mixtures of two regioisomeric pyrazolo[1,5-]pyrimidines due to comparable reactivity&#;s of the two electrophilic centers in the initial diketone. Recently, use of 1,3-dimethyluracil as the electrophile was reported to involve the attack on both endocyclic and exocyclic nitrogen affording either the pyrazolo[1,5-]pyrimidin-5-one or 7-one isomers, depending on the reaction conditions [ 15 ], whereas the reaction of 1-3-aminopyrazole with benzylidenemalononitrile [ 16 ] and with 1-arylbutane-1,3-diones [ 17 ] are established to involve exocyclic amino group. It is thought that there is an equilibrium between possible initial attack at the ring nitrogen and the exocyclic amino group. Structures of the products resulting from reactions of a,b-unsaturated compounds with aminoazoles should be determined in each case, as the outcome of the reactions would be dependent on several factors, including steric consideration, relative basicities and solubility of both isomers in reaction medium. Although it is generally accepted that 3(5)-aminopyrazoles reacts with enaminones to yield the 7-substituted isomers, we noticed that this pattern is not always followed, as the reaction product proved to be dependent on both reaction conditions as well as nature of reagents. In the present article we have found that reaction ofwith enaminonitrilein acetic acid at reflux temperature over a long period of time resulted in selective formation of pyrazolo[1,5-]pyrimidines derivatives in good yields (cf. Scheme 3 ).

Scheme 3. Proposed mechanism for the formation of pyrazolo[1,5-

]pyrimidines 12a-c, 13a-c and 15a-c in acetic acid.

Scheme 3. Proposed mechanism for the formation of pyrazolo[1,5-

]pyrimidines 12a-c, 13a-c and 15a-c in acetic acid. 1H-NMR spectra gave no reliable information on the structure of the products; on the other hand they indicate that only one of the possible isomeric structures, 12 or 14, are formed, rather than their mixture. The condensation products were assigned structures 12a-c on the basis of 1H-15N HMBC measurements. For example compound 12a, showed chemical shifts for N-7a at δ (15N) = 215 ppm, N-4 at δ (15N) = 268 ppm. and N-1 at δ (15N) = 285 ppm. Cross peak correlations for the coupling of the shielded proton H-6 at δ (1H) = 8.05 ppm is observed with N-7a at δ (15N) = 215 ppm 3

(H-6, N-7a), N-4 at δ (15N) = 268 ppm 3

(H-6, N-4) and with N-1 at δ (15N) = 285 ppm 4

(H-6, N-1). Coupling of the deshielded proton at δ (1H) = 8.83 ppm with N-7a at δ (15N) = 215 ppm 4

(H-5, N-7a) and with N-4 at δ (15N) = 268 ppm 2

(H-5, N-4) are also observed. Alternative structure 14 would show coupling of the deshielded H-7 proton to be with N-1 in the spectrum at δ (15N) = 285 ppm. The correlations in the 1H-15N HMBC measurements for compounds 12b,c showed similar coupling correlations as 12a. Reaction of 3-amino-5-aryl-1

-4-pyrazolecarbonitriles 8a-c with enaminonitrile 9 (X = CN) in acetic acid under the same reaction conditions afforded a mixture of (5)7-substituted pyrazolo[1,5-

]pyrimidine derivatives 13a-c and 15a-c, which could not be separated by chromatographical means. Both isomers showed the same molecular weights in LC-MS. Moreover, the 1H-NMR spectra of the reaction products of 8a-c with 9 showed two singlets for two deshielded protons at ca. δH = 9.0 and 9.3 ppm. Based on these data, it is concluded that the compounds obtained are isomeric mixtures of 13 and 15, whose ratio (approximately 1:3) was estimated by integration of the deshielded protons in the corresponding 1H-NMR spectra. Apparently, in AcOH where the aminopyrazoles are most likely protonated, both adducts 10 and 11 are formed, as outlined in

TheH-NMR spectra gave no reliable information on the structure of the products; on the other hand they indicate that only one of the possible isomeric structures,orare formed, rather than their mixture. The condensation products were assigned structureson the basis ofH-N HMBC measurements. For example compound, showed chemical shifts for N-7a at δ (N) = 215 ppm, N-4 at δ (N) = 268 ppm. and N-1 at δ (N) = 285 ppm. Cross peak correlations for the coupling of the shielded proton H-6 at δ (H) = 8.05 ppm is observed with N-7a at δ (N) = 215 ppm(H-6, N-7a), N-4 at δ (N) = 268 ppm(H-6, N-4) and with N-1 at δ (N) = 285 ppm(H-6, N-1). Coupling of the deshielded proton at δ (H) = 8.83 ppm with N-7a at δ (N) = 215 ppm(H-5, N-7a) and with N-4 at δ (N) = 268 ppm(H-5, N-4) are also observed. Alternative structurewould show coupling of the deshielded H-7 proton to be with N-1 in the spectrum at δ (N) = 285 ppm. The correlations in theH-N HMBC measurements for compoundsshowed similar coupling correlations as. Reaction of 3-amino-5-aryl-1-4-pyrazolecarbonitrileswith enaminonitrile(X = CN) in acetic acid under the same reaction conditions afforded a mixture of (5)7-substituted pyrazolo[1,5-]pyrimidine derivativesand, which could not be separated by chromatographical means. Both isomers showed the same molecular weights in LC-MS. Moreover, theH-NMR spectra of the reaction products ofwithshowed two singlets for two deshielded protons at ca. δ= 9.0 and 9.3 ppm. Based on these data, it is concluded that the compounds obtained are isomeric mixtures ofandwhose ratio (approximately 1:3) was estimated by integration of the deshielded protons in the correspondingH-NMR spectra. Apparently, in AcOH where the aminopyrazoles are most likely protonated, both adductsandare formed, as outlined in Scheme 3 . Competing cyclization leading to the 5-isomer would also be possible and mixtures are thus formed.

-4-pyrazolecarbonitriles 8a-c with enaminonitrile 9 (X = CN) by heating in a direct beam microwave oven and under solvent free conditions proceeded regiospecifically to yield the 5-substituted pyrazolo[1,5-

]pyrimidine-3-carbonitrile derivatives 15a-c in good yield. The addition reaction occurs in a manner different to the formation of the 7-substituted pyrazolo[1,5-

]pyrimidine derivatives, as outlined in 15 of the products obtained was assigned on the basis of 1H-15N HMBC measurements. The major discrepancy between the two isomers 13 and 15 was the cross peak correlation observed between the deshielded proton at δ (1H) = 9.06 ppm with N-1 at δ (15N) = 283 ppm, 3

(H-7, N-1). Alternate structure 13 in which the deshielded proton is on C-5, would not show this correlation and thus structure 13 could be ruled out. There is no doubt that adducts at both exocyclic and endocyclic nitrogen atoms occur, but in this case, the latter cyclize more readily into the 5-substituted pyrazolo[1,5-

]pyrimidines derivatives thus shifting the equilibrium. It should be noted that the isomers 12a-c were also obtained as sole products when the reactions of 8a-c with 2c was carried out by heating in a direct beam microwave oven and under solvent free conditions.

On the other hand, reaction of 3-amino-5-aryl-1-4-pyrazolecarbonitrileswith enaminonitrile(X = CN) by heating in a direct beam microwave oven and under solvent free conditions proceeded regiospecifically to yield the 5-substituted pyrazolo[1,5-]pyrimidine-3-carbonitrile derivativesin good yield. The addition reaction occurs in a manner different to the formation of the 7-substituted pyrazolo[1,5-]pyrimidine derivatives, as outlined in Scheme 4 . The structureof the products obtained was assigned on the basis ofH-N HMBC measurements. The major discrepancy between the two isomersandwas the cross peak correlation observed between the deshielded proton at δ (H) = 9.06 ppm with N-1 at δ (N) = 283 ppm,(H-7, N-1). Alternate structurein which the deshielded proton is on C-5, would not show this correlation and thus structurecould be ruled out. There is no doubt that adducts at both exocyclic and endocyclic nitrogen atoms occur, but in this case, the latter cyclize more readily into the 5-substituted pyrazolo[1,5-]pyrimidines derivatives thus shifting the equilibrium. It should be noted that the isomerswere also obtained as sole products when the reactions ofwithwas carried out by heating in a direct beam microwave oven and under solvent free conditions.

Scheme 4. Cyclocondensation reaction of 8a-c with 2c and 9 by heating in a direct beam microwave oven and solvent free conditions resulted in selective formation of pyrazolo[1,5-

]pyrimidines 12a-c and 15a-c.

Scheme 4. Cyclocondensation reaction of 8a-c with 2c and 9 by heating in a direct beam microwave oven and solvent free conditions resulted in selective formation of pyrazolo[1,5-

]pyrimidines 12a-c and 15a-c. 8a-c with 9 under microwave irradiation may be attributed to the formation of hot spots that affect the reaction selectivity due to the increase in heating rate. This may lead to the formation of thermodynamically stable products in preference to the kinetic ones [

The behavior ofwithunder microwave irradiation may be attributed to the formation of hot spots that affect the reaction selectivity due to the increase in heating rate. This may lead to the formation of thermodynamically stable products in preference to the kinetic ones [ 18 19 ]. One can thus conclude that this solvent-free reactions proceeds in a regiospecific fashion by the relative reactivity of exocyclic nitrogen and ring nitrogen atoms.

Preparation method of 6-chloro-1,3-dimethyluracil

The invention belongs to technical field of organic synthesis, relate in particular to a kind of 6-chloro-1, the preparation method of 3-FU dimethyl.

But, prepare 6-chloro-1 at above-mentioned two kinds, in the process of 3-FU dimethyl, the consumption of its chlorination process phosphorus oxychloride is all larger, is generally 10 ~ 15 times of weight of 1,3-dimethyl barbituric acid, not only cost is high, and reaction needs after finishing underpressure distillation to remove excessive phosphorus oxychloride, conversion unit required high, increased operation easier; Also need simultaneously to add a large amount of shrends reaction of going out, produce a large amount of waste acid liquors, still need further to process.

Chinese patent CNA also discloses 6-chloro-1, the synthesis step of 3-FU dimethyl: with 6-amino-1, the 3-FU dimethyl makes first 6-hydroxyl-1 through acid hydrolysis, the 3-FU dimethyl; Then mix with a large amount of phosphorus oxychloride solution that splash into a small amount of water, be warming up to again back flow reaction, react after 2 ~ 5 hours, cooling, solution decompression is concentrated, remove excessive phosphorus oxychloride after; Solution after will diluting at last joins cancellation in a large amount of cold water, obtains 6-chloro-1 after filtration and the centrifugation, and the thick product of 3-FU dimethyl passes through recrystallization again, obtains the finished product.

Then to 1, add a small amount of water in the 3-dimethyl barbituric acid, splash into again a large amount of phosphorus oxychloride and be warming up to back flow reaction, react after 1 ~ 2 hour, cooling, solution decompression is concentrated, add cancellation in a large amount of cold water after removing excessive phosphorus oxychloride, filter and centrifugation after obtain 6-chloro-1, the thick product of 3-FU dimethyl, pass through recrystallization again, obtain the finished product, productive rate is generally about 70%.

At first between 60 ~ 70 &#;, dimethyl urea and propanedioic acid are dissolved in the acetic acid, add aceticanhydride, and with temperature constant temperature to 90 &#;, react after 6 hours again acidifying and make and have 1 of formula II structure, 3-dimethyl barbituric acid;

Prior art discloses multiple 6-chloro-1, the synthetic method of 3-FU dimethyl, and in US Patent No. A, 6-chloro-1, the synthesis step of 3-FU dimethyl is:

6-chloro-1, the 3-FU dimethyl has another name called 6-chloro-1, and the 3-dimethyl uracil has formula I structure, is the important intermediate of synthetic Altace Ramipril urapidil and antiarrhythmic drug Nifekalant.

The invention provides a kind of 6-chloro-1, the preparation method of 3-FU dimethyl, with 1,3-dimethyl barbituric acid and comprise that the chlorizating agent of phosphorus oxychloride is raw material, with the immiscible organic solvent of water in, carry out back flow reaction, at last again after the water cancellation reaction, can obtain 6-chloro-1, the 3-FU dimethyl.Compared with prior art, the present invention with phosphorus oxychloride as chlorizating agent, take with the immiscible organic solvent of water as reaction medium, 1,3-dimethyl barbituric acid and a small amount of phosphorus oxychloride can be reacted obtain 6-chloro-1, the 3-FU dimethyl, reduced the phosphorus oxychloride consumption, the weight ratio that makes phosphorus oxychloride and 1,3-dimethyl barbituric acid is by original (10 ~ 15): 1 is reduced to (0.5 ~ 1.5): 1, reduced cost; Simultaneously, reaction does not need after finishing underpressure distillation to remove excessive phosphorus oxychloride and can add the shrend reaction of going out, reaction conditions gentleness, easy handling; Owing to reduced the consumption of phosphorus oxychloride, need not to use a large amount of shrends reaction of going out, reduced the generation of spent acid, simplified complicated aftertreatment.In addition, the present invention take with the immiscible organic solvent of water as reaction medium, react and be easy to after complete reclaim, can reuse.Further, the present invention has added water or alcohol compound as additive in the reaction process of 1,3-dimethyl barbituric acid and phosphorus oxychloride, so that 6-chloro-1, the productive rate of 3-FU dimethyl is increased to 84% ~ 90%.Further, the present invention with sodium methylate or sodium ethylate as condensing agent, with alcoholic solvent as reaction solvent, make the reaction of 1,3-dimethyl urea and dimethyl malonate obtain 1,3-dimethyl barbituric acid, avoid using a large amount of propanedioic acid and aceticanhydride, reduced cost.Experimental result shows, the present invention is take the phosphorus oxychloride of 0.5 ~ 1.5 times of weight as chlorizating agent, take with the immiscible organic solvent of water as reaction medium, take water or alcohol compound as additive, prepared 6-chloro-1, the 3-FU dimethyl, its productive rate is about more than 80%.

Preferably, the time of described back flow reaction is 3 ~ 8 hours, and the time of cancellation reaction is 0.2 ~ 0.8 hour.

Mix with 1,3-dimethyl barbituric acid, chlorizating agent with the immiscible organic solvent of water ,-5 ~ 10 &#; to wherein adding additive, carry out back flow reaction, obtain reaction mixture.

Preferably, described chlorizating agent also comprises one or both in phosphorus trichloride and the phosphorus pentachloride.

Preferably, the described and immiscible organic solvent of water is one or more in benzene kind solvent, ethyl acetate, methyl chloride and the t-butyl methyl ether.

A1) 1,3-dimethyl barbituric acid, chlorizating agent and additive with the immiscible organic solvent of water in carry out back flow reaction, obtain reaction mixture, described additive is one or more in water and the alcohol compound.

B) add shrend in the described reaction mixture and go out after the reaction, obtain 6-chloro-1, the 3-FU dimethyl.

A) 1,3-dimethyl barbituric acid and chlorizating agent with the immiscible organic solvent of water in carry out back flow reaction, obtain reaction mixture; Described chlorizating agent comprises phosphorus oxychloride;

The invention discloses a kind of 6-chloro-1, the preparation method of 3-FU dimethyl may further comprise the steps:

In view of this, the technical problem to be solved in the present invention is to provide a kind of 6-chloro-1, and the preparation method of 3-FU dimethyl has reduced the usage quantity of phosphorus oxychloride by preparation method provided by the invention, need not the underpressure distillation phosphorus oxychloride after reaction is finished, reaction conditions is gentle, easy handling.

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Fig. 4 is the 6-chloro-1 of preparation in the embodiment of the invention 1,3-FU dimethyl carbon-13 nmr spectra figure.

Fig. 3 is the 6-chloro-1 of preparation in the embodiment of the invention 1,3-FU dimethyl hydrogen nuclear magnetic resonance spectrogram;

Embodiment

In order further to understand the present invention, below in conjunction with embodiment the preferred embodiment of the invention is described, but should be appreciated that these describe just in order to further specify the features and advantages of the present invention, rather than to the restriction of invention claim.

The invention provides a kind of 6-chloro-1, the preparation method of 3-FU dimethyl may further comprise the steps:

A) described 1,3-dimethyl barbituric acid and chlorizating agent with the immiscible organic solvent of water in carry out back flow reaction, obtain reaction mixture; Described chlorizating agent comprises phosphorus oxychloride;

B) add shrend in the described reaction mixture and go out after the reaction, obtain 6-chloro-1, the 3-FU dimethyl.

The present invention is with 1,3-dimethyl barbituric acid and uses the chlorizating agent that comprises phosphorus oxychloride as raw material, with the immiscible organic solvent of water in react, cancellation can obtain 6-chloro-1, the 3-FU dimethyl after reacting.Further, the present invention is 1, in the process of 3-dimethyl barbituric acid and the chlorination reaction that comprises phosphorus oxychloride, take with the immiscible organic solvent of water as reaction medium, can reduce greatly the consumption of phosphorus oxychloride, thereby after reaction is finished, do not need underpressure distillation to remove excessive phosphorus oxychloride and can add the shrend reaction of going out, reaction conditions gentleness, easy handling; Owing to reduced the consumption of phosphorus oxychloride, need not to use a large amount of shrends reaction of going out, reduced the generation of spent acid, simplified complicated aftertreatment.

The present invention is raw material with 1,3-dimethyl barbituric acid, to its source without limits, can buy from the market, also can prepare in accordance with the following methods:

A) 1,3-dimethyl urea, dialkyl malonate and condensing agent react in alcoholic solvent, obtain 1,3-dimethyl barbituric acid sodium salt; Described condensing agent is sodium methylate or sodium ethylate;

B) described 1,3-dimethyl barbituric acid sodium salt obtains 1,3-dimethyl barbituric acid after acidifying.

The present invention at first reacts 1,3-dimethyl urea, dialkyl malonate and condensing agent in alcoholic solvent, obtain 1,3-dimethyl barbituric acid sodium salt; Described dialkyl malonate is preferably propanedioic acid dimethyl esters or propanedioic acid diethyl ester; Described condensing agent is preferably sodium methylate or sodium ethylate; Described alcoholic solvent is preferably methyl alcohol or ethanol.In the present invention, the weight ratio of described condensing agent and 1,3-dimethyl urea is preferably (0.55 ~ 0.68): 1; The weight ratio of described dialkyl malonate and 1,3-dimethyl urea is preferably (1.4 ~ 1.6): 1; The weight ratio of described alcoholic solvent and 1,3-dimethyl urea is preferably (9 ~ 10): 1.

The present invention preferably carries out according to following steps to order of addition(of ingredients) without limits:

At first 1,3-dimethyl urea and condensing agent are mixed in alcoholic solvent, open and stir, churning time is preferably 0.4 ~ 0.7 hour; Add dialkyl malonate, the adding mode is preferably slow adding again; Then heat up and carry out back flow reaction, the reaction times is preferably 5 ~ 7 hours; Cooling, centrifugation obtains 1,3-dimethyl barbituric acid sodium salt.

With described 1,3-dimethyl barbituric acid sodium salt is after acidification, and centrifugation obtains 1,3-dimethyl barbituric acid again; Described acidifying is preferably with concentrated hydrochloric acid carries out acidifying, is that 30% concentrated hydrochloric acid carries out acidifying with concentration more preferably.The present invention preferably will add entry in 1,3-dimethyl barbituric acid sodium salt, add concentrated hydrochloric acid again and carry out acidifying; The weight ratio of described water and 1,3-dimethyl barbituric acid sodium salt is preferably (1.0 ~ 1.2): 1; Described concentrated hydrochloric acid add-on is preferably above-mentioned reaction mixture pH value is adjusted between 1 ~ 2; Centrifugation obtains 1,3-dimethyl barbituric acid more at last.

After obtaining 1,3-dimethyl barbituric acid, it is carried out nuclear magnetic resonance spectroscopy, the result shows that it has formula II structure, shows that method provided by the invention can prepare 1,3-dimethyl barbituric acid.

1,3-dimethyl barbituric acid, chlorizating agent and mix with the immiscible organic solvent of water heat up and carry out back flow reaction, obtain reaction mixture.Described chlorizating agent comprises phosphorus oxychloride, preferably also comprises in phosphorus trichloride or the phosphorus pentachloride one or both.The present invention does not have particular restriction to the weight ratio of phosphorus oxychloride, phosphorus trichloride or phosphorus pentachloride, and is well known to those skilled in the art, can get final product with the weight ratio that 1,3-dimethyl barbituric acid reacts.Described as reaction medium with the immiscible organic solvent of water, can be in benzene kind solvent, ethyl acetate, methyl chloride and the t-butyl methyl ether one or more.Wherein, benzene kind solvent is preferably benzene, toluene or dimethylbenzene, and methyl chloride is preferably methylene dichloride or trichloromethane; Described and the immiscible organic solvent of water be benzene,toluene,xylene, ethyl acetate, methylene dichloride, trichloromethane or t-butyl methyl ether more preferably.In the present invention, the weight ratio of described chlorizating agent and 1,3-dimethyl barbituric acid is preferably (0.5 ~ 1.5): 1, more preferably (0.7 ~ 1.3): 1; The weight ratio of organic solvent and 1,3-dimethyl barbituric acid is preferably (2 ~ 5): 1, more preferably (2.5 ~ 3.5): 1.1,3-dimethyl barbituric acid and chlorizating agent react under reflux temperature, preferred 3 ~ 8 hours of reaction times, more preferably 4 ~ 7 hours.

In the back flow reaction process, in order to improve productive rate, the present invention preferably reacts under the existence effect of additive, that is, 1,3-dimethyl barbituric acid, chlorizating agent and additive with the immiscible organic solvent of water in carry out back flow reaction, obtain reaction mixture.Detailed process is preferably:

Mix with 1,3-dimethyl barbituric acid, chlorizating agent with the immiscible organic solvent of water ,-5 ~ 10 &#; to wherein adding additive, carry out back flow reaction, obtain reaction mixture.

At first with 1,3-dimethyl barbituric acid, chlorizating agent with after the immiscible organic solvent of water mixes, preferably it is cooled to-5 ~ 0 &#;; Slowly add additive, the adding temperature of additive is preferably-5 ~ 10 &#; again, more preferably-2 ~ 7 &#;; Described additive is one or both in water and the alcohol compound, and wherein alcohol compound is preferably methyl alcohol or ethanol; Described additive is one or more of water, methyl alcohol and ethanol more preferably; The weight ratio of additive and 1,3-dimethyl barbituric acid is preferably (0.5 ~ 1.2) in above-mentioned reaction: 1, more preferably (0.7 ~ 1.0): 1.

Additive add complete after, heat up and carry out back flow reaction, obtain reaction mixture, need not to distill in the situation of phosphorus oxychloride, directly add the shrend reaction of going out in the reaction mixture, the preferred slowly adding of the present invention shrend reaction of going out; The temperature of cancellation reaction is preferably below 60 &#;, and the time of cancellation reaction is preferably 0.2 ~ 0.8 hour, more preferably 0.3 ~ 0.7 hour; After the present invention preferably adds entry, cancellation reaction under the condition that stirs.

React complete after, preferably the reaction mixture that obtains is down to room temperature, after filtration, the aftertreatment such as centrifugation obtains solid crude product 6-chloro-1,3-FU dimethyl and centrifuge mother liquor.

Obtain crude product 6-chloro-1, after the 3-FU dimethyl, preferably comprise that also the crude product to obtaining carries out aftertreatment, described aftertreatment concrete steps are: at first crude product, methyl alcohol and gac are mixed, then pass through reflux decolour, filtration, crystallisation by cooling, carry out again centrifugation, oven dry, obtain at last elaboration 6-chloro-1, the 3-FU dimethyl.In described reflux decolour process, the weight ratio of described methyl alcohol and 1,3-dimethyl barbituric acid is (2 ~ 5): 1, and the weight ratio of activated carbon is (0.03 ~ 1): 1.

Obtain 6-chloro-1, after the 3-FU dimethyl, it is carried out nuclear magnetic resonance spectroscopy, the result shows that it has formula I structure, shows that method provided by the invention can prepare 6-chloro-1, the 3-FU dimethyl.

Obtain 6-chloro-1, after the 3-FU dimethyl, measure its fusing point, the result shows that its fusing point is 113 ~ 114 &#;.

In the present invention, described centrifuge mother liquor is mainly and the immiscible organic solvent of water, recycling after preferably it being reclaimed.The present invention does not have particular restriction to described recovery method, is preferably: will obtain organic solvent after centrifuge mother liquor layering, washing, the drying.

The present invention at first carries out described centrifuge mother liquor layering well known to those skilled in the art and processes, and organic solvent is separated mutually with water, and then preferred water washs the organic layer that obtains, and preferred washing times is 1 ~ 5 time; The preferred anhydrous sodium sulphate that adopts is carried out drying treatment to it after the washing, then remove by filter after the sodium sulfate, obtain pure and the immiscible organic solvent of water, this organic solvent can be used as reaction medium and continues on for 6-chloro-1, the preparation of 3-FU dimethyl, thus greatly reduce cost.Experimental result shows, method provided by the invention can reach 80% ~ 92% with the rate of recovery of the immiscible organic solvent of water.

In order further to understand the present invention, to 6-chloro-1 provided by the invention, the preparation method of 3-FU dimethyl is elaborated below in conjunction with embodiment, and protection scope of the present invention is not limited by the following examples.

Embodiment 1

In L dry reaction still, add 440kg methyl alcohol, 44kg1,3-dimethyl urea and 26kg sodium methylate are opened and are stirred, 0.5 after hour, the dimethyl malonate that slowly adds 66kg, adds complete after, back flow reaction is carried out in intensification, react after 6 hours, be down to room temperature, centrifugation obtains 88kg1,3-dimethyl barbituric acid sodium salt; To obtain 1, add 100kg water in the 3-dimethyl barbituric acid sodium salt, use again 30% concentrated hydrochloric acid with 1, the pH value of the mixed solution of 3-dimethyl barbituric acid sodium salt and water is adjusted to 1 ~ 2, last centrifugation obtains 58.5kg1, and 3-dimethyl barbituric acid product, productive rate are 75%.

1,3-dimethyl barbituric acid is carried out nuclear magnetic resonance spectroscopy, and the result is referring to Fig. 1 and Fig. 2, Fig. 1 be in the embodiment of the invention 1 preparation 1,3-dimethyl barbituric acid hydrogen nuclear magnetic resonance spectrogram, Fig. 2 be in the embodiment of the invention 1 preparation 1,3-dimethyl barbituric acid carbon-13 nmr spectra figure.By Fig. 1 and Fig. 2 as can be known, the product that the present invention obtains is 1,3-dimethyl barbituric acid.

Embodiment 2

In 100L dry reaction still, add 50kg dimethylbenzene, 10kg by embodiment 1 prepared 1,3-dimethyl barbituric acid and 12kg phosphorus oxychloride, open and stir, said mixture is cooled to-5 ~ 0 &#;, under less than 10 &#; condition, slowly drip 5kg methyl alcohol, dropwise slow intensification and carry out back flow reaction, react after 5 hours stopped heating, be down to room temperature, under the temperature condition below 40 &#;, slowly to wherein adding 12kg water, add complete, continue to stir after 0.5 hour, be down to room temperature, centrifugal solid crude product and the centrifuge mother liquor of obtaining adds 35kg methyl alcohol to this crude product, 0.5kg activated carbon, through reflux decolour, filter, crystallisation by cooling, centrifugal, oven dry obtains 10.06kg elaboration 6-chloro-1,3-FU dimethyl; Centrifuge mother liquor is carried out layering, with three washings of 30kg moisture, then carries out drying with the 0.5kg anhydrous sodium sulphate,

After removing by filter sodium sulfate, obtain 46kg dimethylbenzene, solvent recovering rate is 92%.

To elaboration 6-chloro-1, the 3-FU dimethyl is measured, and the result shows, its content 99.5%, 113 ~ 114 &#; of fusing points, yield 90%;

To elaboration 6-chloro-1, the 3-FU dimethyl is carried out nuclear magnetic resonance spectroscopy, the result is referring to Fig. 3 and Fig. 4, Fig. 3 is the 6-chloro-1 of preparation in the embodiment of the invention 1,3-FU dimethyl hydrogen nuclear magnetic resonance spectrogram, Fig. 4 is the 6-chloro-1 of preparation in the embodiment of the invention 1,3-FU dimethyl carbon-13 nmr spectra figure.By Fig. 3 and Fig. 4 as can be known, the final product that the present invention obtains is 6-chloro-1, the 3-FU dimethyl.

Embodiment 3

In 100L dry reaction still, add the 25kg trichloromethane, 10kg commercially available 1,3-dimethyl barbituric acid and 12kg phosphorus oxychloride, open and stir, said mixture is cooled to-5 ~ 0 &#;, under less than 10 &#; condition, slowly drip 5kg water, dropwise slow intensification and carry out back flow reaction, react after 5 hours stopped heating, be down to room temperature, under the temperature condition below 40 &#;, slowly to wherein adding 12kg water, add complete, continue to stir after 0.5 hour, be down to room temperature, centrifugal solid crude product and the centrifuge mother liquor of obtaining adds 35kg methyl alcohol to this crude product, 0.5kg activated carbon, through reflux decolour, filter, crystallisation by cooling, centrifugal, oven dry obtains 9.39kg elaboration 6-chloro-1,3-FU dimethyl; Centrifuge mother liquor is carried out layering, with three washings of 15kg moisture, then carries out drying with the 0.5kg anhydrous sodium sulphate, remove by filter sodium sulfate after, obtain the 21.3kg trichloromethane, solvent recovering rate is 86%.

To elaboration 6-chloro-1, the 3-FU dimethyl is measured, and the result shows, its content 99.1%, 113 ~ 114 &#; of fusing points, yield 84%;

To elaboration 6-chloro-1, the 3-FU dimethyl is carried out nuclear magnetic resonance spectroscopy, and the result shows that the final product that the present invention obtains is 6-chloro-1, the 3-FU dimethyl.

Embodiment 4

In 100L dry reaction still, add the 50kg ethyl acetate, 10kg is by embodiment 1 prepared 1,3-dimethyl barbituric acid and 8kg phosphorus oxychloride, open and stir, said mixture is cooled to-5 ~ 0 &#;, under less than 10 &#; condition, slowly drip 5kg ethanol, dropwise slow intensification and carry out back flow reaction, react after 5 hours stopped heating, be down to room temperature, under the temperature condition below 40 &#;, slowly to wherein adding 12kg water, add complete, continue to stir after 0.5 hour, be down to room temperature, centrifugal solid crude product and the centrifuge mother liquor of obtaining adds 35kg methyl alcohol to this crude product, 0.5kg activated carbon, through reflux decolour, filter, crystallisation by cooling, centrifugal, oven dry obtains 9.49kg elaboration 6-chloro-1,3-FU dimethyl; Centrifuge mother liquor is carried out layering, with three washings of 30kg moisture, then carries out drying with the 0.5kg anhydrous sodium sulphate, remove by filter sodium sulfate after, obtain the 44kg ethyl acetate, solvent recovering rate is 88%.

To elaboration 6-chloro-1, the 3-FU dimethyl is measured, and the result shows, its content 99.3%, 267 ~ 268 &#; of fusing points, yield 85%;

Embodiment 5

In 100L dry reaction still, add 20kg toluene, 10kg commercially available 1,3-dimethyl barbituric acid and 5kg phosphorus oxychloride, open and stir, slowly heat up and carry out back flow reaction, react after 5 hours stopped heating, be down to room temperature, under the temperature condition below 60 &#;, slowly to wherein adding 5kg water, add complete, continue to stir after 0.5 hour, be down to room temperature, centrifugal solid crude product and the centrifuge mother liquor of obtaining adds 35kg methyl alcohol to this crude product, 0.5kg activated carbon, through reflux decolour, filter, crystallisation by cooling, centrifugal, oven dry obtains 9.17kg elaboration 6-chloro-1,3-FU dimethyl; Centrifuge mother liquor is carried out layering, uses the 10kg water washing, then carry out drying with the 0.5kg anhydrous sodium sulphate, remove by filter sodium sulfate after, obtain 19kg toluene, solvent recovering rate is 95%.

To elaboration 6-chloro-1, the 3-FU dimethyl is measured, and the result shows, its content 99.2%, 113 ~ 114 &#; of fusing points, yield 82%;

Embodiment 6

In 100L dry reaction still, add the 50kg ethyl acetate, 10kg commercially available 1,3-dimethyl barbituric acid and 12kg phosphorus oxychloride, open and stir, slowly heat up and carry out back flow reaction, react after 5 hours stopped heating, be down to room temperature, under the temperature condition below 40 &#;, slowly to wherein adding 12kg water, add complete, continue to stir after 0.5 hour, be down to room temperature, centrifugal solid crude product and the centrifuge mother liquor of obtaining adds 35kg methyl alcohol to this crude product, 0.5kg activated carbon, through reflux decolour, filter, crystallisation by cooling, centrifugal, oven dry obtains 8.50kg elaboration 6-chloro-1,3-FU dimethyl; Centrifuge mother liquor is carried out layering, with three washings of 30kg moisture, then carries out drying with the 0.5kg anhydrous sodium sulphate, remove by filter sodium sulfate after, obtain the 45kg ethyl acetate, solvent recovering rate is 90%.

To elaboration 6-chloro-1, the 3-FU dimethyl is measured, and the result shows, its content 99.4%, 113 ~ 114 &#; of fusing points, yield 76%;

Embodiment 7

In 100L dry reaction still, add the 50kg t-butyl methyl ether, 10kg commercially available 1,3-dimethyl barbituric acid and 8kg phosphorus oxychloride, open and stir, slowly heat up and carry out back flow reaction, react after 5 hours stopped heating, be down to room temperature, under the temperature condition below 40 &#;, slowly to wherein adding 8kg water, add complete, continue to stir after 0.5 hour, be down to room temperature, centrifugal solid crude product and the centrifuge mother liquor of obtaining adds 35kg methyl alcohol to this crude product, 0.5kg activated carbon, through reflux decolour, filter, crystallisation by cooling, centrifugal, oven dry obtains 8.38kg elaboration 6-chloro-1,3-FU dimethyl; Centrifuge mother liquor is carried out layering,

With 30kg moisture three times washing, then carry out drying with the 0.5kg anhydrous sodium sulphate, remove by filter sodium sulfate after, obtain the 40kg t-butyl methyl ether, solvent recovering rate is 75%.

To elaboration 6-chloro-1, the 3-FU dimethyl is measured, and the result shows, its content 99.4%, 113 ~ 114 &#; of fusing points, yield 78%;

Embodiment 8

In 100L dry reaction still, add the 50kg o-Xylol, 10kg is by embodiment 1 prepared 1,3-dimethyl barbituric acid and 12kg phosphorus oxychloride, open and stir, slowly heat up and carry out back flow reaction, react after 5 hours stopped heating, be down to room temperature, under the temperature condition below 60 &#;, slowly to wherein adding 12kg water, add complete, continue to stir after 0.5 hour, be down to room temperature, centrifugal solid crude product and the centrifuge mother liquor of obtaining adds 35kg methyl alcohol to this crude product, 0.5kg activated carbon, through reflux decolour, filter, crystallisation by cooling, centrifugal, oven dry obtains 9.61kg elaboration 6-chloro-1,3-FU dimethyl; Centrifuge mother liquor is carried out layering, with three washings of 30kg moisture, then carries out drying with the 0.5kg anhydrous sodium sulphate, remove by filter sodium sulfate after, obtain the 46kg o-Xylol, solvent recovering rate is 92%.

To elaboration 6-chloro-1, the 3-FU dimethyl is measured, and the result shows, its content 99.1%, 113 ~ 114 &#; of fusing points, yield 86%;

More than to a kind of 6-chloro-1 provided by the present invention, the preparation method of 3-FU dimethyl is described in detail.Used a concrete example herein principle of the present invention and embodiment are set forth, the explanation of above embodiment just is used for helping to understand method of the present invention and core concept thereof.Should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention, can also carry out some improvement and modification to the present invention, these improvement and modification also fall in the protection domain of claim of the present invention.

For more information, please visit 6-amino-1,3-dimethyluracil manufacturer.

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