CN114524826A - Preparation process of 7-bromo-4-chlorothiophene [3,2-d ] pyrimidine - Google Patents
Preparation process of 7-bromo-4-chlorothiophene [3,2-d ] pyrimidine Download PDFInfo
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Abstract
The invention relates to a preparation process of 7-bromo-4-chlorothiophene [3,2-d ] pyrimidine, which comprises the following steps: dissolving 7-bromo-3H-thieno [3,2-d ] pyrimidine-4-ketone in a solvent A, adding HBr acetic acid solution, reacting, adding phosphorus oxychloride and triethylamine, heating to 80-90 ℃, reacting for 1.5-4.5H, and purifying to obtain the catalyst. The preparation process of the 7-bromo-4-chlorothiophene [3,2-d ] pyrimidine adopts an HBr/phosphorus oxychloride/triethylamine system for preparation, the dosage of the phosphorus oxychloride is less, and the utilization rate of chlorine atoms is high; the method has the advantages of difficult generation of byproducts harmful to the environment, simple quenching, easy purification and higher reaction yield.
Description
Technical Field
The invention belongs to the technical field of compound synthesis, and particularly relates to a preparation process of 7-bromo-4-chlorothieno [3,2-d ] pyrimidine.
Background
7-bromo-4-chlorothieno [3,2-d ] pyrimidine is a medical intermediate, and a plurality of synthesis methods are available. In the prior art, Preparation of bicyclic heterocyclic amides, especial thiopyrimidines, as electroculotide pyrophoridase/phosphorodiesterase 1(ENPP1) modulators (Pinkerton, Anthony et al, From PCT. appl.,2021133915,01Jul 2021) disclosed the use of 7-bromo-3H-thieno [3,2-d ] pyrimidin-4-one reacted with phosphorus oxychloride to give 7-bromo-4-chlorothieno [3,2-d ] pyrimidine, which is at a higher temperature and with more by-products.
Disclosure of Invention
The invention aims to provide a preparation process of 7-bromo-4-chlorothieno [3,2-d ] pyrimidine, which has the advantages of low reaction temperature, few byproducts and high yield.
In order to achieve the above purpose, the invention adopts the technical scheme that:
the preparation process of 7-bromo-4-chlorothieno [3,2-d ] pyrimidine includes the following steps: dissolving 7-bromo-3H-thieno [3,2-d ] pyrimidine-4-ketone in a solvent A, adding HBr acetic acid solution, reacting, adding phosphorus oxychloride and triethylamine, heating to 80-90 ℃, reacting for 1.5-4.5H, and purifying to obtain the catalyst.
Preferably, 0.14mL of HBr in acetic acid is added per gram of said 7-bromo-3H-thieno [3,2-d ] pyrimidin-4-one.
Preferably, the molar ratio of the 7-bromo-3H-thieno [3,2-d ] pyrimidin-4-one to the phosphorus oxychloride is 1: 5-1: 22; the molar ratio of the 7-bromo-3H-thieno [3,2-d ] pyrimidin-4-one to the triethylamine is 1: 1.2-1: 1.4.
Preferably, the solvent A is toluene or benzene.
Preferably, the purification method comprises the following steps: and cooling the mother liquor obtained after the reaction is finished to 20-30 ℃, adding the mother liquor into the obtained saturated sodium carbonate aqueous solution, controlling the pH of the quenched mixed solution to be 7-8, extracting with dichloromethane, drying the obtained organic phase, filtering, concentrating, adsorbing with diatomite, leaching with dichloromethane, performing suction filtration, and concentrating to obtain the product.
Preferably, the preparation method of the 7-bromo-3H-thieno [3,2-d ] pyrimidin-4-one comprises the following steps: dissolving 3H-thieno [3,2-d ] pyrimidine-4-ketone in a solvent B, adding N-bromosuccinimide in batches, raising the reaction temperature to 100-120 ℃ after the addition, reacting for 18-72 hours, cooling after the reaction is finished, distilling to remove the solvent B, pulping with dichloromethane, and carrying out suction filtration to obtain the compound.
Preferably, the molar ratio of the 3H-thieno [3,2-d ] pyrimidine-4-one to the N-bromosuccinimide is 1: 2-1: 4, and the NBS is added in 4-6 times at a rate of 15-20 min each time.
Preferably, the solvent B is acetic acid or butyric acid.
Preferably, the preparation method of the 3H-thieno [3,2-d ] pyrimidine-4-ketone comprises the following steps: dissolving 3-amino-2-thiophenecarboxylic acid methyl ester in a solvent C, adding formamidine acetate, heating to 90-100 ℃, reacting for 2-4 h, and purifying to obtain the compound.
Preferably, the molar ratio of the 3-amino-2-thiophenecarboxylic acid methyl ester to the formamidine acetate is 1: 1.2-1: 1.5.
The invention has the beneficial effects that:
the preparation process of the 7-bromo-4-chlorothiophene [3,2-d ] pyrimidine adopts an HBr/phosphorus oxychloride/triethylamine system for preparation, the dosage of the phosphorus oxychloride is small, and the utilization rate of chlorine atoms is high; the method has the advantages of difficult generation of byproducts harmful to the environment, simple quenching, easy purification and higher reaction yield.
According to the preparation process of the 7-bromo-4-chlorothieno [3,2-d ] pyrimidine, acetic acid is used as a solvent when the 7-bromo-3H-thieno [3,2-d ] pyrimidine-4-ketone is prepared, so that the raw material solvent is good in solubility; the acidic condition can effectively activate the beta-position of the thiophene and improve the bromination efficiency; the crude product is decompressed to remove acetic acid, then is pulped by dichloromethane and is filtered to obtain the 7-bromo-3H-thieno [3,2-d ] pyrimidine-4-ketone, and the purification process is simple and efficient without column separation and purification.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of 3H-thieno [3,2-d ] pyrimidin-4-one;
FIG. 2 is a nuclear magnetic hydrogen spectrum of 7-bromo-3H-thieno [3,2-d ] pyrimidin-4-one;
FIG. 3 is a nuclear magnetic hydrogen spectrum of 7-bromo-4-chlorothieno [3,2-d ] pyrimidine.
Detailed Description
The present invention will be further described with reference to the following examples and accompanying drawings.
Example 1
The process for preparing 7-bromo-4-chlorothieno [3,2-d ] pyrimidine of this example comprises the following steps:
1) synthesis of 3H-thiophene [3,2-d ]]And (c) a pyrimidin-4-one: taking a 500mL three-neck flask, putting a magneton, adding 15.72g of 3-amino-2-thiophenecarboxylic acid methyl ester at 25 ℃, then adding 100mL of absolute ethanol for dissolving, adding 15.61g of formamidine acetate at 25 ℃, stirring for dissolving, raising the temperature to 100 ℃, reacting for 2h, cooling to 25 ℃, filtering, washing the filtrate for three times by using petroleum ether, and pumping out a vacuum drier to obtain 9.81g of a white solid product with the yield of 64.5%. FIG. 1 shows 3H-thiophene [3,2-d ]]Nuclear magnetic hydrogen spectrum of pyrimidine-4-ketone,1H NMR(400MHz,CDCl3):δ(ppm)12.52(s,1H),8.20(d,J＝2.6Hz,1H),8.17(s,1H),7.41(d,J＝2.4Hz 1H)。
2) synthesis of 7-bromo-3H-thiophene [3,2-d ]]And (c) a pyrimidin-4-one: taking a 500mL round-bottomed bottle, and adding 6.30g of 3H-thiophene [3,2-d ] prepared in the step 1)]Pyrimidin-4-one, dissolved in 50mL of acetic acid, was added in equal amounts in four portions to 23.1g of N-bromosuccinimide (NBS) at a rate of 15min each, and after the addition, the temperature was raised to 120 ℃ to react for 18 hours. After the reaction is finished, the mother liquor is cooled to 60 ℃, then most of acetic acid is removed by reduced pressure distillation, and then the mixture is pulped by dichloromethane and filtered to obtain a light yellow product with the yield of 92 percent. FIG. 2 shows 7-bromo-3H-thiophene [3,2-d ]]Nuclear magnetic hydrogen spectrum of pyrimidine-4-ketone,1H NMR(400MHz,CDCl3):δ(ppm)12.78(s,1H),8.39(s,1H),8.28(s,1H)。
3) synthesis of 7-bromo-4-chlorothieno [3,2-d ]]Pyrimidine: taking a 250mL three-neck flask, adding 5.0g of 7-bromo-3H-thiophene [3,2-d ] prepared in the step 2)]And adding 50mL of toluene into the pyrimidine-4-ketone, stirring to obtain a suspension, adding 0.52mL of HBr acetic acid solution with the mass fraction of 33%, and reacting for 30min at 25 ℃. Then adding 21.5mL of phosphorus oxychloride and 4mL of triethylamine, heating to 85 ℃, reacting for 3h, cooling the mother liquor to 25 ℃, slowly adding the mother liquor into a saturated sodium carbonate aqueous solution, and controlling the pH value of the quenched mixture solution to be 7. The obtained mixture solution is extracted by dichloromethane, the obtained organic phase is dried, filtered and concentrated, and then is absorbed by diatomite, and then is leached by dichloromethane, and is filtered under reduced pressure, and the white solid product 5.1g is obtained after concentration, and the yield is 96%. FIG. 3 is 7-bromo-4-chlorothiophene [3,2-d ]]A nuclear magnetic hydrogen spectrum of the pyrimidine,1H NMR(400MHz,CDCl3):δ(ppm)9.17(s,1H),8.80(s,1H)。
Example 2
The process for preparing 7-bromo-4-chlorothieno [3,2-d ] pyrimidine of this example comprises the following steps:
1) taking a 500mL three-neck flask, putting a magneton, adding 15.72g of 3-amino-2-thiophenecarboxylic acid methyl ester at 25 ℃, then adding 100mL of absolute ethanol for dissolving, adding 16.91g of formamidine acetate at 25 ℃, stirring for dissolving, raising the temperature to 100 ℃, reacting for 2h, cooling to 25 ℃, filtering, washing the filtrate for three times by using petroleum ether, and pumping out a vacuum drier to obtain 8.95g of a white solid product with the yield of 58.8%.
2) Synthesis of 7-bromo-3H-thieno [3,2-d ] pyrimidin-4-one: a500 mL round-bottomed flask was charged with 6.30g of the prepared 3H-thieno [3,2-d ] pyrimidin-4-one, dissolved in 50mL of butyric acid, and 23.1g of N-bromosuccinimide (NBS) was added in equal amounts in four portions at a rate of 15min each, and after completion of the addition, the temperature was raised to 120 ℃ to react for 18 hours. After the reaction is finished, the mother liquor is cooled to 60 ℃, then most of acetic acid is removed by reduced pressure distillation, and then the mixture is pulped by dichloromethane and filtered to obtain a light yellow product with the yield of 85 percent.
3) Adding 5.0g of 7-bromo-3H-thieno [3,2-d ] pyrimidine-4-ketone prepared in the step 2) into a 250mL three-neck flask, adding 50mL of benzene, stirring to obtain a suspension, adding 0.52mL of HBr acetic acid solution with the mass fraction of 33%, and reacting at 25 ℃ for 30 min. Then adding 21.5mL of phosphorus oxychloride and 4mL of triethylamine, heating to 85 ℃, reacting for 3h, cooling the mother liquor to 25 ℃, slowly adding the mother liquor into a saturated sodium carbonate aqueous solution, and controlling the pH value of the quenched mixture solution to be 7. The obtained mixture solution is extracted by dichloromethane, the obtained organic phase is dried, filtered and concentrated, and then is absorbed by diatomite, and then is leached by dichloromethane, and is filtered under reduced pressure, and the white solid product 5.1g is obtained after concentration, and the yield is 92%.
Example 3
1) Taking a 500mL three-neck flask, adding magnetons, adding 15.72g of 3-amino-2-thiophenecarboxylic acid methyl ester at 25 ℃, then adding 100mL of absolute ethyl alcohol for dissolving, adding 18.21g of formamidine acetate at 25 ℃, stirring for dissolving, raising the temperature to 100 ℃, reacting for 2h, cooling to 25 ℃, filtering, washing the filtrate for three times by using petroleum ether, and pumping out a vacuum drier to obtain 8.83g of a white solid product with the yield of 58.1%.
2) Synthesis of 7-bromo-3H-thieno [3,2-d ] pyrimidin-4-one: a500 mL round-bottomed flask was charged with 6.30g of the prepared 3H-thieno [3,2-d ] pyrimidin-4-one, dissolved in 50mL of acetic acid, and 23.1g of N-bromosuccinimide (NBS) was added in equal amounts in four portions at a rate of 15min each, and after completion of the addition, the temperature was raised to 100 ℃ to react for 18 hours. After the reaction is finished, the mother liquor is cooled to 60 ℃, then most of acetic acid is removed by reduced pressure distillation, and then the mixture is pulped by dichloromethane and filtered to obtain a light yellow product with 82% yield.
3) Adding 5.0g of 7-bromo-3H-thieno [3,2-d ] pyrimidin-4-one prepared in the step 2) into a 250mL three-neck flask, adding 50mL of toluene, stirring to obtain a suspension, adding 21.5mL of phosphorus oxychloride and 4mL of triethylamine, heating to 85 ℃, reacting for 3 hours, cooling the mother solution to 25 ℃, slowly adding the mother solution into a saturated sodium carbonate aqueous solution, and controlling the pH of the quenched mixture solution to be 7. The obtained mixture solution is extracted by dichloromethane, the obtained organic phase is dried, filtered and concentrated, and then is absorbed by diatomite, and then is leached by dichloromethane, and is filtered under reduced pressure, and the white solid product 5.1g is obtained after concentration, and the yield is 76%.
Example 4
1) Taking a 500mL three-neck flask, putting a magneton, adding 15.72g of 3-amino-2-thiophenecarboxylic acid methyl ester at 25 ℃, then adding 100mL of absolute ethanol for dissolving, adding 19.51g of formamidine acetate at 25 ℃, stirring for dissolving, raising the temperature to 100 ℃, reacting for 2h, cooling to 25 ℃, filtering, washing the filtrate for three times by using petroleum ether, and pumping out a vacuum drier to obtain 8.55g of a white solid product with the yield of 56.2%.
2) Synthesis of 7-bromo-3H-thieno [3,2-d ] pyrimidin-4-one: a500 mL round-bottomed flask was charged with 6.30g of the prepared 3H-thieno [3,2-d ] pyrimidin-4-one, dissolved in 50mL of acetic acid, and 23.1g of N-bromosuccinimide (NBS) was added in equal amounts in four portions at a rate of 15min each, and after completion of the addition, the temperature was raised to 110 ℃ to react for 18 hours. After the reaction is finished, the mother liquor is cooled to 60 ℃, then most of acetic acid is removed by reduced pressure distillation, and then dichloromethane is used for pulping, and light yellow products can be obtained by suction filtration, and the yield is 88%.
3) Adding 5.0g of 7-bromo-3H-thieno [3,2-d ] pyrimidine-4-ketone prepared in the step 2) into a 250mL three-neck flask, adding 50mL of toluene, stirring to obtain a suspension, adding 0.52mL of HBr acetic acid solution with the mass fraction of 33%, and reacting at 25 ℃ for 30 min. Then adding 21.5mL of phosphorus oxychloride and 4mL of triethylamine, heating to 80 ℃, reacting for 3h, cooling the mother liquor to 25 ℃, slowly adding the mother liquor into a saturated sodium carbonate aqueous solution, and controlling the pH value of the quenched mixture solution to be 7. The obtained mixture solution is extracted by dichloromethane, the obtained organic phase is dried, filtered and concentrated, and then is absorbed by diatomite, and then is leached by dichloromethane and is filtered under reduced pressure, and the white solid product 5.1g is obtained after concentration, and the yield is 85 percent.
Example 5
1) Taking a 500mL three-neck flask, adding magnetons, adding 15.72g of 3-amino-2-thiophenecarboxylic acid methyl ester at 25 ℃, then adding 100mL of absolute ethyl alcohol for dissolving, adding 15.61g of formamidine acetate at 25 ℃, stirring for dissolving, heating to 90 ℃, reacting for 2h, cooling to 25 ℃, filtering, washing filtrate for three times by using petroleum ether, and pumping out a vacuum drier to obtain 9.15g of a white solid product with the yield of 60.2%.
2) Synthesis of 7-bromo-3H-thieno [3,2-d ] pyrimidin-4-one: a500 mL round-bottomed flask was charged with 6.30g of the prepared 3H-thieno [3,2-d ] pyrimidin-4-one, dissolved in 50mL of acetic acid, and 23.1g of N-bromosuccinimide (NBS) was added in equal amounts in four portions at a rate of 15min each, and after completion of the addition, the temperature was raised to 120 ℃ to react for 36 hours. After the reaction is finished, the mother liquor is cooled to 60 ℃, then most of acetic acid is removed by reduced pressure distillation, and then dichloromethane is used for pulping, and light yellow products can be obtained by suction filtration, and the yield is 90%.
3) Adding 5.0g of 7-bromo-3H-thieno [3,2-d ] pyrimidine-4-ketone prepared in the step 2) into a 250mL three-neck flask, adding 50mL of toluene, stirring to obtain a suspension, adding 0.52mL of HBr acetic acid solution with the mass fraction of 33%, and reacting at 25 ℃ for 30 min. Then adding 21.5mL of phosphorus oxychloride and 4mL of triethylamine, heating to 90 ℃, reacting for 3h, cooling the mother liquor to 25 ℃, slowly adding the mother liquor into a saturated sodium carbonate aqueous solution, and controlling the pH value of the quenched mixture solution to be 7. The obtained mixture solution is extracted by dichloromethane, the obtained organic phase is dried, filtered and concentrated, and then is absorbed by diatomite, and then is leached by dichloromethane, and is filtered under reduced pressure, and the white solid product 5.1g is obtained after concentration, and the yield is 88%.
Example 6
1) Taking a 500mL three-neck flask, putting a magneton, adding 15.72g of 3-amino-2-thiophenecarboxylic acid methyl ester at 25 ℃, then adding 100mL of absolute ethanol for dissolving, adding 15.61g of formamidine acetate at 25 ℃, stirring for dissolving, raising the temperature to 95 ℃, reacting for 2h, cooling to 25 ℃, filtering, washing the filtrate for three times by using petroleum ether, and pumping out a vacuum drier to obtain 9.52g of a white solid product with the yield of 62.6%.
2) Synthesis of 7-bromo-3H-thieno [3,2-d ] pyrimidin-4-one: a500 mL round-bottomed flask was charged with 6.30g of the prepared 3H-thieno [3,2-d ] pyrimidin-4-one, dissolved in 50mL of acetic acid, and 23.1g of N-bromosuccinimide (NBS) was added in equal amounts in four portions at a rate of 15min each, and after completion of the addition, the temperature was raised to 120 ℃ to react for 72 hours. After the reaction is finished, the mother liquor is cooled to 60 ℃, then most of acetic acid is removed through reduced pressure distillation, then dichloromethane is used for pulping, and light yellow products can be obtained through suction filtration, and the yield is 82%.
3) Adding 5.0g of 7-bromo-3H-thieno [3,2-d ] pyrimidine-4-ketone prepared in the step 2) into a 250mL three-neck flask, adding 50mL of toluene, stirring to obtain a suspension, adding 0.52mL of HBr acetic acid solution with the mass fraction of 33%, and reacting at 25 ℃ for 30 min. Then 21.5mL of phosphorus oxychloride and 4mL of triethylamine are added, the temperature is raised to 85 ℃, the mother liquor is cooled to 25 ℃ after 1.5h of reaction, and the mother liquor is slowly added into saturated sodium carbonate aqueous solution, and the pH value of the quenched mixture solution is controlled to be 7. The obtained mixture solution is extracted by dichloromethane, the obtained organic phase is dried, filtered and concentrated, and then is absorbed by diatomite, and then is leached by dichloromethane, and is filtered under reduced pressure, and the white solid product 5.1g is obtained after concentration, and the yield is 80%.
Example 7
1) Taking a 500mL three-neck flask, putting a magneton, adding 15.72g of 3-amino-2-thiophenecarboxylic acid methyl ester at 25 ℃, then adding 100mL of absolute ethanol for dissolving, adding 15.61g of formamidine acetate at 25 ℃, stirring for dissolving, heating to 100 ℃, reacting for 3h, cooling to 25 ℃, filtering, washing the filtrate for three times by using petroleum ether, and pumping out a vacuum drier to obtain 9.80g of a white solid product with the yield of 64.4%.
2) Synthesis of 7-bromo-3H-thieno [3,2-d ] pyrimidin-4-one: a500 mL round-bottomed flask was charged with 6.30g of the prepared 3H-thieno [3,2-d ] pyrimidin-4-one, dissolved in 50mL of acetic acid, and 15.4g of N-bromosuccinimide (NBS) was added in equal amounts in four portions at a rate of 15min each, and after completion of the addition, the temperature was raised to 120 ℃ to react for 18 hours. After the reaction is finished, the mother liquor is cooled to 60 ℃, then most of acetic acid is removed by reduced pressure distillation, and then the product is pulped by dichloromethane and filtered by suction to obtain a light yellow product with the yield of 78%.
3) Adding 5.0g of 7-bromo-3H-thieno [3,2-d ] pyrimidine-4-ketone prepared in the step 2) into a 250mL three-neck flask, adding 50mL of toluene, stirring to obtain a suspension, adding 0.52mL of HBr acetic acid solution with the mass fraction of 33%, and reacting at 25 ℃ for 30 min. Then 21.5mL of phosphorus oxychloride and 4mL of triethylamine are added, the temperature is raised to 85 ℃, the mother liquor is cooled to 25 ℃ after 4.5h of reaction, and the mother liquor is slowly added into saturated sodium carbonate aqueous solution, and the pH value of the quenched mixture solution is controlled to be 7. The obtained mixture solution is extracted by dichloromethane, the obtained organic phase is dried, filtered and concentrated, and then is absorbed by diatomite, and then is leached by dichloromethane, and is filtered under reduced pressure, and the white solid product 5.1g is obtained after concentration, and the yield is 75%.
Example 8
1) Taking a 500mL three-neck flask, adding magnetons, adding 15.72g of 3-amino-2-thiophenecarboxylic acid methyl ester at 25 ℃, then adding 100mL of absolute ethyl alcohol for dissolving, adding 15.61g of formamidine acetate at 25 ℃, stirring for dissolving, raising the temperature to 100 ℃, reacting for 4 hours, cooling to 25 ℃, filtering, washing filtrate for three times by using petroleum ether, and pumping out a vacuum drier to obtain 9.77g of a white solid product with the yield of 64.2%.
2) Synthesis of 7-bromo-3H-thieno [3,2-d ] pyrimidin-4-one: a500 mL round-bottomed flask was charged with 6.30g of the prepared 3H-thieno [3,2-d ] pyrimidin-4-one, dissolved in 50mL of acetic acid, and 30.8g of N-bromosuccinimide (NBS) was added in equal amounts in four portions at a rate of 15min each, and after completion of the addition, the temperature was raised to 120 ℃ to react for 18 hours. After the reaction is finished, the mother liquor is cooled to 60 ℃, then most of acetic acid is removed by reduced pressure distillation, and then dichloromethane is used for pulping, and light yellow products can be obtained by suction filtration, and the yield is 80%.
3) Adding 5.0g of 7-bromo-3H-thieno [3,2-d ] pyrimidine-4-ketone prepared in the step 2) into a 250mL three-neck flask, adding 50mL of toluene, stirring to obtain a suspension, adding 0.52mL of HBr acetic acid solution with the mass fraction of 33%, and reacting at 25 ℃ for 30 min. Then adding 10.7mL of phosphorus oxychloride and 4mL of triethylamine, heating to 85 ℃, reacting for 3h, cooling the mother liquor to 25 ℃, slowly adding the mother liquor into a saturated sodium carbonate aqueous solution, and controlling the pH value of the quenched mixture solution to be 7. The obtained mixture solution is extracted by dichloromethane, the obtained organic phase is dried, filtered and concentrated, and then is absorbed by diatomite, and then is leached by dichloromethane, and is filtered under reduced pressure, and the white solid product 5.1g is obtained after concentration, and the yield is 67%.
Example 9
1) Taking a 500mL three-neck flask, putting a magneton, adding 15.72g of 3-amino-2-thiophenecarboxylic acid methyl ester at 25 ℃, then adding 100mL of absolute ethanol for dissolving, adding 15.61g of formamidine acetate at 25 ℃, stirring for dissolving, raising the temperature to 100 ℃, reacting for 2h, cooling to 25 ℃, filtering, washing the filtrate for three times by using petroleum ether, and pumping out a vacuum drier to obtain 9.81g of a white solid product with the yield of 64.5%.
2) Synthesis of 7-bromo-3H-thieno [3,2-d ] pyrimidin-4-one: a500 mL round-bottomed flask was charged with 6.30g of the prepared 3H-thieno [3,2-d ] pyrimidin-4-one, dissolved in 50mL of acetic acid, and 23.1g of N-bromosuccinimide (NBS) was added in equal amounts in four divided portions at a rate of 15min each, and after completion of the addition, the temperature was raised to 120 ℃ to effect a reaction for 18 hours. After the reaction is finished, the mother liquor is cooled to 60 ℃, then most of acetic acid is removed by reduced pressure distillation, and then the mixture is pulped by dichloromethane and filtered to obtain a light yellow product with the yield of 92 percent.
3) Adding 5.0g of 7-bromo-3H-thieno [3,2-d ] pyrimidine-4-ketone prepared in the step 2) into a 250mL three-neck flask, adding 50mL of toluene, stirring to obtain a suspension, adding 0.52mL of HBr acetic acid solution with the mass fraction of 33%, and reacting at 25 ℃ for 30 min. Then 43mL of phosphorus oxychloride and 4mL of triethylamine are added, the temperature is raised to 85 ℃, the mother liquor is cooled to 25 ℃ after 3 hours of reaction, and the mother liquor is slowly added into a saturated sodium carbonate aqueous solution, and the pH value of the quenched mixture solution is controlled to be 7. The obtained mixture solution is extracted by dichloromethane, the obtained organic phase is dried, filtered and concentrated, and then is absorbed by diatomite, and then is leached by dichloromethane, and is filtered under reduced pressure, and the white solid product 5.1g is obtained after concentration, and the yield is 79%.
Claims (9)
- A preparation process of 7-bromo-4-chlorothiophene [3,2-d ] pyrimidine is characterized by comprising the following steps: dissolving 7-bromo-3H-thieno [3,2-d ] pyrimidine-4-ketone in a solvent A, adding HBr acetic acid solution, reacting, adding phosphorus oxychloride and triethylamine, heating to 80-90 ℃, reacting for 1.5-4.5H, and purifying to obtain the catalyst.
- 2. The preparation process of 7-bromo-4-chlorothieno [3,2-d ] pyrimidine according to claim 1, wherein the molar ratio of 7-bromo-3H-thieno [3,2-d ] pyrimidine-4-one to phosphorus oxychloride is 1:5 to 1: 22; the molar ratio of the 7-bromo-3H-thieno [3,2-d ] pyrimidin-4-one to the triethylamine is 1: 1.2-1: 1.4.
- 3. The process for the preparation of 7-bromo-4-chlorothieno [3,2-d ] pyrimidine according to claim 1, characterized in that the solvent a is toluene or benzene.
- 4. The process for the preparation of 7-bromo-4-chlorothieno [3,2-d ] pyrimidine according to claim 1, characterized in that the purification process is: and cooling the mother liquor obtained after the reaction is finished to 20-30 ℃, adding the mother liquor into the obtained saturated sodium carbonate aqueous solution, controlling the pH of the quenched mixed solution to be 7-8, extracting with dichloromethane, drying the obtained organic phase, filtering, concentrating, adsorbing with diatomite, leaching with dichloromethane, performing suction filtration, and concentrating to obtain the product.
- 5. The process for the preparation of 7-bromo-4-chlorothieno [3,2-d ] pyrimidine according to claim 1, characterized in that the process for the preparation of 7-bromo-3H-thieno [3,2-d ] pyrimidin-4-one comprises the following steps: dissolving 3H-thieno [3,2-d ] pyrimidine-4-ketone in a solvent B, adding N-bromosuccinimide in batches, raising the reaction temperature to 100-120 ℃ after the addition, reacting for 18-72 hours, cooling after the reaction is finished, distilling to remove the solvent B, pulping with dichloromethane, and carrying out suction filtration to obtain the compound.
- 6. The preparation process of 7-bromo-4-chlorothieno [3,2-d ] pyrimidine according to claim 5, wherein the molar ratio of 3H-thieno [3,2-d ] pyrimidine-4-one to N-bromosuccinimide is 1:2 to 1:4, and the NBS is added at a rate of 15 to 20min per time in 4 to 6 times in equal amounts.
- 7. The process for the preparation of 7-bromo-4-chlorothieno [3,2-d ] pyrimidine according to claim 5, characterized in that the solvent B is acetic acid or butyric acid.
- 8. The process for the preparation of 7-bromo-4-chlorothieno [3,2-d ] pyrimidine according to claim 5, characterized in that the process for the preparation of 3H-thieno [3,2-d ] pyrimidin-4-one comprises the following steps: dissolving 3-amino-2-thiophenecarboxylic acid methyl ester in a solvent C, adding formamidine acetate, heating to 90-100 ℃, reacting for 2-4 h, and purifying to obtain the compound.
- 9. The preparation process of 7-bromo-4-chlorothieno [3,2-d ] pyrimidine according to claim 8, wherein the molar ratio of methyl 3-amino-2-thiophenecarboxylate to formamidine acetate is 1:1.2 to 1: 1.5.
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