CN112062728A - Synthetic method of 3, 5-dichloro-6-ethylpyrazine formamide - Google Patents
Synthetic method of 3, 5-dichloro-6-ethylpyrazine formamide Download PDFInfo
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- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a synthesis method of 3, 5-dichloro-6-ethylpyrazine formamide, which relates to the technical field of intermediates for synthesizing Gilitinib, and has the technical key points that 2, 6-dichloropyrazine and formamide are heated to 70-130 ℃ and undergo free radical oxidation reaction under the action of persulfate to obtain 3, 5-dichloropyrazine formamide; heating and refluxing the 3, 5-dichloropyrazine formamide for 3-6h under the action of a dehydrating agent, and dehydrating to synthesize 3, 5-dichloropyrazine formonitrile; 3, 5-dichloro-2-acetylpyrazine is prepared by Grignard reaction of 3, 5-dichloro-pyrazinecarbonitrile in an organic solvent A under the action of a methylating agent; reducing 3, 5-dichloro-2-acetylpyrazine in an organic solvent B under the action of an acid catalyst and a silicon-hydrogen reducing agent to obtain 3, 5-dichloro-2-ethylpyrazine; heating 3, 5-dichloro-2-ethyl pyrazine and formamide to 50-120 ℃, and performing free radical oxidation reaction under the action of persulfate to obtain 3, 5-dichloro-6-ethyl pyrazine formamide. The method has the advantages of simple operation method, mild reaction conditions of the synthesis process, cost reduction and higher economic benefit.
Description
Technical Field
The invention relates to the technical field of intermediates for synthesizing Gilitinib, in particular to a method for synthesizing 3, 5-dichloro-6-ethylpyrazine formamide.
Background
Gelitinib is a small molecule drug for inhibiting multiple receptor tyrosine kinases including FMS-like tyrosine kinase 3. Gilitinib can inhibit FLT3 receptor signaling, proliferation and expression in exogenous cells, including FLT33-ITD, tyrosine kinase domain mutation (TKD) FLT3-ITD-D835Y and FLT3-ITD-D835Y, so as to induce apoptosis of leukemia cells expressing FLT3-ITD, and the chemical structural formula of the Gilitinib is shown in the specification
Wherein, 3, 5-dichloro-6-ethyl pyrazine formamide is a key intermediate for synthesizing the Gilitinib, and the CAS number of the compound is as follows: 313340-08-8, the molecular structural formula is:
3, 5-dichloro-6-ethylpyrazine formamide on the market does not only clearly indicate a route for synthesizing the chemicals by using 2, 6-dichloropyrazine as a raw material, but also has high purchase price. Therefore, a new technical solution is needed to solve the above problems.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide the synthesis method of the 3, 5-dichloro-6-ethylpyrazine formamide, which is simple in operation method, mild in reaction conditions of the synthesis process, low in cost and capable of bringing high economic benefits.
In order to achieve the purpose, the invention provides the following technical scheme: a synthetic method of 3, 5-dichloro-6-ethylpyrazine formamide comprises the following steps:
the method comprises the following steps: heating 2, 6-dichloropyrazine and formamide to 70-130 ℃, and carrying out free radical oxidation reaction under the action of persulfate to obtain 3, 5-dichloropyrazine formamide;
step two: under the action of a dehydrating agent, heating and refluxing the 3, 5-dichloropyrazine formamide for 3-6h, and dehydrating to synthesize 3, 5-dichloropyrazine formonitrile;
step three: under the action of a methylating agent, 3, 5-dichloropyrazine formonitrile is prepared into 3, 5-dichloro-2-acetylpyrazine through Grignard reaction in an organic solvent A at the temperature of-70-30 ℃;
step four: under the action of an acid catalyst and a hydrosilation reducing agent, reducing 3, 5-dichloro-2-acetylpyrazine in an organic solvent B to obtain 3, 5-dichloro-2-ethylpyrazine;
step five: heating 3, 5-dichloro-2-ethyl pyrazine and formamide to 10-120 ℃, and performing free radical oxidation reaction under the action of persulfate to obtain 3, 5-dichloro-6-ethyl pyrazine formamide.
By adopting the technical scheme, the low-price 2, 6-dichloropyrazine is used as a raw material for reaction, the product 3, 5-dichloro-6-ethylpyrazine formamide is obtained after two times of free radical oxidation reaction of persulfate, one time of dehydration synthesis reaction, one time of Grignard reaction and silicon hydrogen reduction reaction, the whole reaction has 5 steps in total, the synthesis process is short, the operation and reaction conditions of each step are relatively mild, and the control and industrialization are easy.
Further, in the first step, formamide is 5-18 equivalent of 2, 6-dichloropyrazine; the persulfate is 0.9-1.1 equivalent of 2, 6-dichloropyrazine.
Further, in the second step, the dehydrating agent is 1.5-5 equivalent of 3, 5-dichloropyrazine formamide; in step three, the methylating agent is 1-1.5 equivalent of 3, 5-dichloropyrazine formonitrile.
Further, in the fourth step, the acid catalyst is 0.1-3 equivalent of 3, 5-dichloro-2-acetylpyrazine; the hydrosilation reducing agent is 1-4 equivalent of 3, 5-dichloro-2-acetylpyrazine.
Further, in step five, the formamide is 5-20 equivalents of 3, 5-dichloro-2-ethylpyrazine; persulfate is 0.8-1 equivalent of 3, 5-dichloro-2-ethylpyrazine.
By adopting the technical scheme and optimizing the proportion among the substances such as formamide, persulfate, dehydrating agent, methylating agent, acid catalyst, hydrosilation reducing agent and the like, the waste of chemical reagents can be reduced, and the yield of products can be effectively improved.
Further, the method comprises the following steps:
the method comprises the following steps: heating 2, 6-dichloropyrazine and formamide to 90-100 ℃, and adding sodium persulfate; after the addition is finished, the reaction is carried out for 10-15min, and 3000ml of water of 2000-; cooling to room temperature, adding dichloromethane for extraction, washing an organic phase with 150ml of saturated saline, drying anhydrous sodium sulfate, and removing the solvent to obtain 3, 5-dichloropyrazine formamide;
step two: adding 3, 5-dichloropyrazine formamide into phosphorus oxychloride, and heating and refluxing for reaction for 4-5 h. Cooling, pouring into ice water, adding dichloromethane for extraction, washing an organic phase by using 150ml of saturated saline and 250ml of anhydrous sodium sulfate, drying, and removing a solvent to obtain 3, 5-dichloropyrazine formonitrile;
step three: adding 3, 5-dichloropyrazine formonitrile into 600-800ml tetrahydrofuran THF, cooling to-10 ℃, beginning to dropwise add 3mol/L methyl magnesium chloride, and controlling the temperature to be less than or equal to 0 ℃; after the dropwise addition, naturally raising the temperature, stirring for 2-3h, and then adding the mixture into 500-600ml of saturated ammonium chloride aqueous solution; extracting the separated aqueous phase with ethyl acetate, washing the organic phase with saturated saline, drying with anhydrous sodium sulfate, and removing the solvent to obtain 3, 5-dichloro-2-acetylpyrazine;
step four: 3, 5-dichloro-2-acetylpyrazine and acetonitrile, starting to cool to 0 ℃, adding boron trifluoride diethyl ether, dropwise adding triethylsilane, stirring at room temperature for 2-3h, removing the solvent, and directly putting the obtained unpurified 3, 5-dichloro-2-ethylpyrazine into the next step; step five: adding 3, 5-dichloro-2-ethylpyrazine and formamide, heating to 80-90 ℃, adding sodium persulfate, keeping the external temperature at 80-90 ℃, reacting for 3-4h, cooling to below 40 ℃, adding 1.5-2.0L of water and 1.5-2.0L of DCM, extracting the water phase obtained by liquid separation with DCM, washing the obtained organic phase with 600ml of saturated saline water, directly removing the solvent after drying the anhydrous sodium sulfate, then adding 200ml of ethyl acetate, spin-drying, then adding 800ml of ethyl acetate, and pulping to obtain the 3, 5-dichloro-6-ethylpyrazine formamide.
By adopting the technical scheme, the most appropriate and convenient operation mode is selected to carry out purification and purification treatment in each step according to the property of each intermediate product, which is beneficial to improving the purity of the intermediate and the final product, and meanwhile, the whole reaction has 5 steps in total, the synthesis flow is short, and the operation and reaction conditions of each step are relatively mild, thus being easy to control and industrialize.
Further, the persulfate is selected from one of sodium persulfate, ammonium persulfate or potassium persulfate; the dehydrating agent is selected from one of phosphorus oxychloride, thionyl chloride or acyl chloride.
Further, the methylating agent is selected from one of methyl magnesium chloride, methyl magnesium bromide or methyl magnesium iodide.
Further, the acidic catalyst is selected from one of boron fluoride ethyl ether, trifluoroacetic acid, silver tribromide or titanium tetrachloride.
Further, the silicon-hydrogen reducing agent is triethylsilane; the organic solvent A is tetrahydrofuran, and the organic solvent B is acetonitrile.
In conclusion, the invention has the following beneficial effects:
1. the method has the advantages of simple operation method, mild reaction conditions of the synthesis process, cost reduction and higher economic benefit;
2. according to the properties of raw materials and intermediates, the most appropriate mode and operation mode are selected for purification and purification treatment, so that the purity of the whole intermediate and a final product is effectively improved, meanwhile, the synthesis process is short, the operation and reaction conditions of each step are relatively mild, and the method is easy to control and industrialize.
Drawings
FIG. 1 is a general reaction scheme of a synthesis method of 3, 5-dichloro-6-ethylpyrazine-carboxamide;
FIG. 2 is a chemical reaction formula of a first step in a synthesis method of 3, 5-dichloro-6-ethylpyrazine formamide;
FIG. 3 is a chemical reaction formula of step two in a synthesis method of 3, 5-dichloro-6-ethylpyrazine formamide;
FIG. 4 is a chemical reaction formula of step three in a synthetic method of 3, 5-dichloro-6-ethylpyrazine-carboxamide;
FIG. 5 is a chemical reaction formula of step four in a method for synthesizing 3, 5-dichloro-6-ethylpyrazine-carboxamide;
FIG. 6 is a chemical reaction formula of step five in the synthetic method of 3, 5-dichloro-6-ethylpyrazine formamide.
Detailed Description
The present invention will be described in further detail with reference to examples.
Example 1: a synthetic method of 3, 5-dichloro-6-ethylpyrazine formamide comprises the following operation steps:
the method comprises the following steps: heating 330g of 2, 6-dichloropyrazine and 1980g of formamide to 90 ℃, and adding 513g of sodium persulfate in three batches; after the addition is finished, the reaction is carried out for 10min, and 2500ml of water is added; after cooling to room temperature (i.e., 25 ℃) 4 extractions with 1000ml of dichloromethane were performed, the organic phases were combined and the combined organic phases were washed three times with 150ml of saturated brine, followed by drying over anhydrous sodium sulfate to remove the solvent to obtain an off-white solid, i.e., 281g of 3, 5-dichloropyrazine carboxamide in 65.9% yield.
Nuclear magnetic data of 3, 5-dichloropyrazine formamide:
CDCl3,CONH(6.342,br),CONH(7.415,br),CH(8.491,s)。
step two: adding 150g of the 3, 5-dichloropyrazine formamide obtained in the step one into 200g of phosphorus oxychloride, and heating and refluxing for reaction for 4 h. The mixture was cooled and poured into 1L of ice water, extracted twice with 500ml of dichloromethane each time, the organic phases were combined, and the combined organic phases were washed three times with 200ml of saturated brine each time, then dried over anhydrous sodium sulfate, and the solvent was removed to obtain a white solid, i.e., 98g of 3, 5-dichloropyrazine carbonitrile, with a yield of 72.6%.
Step three: adding 120g of the 3, 5-dichloropyrazine formonitrile obtained in the second step into 700ml of tetrahydrofuran THF, cooling to-10 ℃, beginning to dropwise add 3 mol/L254 ml of methyl magnesium chloride, and controlling the temperature to be-15 +/-5 ℃; after the dropwise addition, the mixture is naturally cooled to room temperature (25 ℃), stirred for 2 hours and then added into 500ml of saturated ammonium chloride aqueous solution; the aqueous phase after separation was extracted with 200ml of ethyl acetate each time for 2 times, the organic phases were combined, and the combined organic phases were washed three times with 150ml of saturated brine, and then dried over anhydrous sodium sulfate, and the solvent was removed to obtain 117g of 3, 5-dichloro-2-acetylpyrazine with a yield of 87.9%.
Step four: and (3) cooling 150g of the 3, 5-dichloro-2-acetylpyrazine obtained in the third step and 1L of acetonitrile to 0 ℃, adding 15ml of boron trifluoride diethyl ether, dropwise adding 182g of triethylsilane, stirring at room temperature for 2 hours, and removing the solvent to obtain 120g of unpurified 3, 5-dichloro-2-ethylpyrazine.
Nuclear magnetic data for 3, 5-dichloro-2-ethylpyrazine:
CDCl3,CH3(1,292-1.322,t),CH2(2.933-2,978,q),CH(8.49,s)。
step five: the unpurified 3, 5-dichloro-2-ethylpyrazine obtained in step four (500 g) and formamide (1500 ml) were charged in a 3000ml three-necked flask, followed by heating to 90 ℃ and addition of sodium persulfate (580 g), and the reaction was carried out for 3 hours while maintaining the external temperature at 80 ℃. Naturally cooling to about 35 ℃ (colloid stirring will be formed), adding 1.5L water and 1.5L DCM, extracting the water phase obtained by liquid separation twice with 700ml DCM each time, combining the organic phases, washing the obtained organic phase with 600ml saturated saline, then directly removing the solvent after drying with anhydrous sodium sulfate, then using 200ml ethyl acetate, adding 600ml ethyl acetate after drying, and pulping to obtain white-like solid, namely 300g of 3, 5-dichloro-6-ethyl pyrazine formamide, with the yield of 48.3%,
nuclear magnetic data of 3, 5-dichloro-6-ethylpyrazine carboxamide:
CDCl3,CH3(1,344-1.374,t),CH2(2.988-3.033,q),CONH(5.861,br),CONH(7.470,br)。
example 2: a synthetic method of 3, 5-dichloro-6-ethylpyrazine formamide comprises the following operation steps:
the method comprises the following steps: 330g of 2, 6-dichloropyrazine and 1950g of formamide are heated to 95 ℃, 428.6g of sodium persulfate is added in four portions; after the addition is finished, reacting for 12min, and adding 2000ml of water; after cooling to room temperature (20 ℃) 4 extractions with 1000ml of dichloromethane each time were carried out, the organic phases were combined and the combined organic phases were washed three times with 200ml of saturated brine, and then dried over anhydrous sodium sulfate to remove the solvent to obtain an off-white solid, namely 295g of 3, 5-dichloropyrazinecarboxamide, with a yield of 69.3%.
Step two: 150g of the 3, 5-dichloropyrazine formamide obtained in the first step is added into 179.3g of phosphorus oxychloride, and the mixture is heated and refluxed for reaction for 4.5 hours. The mixture was cooled and poured into 1L of ice water, and each time 500ml of dichloromethane was added for extraction, the organic phases were combined, and the combined organic phases were washed 2 times with 150ml of saturated brine, and then dried over anhydrous sodium sulfate, and the solvent was removed to obtain a white solid, i.e., 100.5g of 3, 5-dichloropyrazine carbonitrile, with a yield of 79.4%.
Step three: adding 120g of the 3, 5-dichloropyrazine formonitrile obtained in the second step into 600ml of tetrahydrofuran THF, cooling to-12 ℃, and beginning to dropwise add 3 mol/L229.9 ml of methyl magnesium chloride, wherein the temperature is controlled to be-10 +/-5 ℃; after the dropwise addition, the mixture is naturally cooled to room temperature (20 ℃), stirred for 2.5 hours and then added into 550ml of saturated ammonium chloride aqueous solution; the aqueous phase after separation was extracted with 200ml of ethyl acetate each time for 2 times, the organic phases were combined, and the combined organic phase was washed three times with 200ml of saturated brine, and then dried over anhydrous sodium sulfate, and the solvent was removed to obtain 122g of 3, 5-dichloro-2-acetylpyrazine in a yield of 92.6%.
Step four: 150g of 3, 5-dichloro-2-acetylpyrazine obtained in the third step and 1L of acetonitrile were initially cooled to 0 ℃, 9.9ml of boron trifluoride diethyl ether was added, 136.6g of triethylsilane was added dropwise, the mixture was stirred at room temperature for 2.5 hours, and the solvent was removed to obtain 132g of unpurified 3, 5-dichloro-2-ethylpyrazine in a yield of 94.9%.
Step five: in a 3000ml three-necked flask were charged 500g of unpurified 3, 5-dichloro-2-ethylpyrazine obtained in step four and 1178.8ml of formamide, followed by heating to 80 ℃ and adding 485.9g of sodium persulfate, and the reaction was carried out for 3.5 hours while maintaining the external temperature at 75 ℃. Naturally cooling to about 25 ℃ (colloid stirring will be formed), adding 1.8L water and 1.8L DCM, extracting the water phase obtained by liquid separation twice with 700ml DCM each time, combining the organic phases, washing the obtained organic phase with 500ml saturated saline, then directly removing the solvent after drying with anhydrous sodium sulfate, then using 200ml ethyl acetate, adding 700ml ethyl acetate after drying in a spinning way, and pulping to obtain a white-like solid, namely 401g of 3, 5-dichloro-6-ethyl pyrazine formamide, wherein the yield is 82.3%
Example 3: a synthetic method of 3, 5-dichloro-6-ethylpyrazine formamide comprises the following operation steps:
the method comprises the following steps: heating 330g of 2, 6-dichloropyrazine and 2340g of formamide to 100 ℃, and adding 523.8g of sodium persulfate in three batches; after the addition is finished, reacting for 15min, and adding 3000ml of water; after cooling to room temperature (25 ℃) 4 extractions with 1000ml of dichloromethane were carried out, the organic phases were combined and the combined organic phases were washed three times with 250ml of saturated brine, and then dried over anhydrous sodium sulfate to remove the solvent, to obtain a white-like solid, i.e. 310g of 3, 5-dichloropyrazinecarboxamide, with a yield of 72.9%.
Step two: 150g of the 3, 5-dichloropyrazine formamide obtained in the first step is added into 215.2g of phosphorus oxychloride, and the mixture is heated and refluxed for reaction for 5 hours. The mixture was cooled and poured into 1L of ice water, and extracted 2 times with 500ml of dichloromethane each time, the organic phases were combined, and the combined organic phases were washed three times with 250ml of saturated brine, then dried over anhydrous sodium sulfate, and the solvent was removed to obtain a white solid, i.e., 109.5g of 3, 5-dichloropyrazine carbonitrile, with a yield of 90.6%.
Step three: adding 120g of the 3, 5-dichloropyrazine formonitrile obtained in the second step into 800ml of tetrahydrofuran THF, cooling to-15 ℃, beginning to dropwise add 3 mol/L275.9 ml of methyl magnesium chloride, and controlling the temperature to be about-20 ℃; after the dropwise addition, the mixture is naturally cooled to room temperature (25 ℃), stirred for 3 hours and then added into 600ml of saturated ammonium chloride aqueous solution; the aqueous phase after separation was extracted with 200ml of ethyl acetate each time for 2 times, the organic phases were combined, and the combined organic phases were washed three times with 250ml of saturated brine, and then dried over anhydrous sodium sulfate, and the solvent was removed to obtain 120.6g of 3, 5-dichloro-2-acetylpyrazine with a yield of 92%.
Step four: 150g of 3, 5-dichloro-2-acetylpyrazine obtained in the third step and 1L of acetonitrile were initially cooled to 0 ℃, 14.9ml of boron trifluoride diethyl ether was added, 182.2g of triethylsilane was added dropwise, the mixture was stirred at room temperature for 3 hours, and then the solvent was removed to obtain 127g of unpurified 3, 5-dichloro-2-ethylpyrazine, with a yield of 91.4%.
Step five: in a 3000ml three-necked flask were charged 500g of unpurified 3, 5-dichloro-2-ethylpyrazine obtained in step four and 1616.7ml of formamide, followed by heating to 90 ℃ and adding 607.3g of sodium persulfate, and the reaction was carried out for 4 hours while maintaining the external temperature at 85 ℃. Naturally cooling to about 30 ℃ (colloid stirring will be formed), adding 2.0L water and 2.0L DCM, extracting the water phase obtained by separating liquid twice with 700ml DCM each time, combining the organic phases, washing the obtained organic phase with 600ml saturated saline, then directly removing the solvent after drying with anhydrous sodium sulfate, then using 200ml ethyl acetate, adding 800ml ethyl acetate after drying, and pulping to obtain a white-like solid, namely 425.6g of 3, 5-dichloro-6-ethyl pyrazine formamide, wherein the yield is 87.4%
Example 4: the difference between the synthesis method of 3, 5-dichloro-6-ethylpyrazine formamide and the example 1 is that: in step one, the persulfate is selected from ammonium persulfate.
Example 5: the difference between the synthesis method of 3, 5-dichloro-6-ethylpyrazine formamide and the example 1 is that: in the first step, the persulfate is selected from potassium persulfate.
Example 6: the difference between the synthesis method of 3, 5-dichloro-6-ethylpyrazine formamide and the example 1 is that: in the second step, thionyl chloride is used as the dehydrating agent.
Example 7: the difference between the synthesis method of 3, 5-dichloro-6-ethylpyrazine formamide and the example 1 is that: in the second step, acyl chloride is used as the dehydrating agent.
Example 8: the difference between the synthesis method of 3, 5-dichloro-6-ethylpyrazine formamide and the example 1 is that: in step two, the methylating agent is selected from methyl magnesium bromide.
Example 9: the difference between the synthesis method of 3, 5-dichloro-6-ethylpyrazine formamide and the example 1 is that: in step three, the methylating agent is selected from methyl magnesium iodide.
Example 10: the difference between the synthesis method of 3, 5-dichloro-6-ethylpyrazine formamide and the example 1 is that: in step three, the acidic catalyst is selected from trifluoroacetic acid.
Example 11: the difference between the synthesis method of 3, 5-dichloro-6-ethylpyrazine formamide and the example 1 is that: in step three, the acidic catalyst is selected from silver tribromide.
Example 12: the difference between the synthesis method of 3, 5-dichloro-6-ethylpyrazine formamide and the example 1 is that: in step three, the acidic catalyst is selected from titanium tetrachloride.
The specific embodiments are only for explaining the present invention, and the present invention is not limited thereto, and those skilled in the art can make modifications without inventive contribution to the present embodiments as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present invention.
Claims (10)
1. A synthetic method of 3, 5-dichloro-6-ethylpyrazine formamide is characterized by comprising the following steps:
the method comprises the following steps: heating 2, 6-dichloropyrazine and formamide to 70-130 ℃, and carrying out free radical oxidation reaction under the action of persulfate to obtain 3, 5-dichloropyrazine formamide;
step two: under the action of a dehydrating agent, heating and refluxing the 3, 5-dichloropyrazine formamide for 3-6h, and dehydrating to synthesize 3, 5-dichloropyrazine formonitrile;
step three: under the action of a methylating agent, 3, 5-dichloropyrazine formonitrile is prepared into 3, 5-dichloro-2-acetylpyrazine through Grignard reaction in an organic solvent A at the temperature of-70-30 ℃;
step four: under the action of an acid catalyst and a hydrosilation reducing agent, reducing 3, 5-dichloro-2-acetylpyrazine in an organic solvent B to obtain 3, 5-dichloro-2-ethylpyrazine;
step five: heating 3, 5-dichloro-2-ethyl pyrazine and formamide to 10-120 ℃, and performing free radical oxidation reaction under the action of persulfate to obtain 3, 5-dichloro-6-ethyl pyrazine formamide.
2. The method for synthesizing 3, 5-dichloro-6-ethylpyrazine-carboxamide according to claim 1, characterized in that in the first step, the carboxamide is 5-18 equivalents of 2, 6-dichloropyrazine; the persulfate is 0.9-1.1 equivalent of 2, 6-dichloropyrazine.
3. The method for synthesizing 3, 5-dichloro-6-ethylpyrazine carboxamide according to claim 1, wherein in the second step, the dehydrating agent is 1.5 to 5 equivalents of 3, 5-dichloropyrazine carboxamide; in step three, the methylating agent is 1-1.5 equivalent of 3, 5-dichloropyrazine formonitrile.
4. The method for synthesizing 3, 5-dichloro-6-ethylpyrazine carboxamide according to claim 1, wherein in step four, the acidic catalyst is 0.1-3 equivalent of 3, 5-dichloro-2-acetylpyrazine; the hydrosilation reducing agent is 1-4 equivalent of 3, 5-dichloro-2-acetylpyrazine.
5. The method for synthesizing 3, 5-dichloro-6-ethylpyrazine carboxamide according to claim 1, characterized in that in step five, the carboxamide is 5-20 equivalents of 3, 5-dichloro-2-ethylpyrazine; persulfate is 0.8-1 equivalent of 3, 5-dichloro-2-ethylpyrazine.
6. The method for synthesizing 3, 5-dichloro-6-ethylpyrazine-carboxamide according to any one of claims 1 to 5, characterized by comprising the following steps:
the method comprises the following steps: heating 2, 6-dichloropyrazine and formamide to 90-100 ℃, and adding sodium persulfate; after the addition is finished, the reaction is carried out for 10-15min, and 3000ml of water of 2000-; cooling to room temperature, adding dichloromethane for extraction, washing an organic phase with 150ml of saturated saline, drying anhydrous sodium sulfate, and removing the solvent to obtain 3, 5-dichloropyrazine formamide;
step two: adding 3, 5-dichloropyrazine formamide into phosphorus oxychloride, and heating and refluxing for reaction for 4-5 h; cooling, pouring into ice water, adding dichloromethane for extraction, washing an organic phase by using 150ml of saturated saline and 250ml of anhydrous sodium sulfate, drying, and removing a solvent to obtain 3, 5-dichloropyrazine formonitrile;
step three: adding 3, 5-dichloropyrazine formonitrile into 600-800ml tetrahydrofuran THF, cooling to-10 ℃, beginning to dropwise add 3mol/L methyl magnesium chloride, and controlling the temperature to be less than or equal to 0 ℃; after the dropwise addition, naturally raising the temperature, stirring for 2-3h, and then adding the mixture into 500-600ml of saturated ammonium chloride aqueous solution; extracting the separated aqueous phase with ethyl acetate, washing the organic phase with saturated saline, drying with anhydrous sodium sulfate, and removing the solvent to obtain 3, 5-dichloro-2-acetylpyrazine;
step four: 3, 5-dichloro-2-acetylpyrazine and acetonitrile, starting to cool to 0 ℃, adding boron trifluoride diethyl ether, dropwise adding triethylsilane, stirring at room temperature for 2-3h, removing the solvent, and directly putting the obtained unpurified 3, 5-dichloro-2-ethylpyrazine into the next step;
step five: adding 3, 5-dichloro-2-ethylpyrazine and formamide, heating to 80-90 ℃, adding sodium persulfate, keeping the external temperature at 80-90 ℃, reacting for 3-4h, cooling to below 40 ℃, adding 1.5-2.0L of water and 1.5-2.0L of DCM, extracting the water phase obtained by liquid separation with DCM, washing the obtained organic phase with 600ml of saturated saline water, directly removing the solvent after drying the anhydrous sodium sulfate, then adding 200ml of ethyl acetate, spin-drying, then adding 800ml of ethyl acetate, and pulping to obtain the 3, 5-dichloro-6-ethylpyrazine formamide.
7. The method for synthesizing 3, 5-dichloro-6-ethylpyrazine carboxamide according to claim 1, characterized in that said persulfate is selected from one of sodium persulfate, ammonium persulfate and potassium persulfate; the dehydrating agent is selected from one of phosphorus oxychloride, thionyl chloride or acyl chloride.
8. The method for synthesizing 3, 5-dichloro-6-ethylpyrazine carboxamide according to claim 1, wherein said methylating agent is selected from one of methyl magnesium chloride, methyl magnesium bromide or methyl magnesium iodide.
9. The method for synthesizing 3, 5-dichloro-6-ethylpyrazine carboxamide according to claim 1, characterized in that the acidic catalyst is selected from one of boron fluoride ethyl ether, trifluoroacetic acid, silver tribromide or titanium tetrachloride.
10. The method for synthesizing 3, 5-dichloro-6-ethylpyrazine carboxamide according to claim 1, wherein said silicon hydrogen reducing agent is triethylsilane; the organic solvent A is tetrahydrofuran, and the organic solvent B is acetonitrile.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104080774A (en) * | 2012-01-17 | 2014-10-01 | 安斯泰来制药株式会社 | Pyrazine carboxamide compound |
| CN105061373A (en) * | 2015-09-06 | 2015-11-18 | 合肥华方医药科技有限公司 | Synthesis method of dapagliflozin isomer impurity |
| CN109789146A (en) * | 2016-07-29 | 2019-05-21 | Flx生物公司 | Chemokine receptor modulators and application thereof |
-
2019
- 2019-05-25 CN CN201910442769.1A patent/CN112062728A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104080774A (en) * | 2012-01-17 | 2014-10-01 | 安斯泰来制药株式会社 | Pyrazine carboxamide compound |
| CN105061373A (en) * | 2015-09-06 | 2015-11-18 | 合肥华方医药科技有限公司 | Synthesis method of dapagliflozin isomer impurity |
| CN109789146A (en) * | 2016-07-29 | 2019-05-21 | Flx生物公司 | Chemokine receptor modulators and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| CINDY C. PHAM ET AL.,: "Modular Preparation of Diverse Dipyrrolemethanes", 《SYNTHESIS》, vol. 45, pages 1166 * |
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