CN102952084A - A kind of synthetic method of 4,6-dichloro-2-methylthio-5-nitropyrimidine - Google Patents
A kind of synthetic method of 4,6-dichloro-2-methylthio-5-nitropyrimidine Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title claims description 4
- GHAWBARMICSLQS-UHFFFAOYSA-N 4,6-dichloro-2-methylsulfanyl-5-nitropyrimidine Chemical compound CSC1=NC(Cl)=C([N+]([O-])=O)C(Cl)=N1 GHAWBARMICSLQS-UHFFFAOYSA-N 0.000 title abstract description 9
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical group ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000011734 sodium Substances 0.000 claims abstract description 15
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 11
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims abstract description 10
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 9
- -1 thiourea form pyrimidine heterocyclic compound Chemical class 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 7
- 229910017604 nitric acid Inorganic materials 0.000 claims abstract description 7
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 21
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 18
- UHRGFIRINCINPH-UHFFFAOYSA-N 6-hydroxy-5-nitro-2-sulfanylidene-1h-pyrimidin-4-one Chemical compound OC=1NC(=S)NC(=O)C=1[N+]([O-])=O UHRGFIRINCINPH-UHFFFAOYSA-N 0.000 claims description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 238000001556 precipitation Methods 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims 2
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 claims 2
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical group CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 claims 1
- 238000003810 ethyl acetate extraction Methods 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- 238000000638 solvent extraction Methods 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 230000011987 methylation Effects 0.000 abstract description 9
- 238000007069 methylation reaction Methods 0.000 abstract description 9
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 abstract description 8
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical group COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 abstract description 7
- 239000003054 catalyst Substances 0.000 abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000006396 nitration reaction Methods 0.000 abstract description 4
- 238000001308 synthesis method Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 150000003230 pyrimidines Chemical class 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 description 19
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 11
- LMCNSMCHUYZUFF-UHFFFAOYSA-N 4-hydroxy-2-methylsulfanyl-5-nitro-1h-pyrimidin-6-one Chemical compound CSC1=NC(O)=C([N+]([O-])=O)C(O)=N1 LMCNSMCHUYZUFF-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- DAKKWKYIQGMKOS-UHFFFAOYSA-N diethyl 2-nitropropanedioate Chemical compound CCOC(=O)C([N+]([O-])=O)C(=O)OCC DAKKWKYIQGMKOS-UHFFFAOYSA-N 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 239000005457 ice water Substances 0.000 description 6
- 238000010907 mechanical stirring Methods 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000010410 layer Substances 0.000 description 5
- 239000012467 final product Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000004202 carbamide Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 238000006798 ring closing metathesis reaction Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004807 desolvation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000000802 nitrating effect Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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Abstract
Description
技术领域technical field
本发明涉及一种4，6-二氯－2－甲硫基－5－硝基嘧啶的合成方法，属于嘧啶类化合物的合成。 The invention relates to a synthesis method of 4,6-dichloro-2-methylthio-5-nitropyrimidine, which belongs to the synthesis of pyrimidine compounds. the
背景技术 Background technique
嘧啶类化合物是许多医药、农药的中间体，应用前景非常广阔。4，6-二氯－2－甲硫基－5－硝基嘧啶的合成文献中没有现成的全合成方法，因此研究此化合物的合成是比较有意义和有价值的。 Pyrimidine compounds are intermediates of many medicines and pesticides, and their application prospects are very broad. The synthetic literature of 4,6-dichloro-2-methylthio-5-nitropyrimidine does not have a ready-made total synthesis method, so it is meaningful and valuable to study the synthesis of this compound. the
发明内容 Contents of the invention
本发明提供了一种4，6-二氯－2－甲硫基－5－硝基嘧啶的合成方法。 The invention provides a synthesis method of 4,6-dichloro-2-methylthio-5-nitropyrimidine. the
本发明的技术方案是：一种4，6-二氯－2－甲硫基－5－硝基嘧啶的合成方法的操作步骤为： The technical scheme of the present invention is: a kind of 4,6-dichloro-2-methylthio-5-nitropyrimidine The operation steps of the synthetic method are:
（1）第一步硝化 (1) The first step of nitrification
丙二酸二乙酯在过量的浓硝酸或发烟硝酸硝化，水解，有机溶剂萃取，干燥，脱溶，减压蒸馏，得一步产物2-硝基丙二酸二乙酯，反应温度0～30℃,硝酸相对于丙二酸二乙酯的摩尔当量比为4.0—10.0;有机溶剂为常用溶剂，优选甲苯，乙酸乙酯； Diethyl malonate is nitrated in excess concentrated nitric acid or fuming nitric acid, hydrolyzed, extracted with an organic solvent, dried, precipitated, and distilled under reduced pressure to obtain the one-step product 2-nitromalonate diethyl ester, the reaction temperature is 0～ 30°C, the molar equivalent ratio of nitric acid to diethyl malonate is 4.0-10.0; organic solvents are common solvents, preferably toluene and ethyl acetate;
（2）第二步环化 (2) The second step of cyclization
硫脲在甲醇或乙醇溶剂中加热溶解，在相应醇钠的作用下，与2-硝基丙二酸二乙酯关环反应生成4，6-二羟基－2－巯基－5－硝基嘧啶；环化反应温度在40—80℃，硫脲相对于2-硝基丙二酸二乙酯的摩尔当量为1.0—1.05，醇钠相对于2-硝基丙二酸二乙酯的摩尔当量为2.0—2.5； Thiourea is heated and dissolved in methanol or ethanol solvent, and under the action of corresponding sodium alkoxide, it reacts with diethyl 2-nitromalonate to form 4,6-dihydroxy-2-mercapto-5-nitropyrimidine ; The cyclization reaction temperature is 40-80 ° C, the molar equivalent of thiourea relative to 2-nitromalonate diethyl ester is 1.0-1.05, and the molar equivalent of sodium alkoxide relative to 2-nitromalonic acid diethyl ester 2.0-2.5;
（3）第三步甲基化 (3) The third step of methylation
4，6-二羟基－2－巯基－5－硝基嘧啶在氢氧化钠水溶液中溶解，用硫酸二甲酯甲基化生成三步产物4，6-二羟基－2－甲硫基－5－硝基嘧啶，反应温度10-40℃，氢氧化钠相对于4，6-二羟基－2－巯基－5－硝基嘧啶的摩尔当量为3-6，硫酸二甲酯相对于4，6-二羟基－2－巯基－5－硝基嘧啶的摩尔当量为1.0－1.5； 4,6-dihydroxy-2-mercapto-5-nitropyrimidine is dissolved in aqueous sodium hydroxide solution and methylated with dimethyl sulfate to produce a three-step product 4,6-dihydroxy-2-methylthio-5 - Nitropyrimidine, the reaction temperature is 10-40°C, the molar equivalent of sodium hydroxide relative to 4,6-dihydroxy-2-mercapto-5-nitropyrimidine is 3-6, dimethyl sulfate relative to 4,6 - The molar equivalent of dihydroxy-2-mercapto-5-nitropyrimidine is 1.0-1.5;
（4）第四步氯化 (4) The fourth step of chlorination
三步产物4，6-二羟基－2－甲硫基－5－硝基嘧啶在过量的三氯氧磷（既作为反应物，又作为溶剂）中氯化，水解，乙酸乙酯萃取，干燥，脱溶，纯化得最终产品4，6-二氯－2－甲硫基－5－硝基嘧啶；反应温度为回流反应温度100—110℃,收率40-80%；氯化过程加入少量的N，N—二甲基苯胺做催化剂。 The three-step product 4,6-dihydroxy-2-methylthio-5-nitropyrimidine was chlorinated in excess phosphorus oxychloride (both as a reactant and as a solvent), hydrolyzed, extracted with ethyl acetate, and dried , precipitation, and purification to obtain the final product 4,6-dichloro-2-methylthio-5-nitropyrimidine; the reaction temperature is reflux reaction temperature 100-110°C, and the yield is 40-80%; a small amount of N, N-dimethylaniline as a catalyst.
采用上述的技术方案，从基础原料丙二酸二乙酯和硫脲出发，经过硝化，环化，甲基化和氯化生成目标产物。 Using the above-mentioned technical scheme, starting from basic raw materials diethyl malonate and thiourea, the target product is generated through nitration, cyclization, methylation and chlorination. the
反应方程式： Reaction equation:
本发明的有益效果是：这种4，6-二氯－2－甲硫基－5－硝基嘧啶的合成方法，从丙二酸二乙酯出发，经过硝化，环化，甲基化，氯化四步反应合成。 The beneficial effects of the present invention are: the synthesis method of this 4,6-dichloro-2-methylthio-5-nitropyrimidine starts from diethyl malonate, and undergoes nitration, cyclization, methylation, Chlorination four-step reaction synthesis.
第一步硝化试剂为浓硝酸或发烟硝酸，第二步与硫脲在醇钠的作用下形成嘧啶杂环化合物，第三步的甲基化试剂为硫酸二甲酯，第四步的氯化试剂为三氯氧磷，同时用少量的N，N—二甲基苯胺做催化剂。该技术路线的选择合理、简便，容易操作，成功的合成了目标化合物。 The first step of nitrating reagent is concentrated nitric acid or fuming nitric acid, the second step forms pyrimidine heterocyclic compound with thiourea under the action of sodium alkoxide, the third step of methylation reagent is dimethyl sulfate, and the fourth step of chlorine The chemical reagent is phosphorus oxychloride, and a small amount of N, N-dimethylaniline is used as a catalyst. The selection of the technical route is reasonable, simple and easy to operate, and the target compound is successfully synthesized. the
具体实施方式 Detailed ways
以下用具体实施例对本发明作进一步的说明。 The present invention will be further described below with specific examples. the
实施例1Example 1
第一步硝化： The first step of nitrification:
向500ml的带有机械搅拌的四口反应瓶中加入丙二酸二乙酯80g（0.5mol,1.0eq），搅拌降温降至10-12℃，滴加20%的发烟硝酸184ml(4.3mol,8.6eq),滴加过程中控制内温在15-20℃，滴加完后在15℃反应2-3小时，后将反应液慢慢倒入盛有200g冰水的烧杯中搅拌水解，分层。水层用甲苯萃取，合并有机层，依次用5%的尿素水溶液，10%Na2CO3水溶液洗有机层至弱酸性，无水MgSO4干燥。脱溶，减压蒸馏得一步产物2-硝基丙二酸二乙酯。收率83%。 Add 80g (0.5mol, 1.0eq) of diethyl malonate into a 500ml four-necked reaction flask with mechanical stirring, stir and cool down to 10-12°C, add dropwise 184ml (4.3mol ,8.6eq), control the internal temperature at 15-20°C during the dropping process, react at 15°C for 2-3 hours after the dropwise addition, and then slowly pour the reaction solution into a beaker filled with 200g of ice water and stir for hydrolysis. layered. The aqueous layer was extracted with toluene, the organic layers were combined, and the organic layer was washed with 5% urea aqueous solution and 10% Na 2 CO 3 aqueous solution to weak acidity, and dried with anhydrous MgSO 4 . Precipitation and distillation under reduced pressure yielded the one-step product 2-diethyl nitromalonate. The yield is 83%.
第二步环合： The second step of ring closure:
向带有机械搅拌的500ml四口反应瓶中加入乙醇200ml,分批加入金属Na 23g（1.0mol,2.0eq）回流。待Na完全溶解后加入硫脲38g(0.5mol,1.0eq)。升温至50-60℃搅拌至全部溶解，滴加2-硝基丙二酸二乙酯108g（95%，0.5mol,1.0eq）,滴加完后反应3小时后停止反应，降至常温，脱溶，加入300克水溶解，盐酸调PH 5-6，析出固体，抽滤，真空烘干得二步产物4，6－二羟基－2－巯基－5－硝基嘧啶57.7g，含量95%；收率58 %。 Add 200ml of ethanol to a 500ml four-neck reaction flask with mechanical stirring, and add 23g (1.0mol, 2.0eq) of metal Na in batches to reflux. After Na was completely dissolved, thiourea 38g (0.5mol, 1.0eq) was added. Raise the temperature to 50-60°C and stir until completely dissolved, add 108g (95%, 0.5mol, 1.0eq) of diethyl 2-nitromalonate dropwise, stop the reaction after 3 hours after the dropwise addition, and cool down to room temperature. Desolvation, add 300 grams of water to dissolve, adjust the pH to 5-6 with hydrochloric acid, precipitate solids, filter with suction, and dry in vacuum to obtain 57.7g of the second-step product 4,6-dihydroxy-2-mercapto-5-nitropyrimidine with a content of 95 %; Yield 58%.
第三步甲基化： The third step of methylation:
将二步产物4，6－二羟基－2－巯基－5－硝基嘧啶99.6g(95%,0.5mol,1.0eq)加入20%的NaOH(2.5mol,5.0eq)水溶液中， Add 99.6g (95%, 0.5mol, 1.0eq) of the second-step product 4,6-dihydroxy-2-mercapto-5-nitropyrimidine into 20% NaOH (2.5mol, 5.0eq) aqueous solution,
搅拌溶解，降温至10℃，滴加硫酸二甲酯63.6g（99%，0.5mol,1.0eq），滴加完毕后保持温度10-20℃反应4小时，盐酸调PH 2-3，有固体析出，过滤，干燥，得三步产物4，6－二羟基－2－甲硫基－5－硝基嘧啶84.7g,含量97%，收率81%。 Stir to dissolve, cool down to 10°C, add 63.6g (99%, 0.5mol, 1.0eq) of dimethyl sulfate dropwise, keep the temperature at 10-20°C for 4 hours after the dropwise addition, adjust the pH to 2-3 with hydrochloric acid, and there is solid Precipitate, filter, and dry to obtain 84.7 g of the three-step product 4,6-dihydroxy-2-methylthio-5-nitropyrimidine, with a content of 97% and a yield of 81%.
第四步氯化： The fourth step of chlorination:
将三步产物4，6－二羟基－2－甲硫基－5－硝基嘧啶21g（97%，0.1mol,1.0eq）加入100ml 三氯氧磷中，并补加5ml N，N—二甲基苯胺（简称DMA）做催化剂，加热至回流反应8小时，蒸馏出过量的三氯氧磷，加入冰水中水解，用乙酸乙酯萃取，无水硫酸钠干燥，过滤，脱溶，纯化得最终产品17.5克，含量96%，收率70%。 Add 21g (97%, 0.1mol, 1.0eq) of the three-step product 4,6-dihydroxy-2-methylthio-5-nitropyrimidine into 100ml of phosphorus oxychloride, and add 5ml of N,N-di Methylaniline (referred to as DMA) as a catalyst, heated to reflux for 8 hours, distilled excess phosphorus oxychloride, hydrolyzed in ice water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, desolventized, and purified to obtain Final product 17.5 grams, content 96%, yield 70%.
实施例2Example 2
第一步硝化： The first step of nitrification:
向500ml的带有机械搅拌的四口反应瓶中加入丙二酸二乙酯80g（0.5mol,1.0eq），搅拌降温至0-5℃，滴加20%的发烟硝酸90ml(2.1mol,4.2eq),滴加过程中控制内温在0-10℃，滴加完后在10℃反应5-6小时，后将反应液慢慢倒入盛有200g冰水的烧杯中搅拌水解，分层。水层用甲苯萃取，合并有机层，依次用5%的尿素水溶液，10%Na2CO3水溶液洗有机层至弱酸性，无水MgSO4干燥。脱溶，减压蒸馏得一步产物2-硝基丙二酸二乙酯。收率67%。 Add 80g (0.5mol, 1.0eq) of diethyl malonate into a 500ml four-necked reaction flask with mechanical stirring, stir and cool down to 0-5°C, add dropwise 90ml (2.1mol, 4.2eq), control the internal temperature at 0-10°C during the dropping process, react at 10°C for 5-6 hours after the dropwise addition, and then slowly pour the reaction solution into a beaker filled with 200g of ice water, stir and hydrolyze, divide layer. The aqueous layer was extracted with toluene, the organic layers were combined, and the organic layer was washed with 5% urea aqueous solution and 10% Na 2 CO 3 aqueous solution to weak acidity, and dried with anhydrous MgSO 4 . Precipitation and distillation under reduced pressure yielded the one-step product 2-diethyl nitromalonate. Yield 67%.
第二步环合： The second step of ring closure:
向带有机械搅拌的500ml四口反应瓶中加入乙醇200ml,分批加入金属Na 28.8g（1.25mol,2.5eq）回流。待Na完全溶解后加入硫脲40g(0.525mol,1.05eq)。升温至40-50℃搅拌至全部溶解，滴加2-硝基丙二酸二乙酯105.8g（97%，0.5mol,1.0eq）,滴加完后反应6小时后停止反应，降至常温，脱溶，加入300克水溶解，盐酸调PH 5-6，析出固体，抽滤，真空烘干得二步产物4，6－二羟基－2－巯基－5－硝基嘧啶80.8g，含量96%；收率82 %。 Add 200ml of ethanol to a 500ml four-necked reaction flask with mechanical stirring, and add 28.8g (1.25mol, 2.5eq) of metal Na in batches to reflux. After Na was completely dissolved, thiourea 40g (0.525mol, 1.05eq) was added. Heat up to 40-50°C and stir until completely dissolved, add 105.8g (97%, 0.5mol, 1.0eq) of diethyl 2-nitromalonate dropwise, stop the reaction after 6 hours after the dropwise addition, and cool down to room temperature , precipitation, adding 300 grams of water to dissolve, hydrochloric acid to adjust PH 5-6, precipitate solid, suction filtration, vacuum drying to obtain 80.8g of the second-step product 4,6-dihydroxy-2-mercapto-5-nitropyrimidine, content 96%; yield 82%.
第三步甲基化： The third step of methylation:
将二步产物4，6－二羟基－2－巯基－5－硝基嘧啶98.6g(96%,0.5mol,1.0eq)加入20%的NaOH(1.5mol,3.0eq)水溶液中， Add 98.6g (96%, 0.5mol, 1.0eq) of the second-step product 4,6-dihydroxy-2-mercapto-5-nitropyrimidine into 20% NaOH (1.5mol, 3.0eq) aqueous solution,
搅拌溶解，降温至10℃，滴加硫酸二甲酯76.4g（99%，0.6mol,1.2eq），滴加完毕后保持温度20-30℃反应6小时，盐酸调PH 2-3，有固体析出，过滤，干燥，得三步产物4，6－二羟基－2－甲硫基－5－硝基嘧啶81.3g,含量96%，收率77%。 Stir to dissolve, cool down to 10°C, add 76.4g (99%, 0.6mol, 1.2eq) of dimethyl sulfate dropwise, keep the temperature at 20-30°C for 6 hours after the dropwise addition, adjust the pH to 2-3 with hydrochloric acid, and there is solid Precipitate, filter, and dry to obtain 81.3 g of the three-step product 4,6-dihydroxy-2-methylthio-5-nitropyrimidine, with a content of 96% and a yield of 77%.
第四步氯化： The fourth step of chlorination:
将三步产物4，6－二羟基－2－甲硫基－5－硝基嘧啶21g（97%，0.1mol,1.0eq）加入80ml 三氯氧磷中，并补加5ml N，N—二甲基苯胺（简称DMA）做催化剂，加热至回流反应10小时，蒸馏出过量的三氯氧磷，加入冰水中水解，用乙酸乙酯萃取，无水硫酸钠干燥，过滤，脱溶，纯化得最终产品20.2克，含量95%，收率80%。 Add 21g (97%, 0.1mol, 1.0eq) of the three-step product 4,6-dihydroxy-2-methylthio-5-nitropyrimidine into 80ml phosphorus oxychloride, and add 5ml N,N-di Methylaniline (referred to as DMA) as a catalyst, heated to reflux for 10 hours, distilled excess phosphorus oxychloride, added to ice water for hydrolysis, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, desolvated, and purified to obtain The final product is 20.2 grams, the content is 95%, and the yield is 80%.
the
实施例3Example 3
第一步硝化： The first step of nitrification:
向500ml的带有机械搅拌的四口反应瓶中加入丙二酸二乙酯80g（0.5mol,1.0eq），搅拌降温降至10-12℃，滴加98%的浓硝酸128ml(3.0mol, 6eq),滴加过程中控制内温在20-30℃，滴加完后在25℃反应8小时，后将反应液慢慢倒入盛有200g冰水的烧杯中搅拌水解，分层。水层用乙酸乙酯萃取，合并有机层，依次用5%的尿素水溶液，10%Na2CO3水溶液洗有机层至弱酸性，无水MgSO4干燥。脱溶，减压蒸馏一步产物2-硝基丙二酸二乙酯。收率53%。 Add 80g (0.5mol, 1.0eq) of diethyl malonate into a 500ml four-necked reaction flask with mechanical stirring, stir and cool down to 10-12°C, add 128ml (3.0mol, 98% concentrated nitric acid) dropwise 6eq), during the dropping process, the internal temperature was controlled at 20-30°C, and after the dropwise addition, it was reacted at 25°C for 8 hours, and then the reaction solution was slowly poured into a beaker containing 200g of ice water, stirred and hydrolyzed, and separated into layers. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined. The organic layer was washed with 5% aqueous urea and 10% Na 2 CO 3 in sequence until weakly acidic, and dried over anhydrous MgSO 4 . Precipitation, vacuum distillation step product 2-diethyl nitromalonate. Yield 53%.
第二步环合： The second step of ring closure:
向带有机械搅拌的500ml四口反应瓶中加入乙醇200ml,分批加入金属Na 26.5g（1.15mol,2.3eq）回流。待Na完全溶解后加入硫脲38g(0.5mol,1.0eq)。升温至70℃搅拌至全部溶解，滴加2-硝基丙二酸二乙酯110g（93%，0.5mol,1.0eq）,滴加完后回流反应5小时后停止反应，降至常温，脱溶，加入300克水溶解，盐酸调PH 5-6，析出固体，抽滤，真空烘干得二步产物4，6－二羟基－2－巯基－5－硝基嘧啶69.4g，含量98%；收率72 %。 Add 200ml of ethanol to a 500ml four-necked reaction flask with mechanical stirring, and add 26.5g (1.15mol, 2.3eq) of metal Na in batches to reflux. After Na was completely dissolved, thiourea 38g (0.5mol, 1.0eq) was added. Raise the temperature to 70°C and stir until completely dissolved, add 110g of diethyl 2-nitromalonate (93%, 0.5mol, 1.0eq) dropwise. Add 300 grams of water to dissolve, adjust pH to 5-6 with hydrochloric acid, precipitate solid, filter with suction, and dry in vacuum to obtain 69.4g of the second-step product 4,6-dihydroxy-2-mercapto-5-nitropyrimidine, content 98% ; Yield 72%.
第三步甲基化： The third step of methylation:
将二步产物4，6－二羟基－2－巯基－5－硝基嘧啶99.6g(95%,0.5mol,1.0eq)加入10%的NaOH(2.5mol,5.0eq)水溶液中， Add 99.6g (95%, 0.5mol, 1.0eq) of the second-step product 4,6-dihydroxy-2-mercapto-5-nitropyrimidine into 10% NaOH (2.5mol, 5.0eq) aqueous solution,
搅拌溶解，降温至10℃，滴加硫酸二甲酯95.5g（99%,0.5mol,1.5eq），滴加完毕后保持温度10-20℃反应4小时，盐酸调PH 2-3，有固体析出，过滤，干燥，得三步产物4，6－二羟基－2－甲硫基－5－硝基嘧啶84.7g,含量97%，收率81%。 Stir to dissolve, lower the temperature to 10°C, add 95.5g (99%, 0.5mol, 1.5eq) of dimethyl sulfate dropwise, keep the temperature at 10-20°C for 4 hours after the dropwise addition, adjust the pH to 2-3 with hydrochloric acid, and there will be solid Precipitate, filter, and dry to obtain 84.7 g of the three-step product 4,6-dihydroxy-2-methylthio-5-nitropyrimidine, with a content of 97% and a yield of 81%.
第四步氯化： The fourth step of chlorination:
将三步产物4，6－二羟基－2－甲硫基－5－硝基嘧啶21g（97%，0.1mol,1.0eq）加入100ml 三氯氧磷中，并补加5ml N，N—二甲基苯胺（简称DMA）做催化剂，加热至回流反应6小时，蒸馏出过量的三氯氧磷，加入冰水中水解，用乙 酸乙酯萃取，无水硫酸钠干燥，过滤，脱溶，纯化得最终产品11.6克。 Add 21g (97%, 0.1mol, 1.0eq) of the three-step product 4,6-dihydroxy-2-methylthio-5-nitropyrimidine into 100ml of phosphorus oxychloride, and add 5ml of N,N-di Use methylaniline (DMA for short) as a catalyst, heat to reflux for 6 hours, distill off excess phosphorus oxychloride, add ice water for hydrolysis, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, desolventize, and purify 11.6 g of the final product were obtained.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103333117A (en) * | 2013-05-18 | 2013-10-02 | 嘉兴中科化学有限公司 | Preparation method of 4[(4-chloro-2-pyrmidyl)amino]cyanophenyl |
| CN103787984A (en) * | 2014-01-26 | 2014-05-14 | 苏州特瑞药业有限公司 | Preparation method of Ticagrelor intermediate 4, 6-dichloro-5-nitro-2-(propylthio) pyrimidine |
| CN103923020A (en) * | 2014-04-02 | 2014-07-16 | 黄河三角洲京博化工研究院有限公司 | Preparation method of 2-propylthio-4,6-dichloro-5-aminopyrimidine |
| CN104003943A (en) * | 2014-05-06 | 2014-08-27 | 南通常佑药业科技有限公司 | Preparation method for ticagrelor intermediate |
| CN106496133A (en) * | 2016-10-19 | 2017-03-15 | 青岛云天生物技术有限公司 | The preparation method of ticagrelor midbody |
| CN110372605A (en) * | 2019-06-24 | 2019-10-25 | 南京普锐达医药科技有限公司 | Synthesis method of 2-methylthio-4, 6-dichloro-5-nitropyrimidine |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003002544A1 (en) * | 2001-06-26 | 2003-01-09 | Bristol-Myers Squibb Company | N-heterocyclic inhibitors of tnf-alpha expression |
| CN101613322A (en) * | 2009-07-28 | 2009-12-30 | 华中师范大学 | Synthesis and herbicidal activity of a class of chiral aryloxyphenoxypropionate derivatives containing pyrimidine |
| CN101679426A (en) * | 2007-05-04 | 2010-03-24 | 阿斯利康(瑞典)有限公司 | 9- (pyrazol-3-yl) -9H-purin-2-amine and 3- (pyrazol-3-yl) -3H-imidazo [4, 5-b ] pyridin-5-amine derivatives and their use to treat cancer |
| WO2011119518A1 (en) * | 2010-03-25 | 2011-09-29 | Merck Sharp & Dohme Corp. | Soluble guanylate cyclase activators |
| CN102272134A (en) * | 2008-12-09 | 2011-12-07 | 吉里德科学公司 | TOLL-like receptor modulators |
-
2012
- 2012-11-15 CN CN2012104579508A patent/CN102952084A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003002544A1 (en) * | 2001-06-26 | 2003-01-09 | Bristol-Myers Squibb Company | N-heterocyclic inhibitors of tnf-alpha expression |
| CN101679426A (en) * | 2007-05-04 | 2010-03-24 | 阿斯利康(瑞典)有限公司 | 9- (pyrazol-3-yl) -9H-purin-2-amine and 3- (pyrazol-3-yl) -3H-imidazo [4, 5-b ] pyridin-5-amine derivatives and their use to treat cancer |
| CN102272134A (en) * | 2008-12-09 | 2011-12-07 | 吉里德科学公司 | TOLL-like receptor modulators |
| CN101613322A (en) * | 2009-07-28 | 2009-12-30 | 华中师范大学 | Synthesis and herbicidal activity of a class of chiral aryloxyphenoxypropionate derivatives containing pyrimidine |
| WO2011119518A1 (en) * | 2010-03-25 | 2011-09-29 | Merck Sharp & Dohme Corp. | Soluble guanylate cyclase activators |
Non-Patent Citations (3)
| Title |
|---|
| D.I.WEISBLAT等: "Chemistry of nitroacetic acid and its esters. II.The synthesis of ethyl a-nitro-b-(3-indolo)propionate from gramine and ethyl nitromalonate", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
| STANISLAW OSTROWSKI等: "A preparative method for Synthesis of 4,5,6-trichloropyrimidine", 《ARKIVOC》 * |
| TONG-HUI HUANG等: "Synthesis and herbicidal activity of new substituted 2- and 4-pyrimidinyloxyphenoxypropionate derivatives", 《ARKIVOC》 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103333117A (en) * | 2013-05-18 | 2013-10-02 | 嘉兴中科化学有限公司 | Preparation method of 4[(4-chloro-2-pyrmidyl)amino]cyanophenyl |
| CN103333117B (en) * | 2013-05-18 | 2015-11-25 | 嘉兴中科化学有限公司 | The preparation method of a kind of 4 [(the chloro-2-pyrimidyl of 4-) is amino] cyanophenyl |
| CN103787984A (en) * | 2014-01-26 | 2014-05-14 | 苏州特瑞药业有限公司 | Preparation method of Ticagrelor intermediate 4, 6-dichloro-5-nitro-2-(propylthio) pyrimidine |
| CN103787984B (en) * | 2014-01-26 | 2015-10-07 | 苏州特瑞药业有限公司 | The preparation method of ticagrelor intermediate 4,6-bis-chloro-5-nitro-2-(rosickyite base) pyrimidine |
| CN103923020A (en) * | 2014-04-02 | 2014-07-16 | 黄河三角洲京博化工研究院有限公司 | Preparation method of 2-propylthio-4,6-dichloro-5-aminopyrimidine |
| CN104003943A (en) * | 2014-05-06 | 2014-08-27 | 南通常佑药业科技有限公司 | Preparation method for ticagrelor intermediate |
| CN106496133A (en) * | 2016-10-19 | 2017-03-15 | 青岛云天生物技术有限公司 | The preparation method of ticagrelor midbody |
| CN110372605A (en) * | 2019-06-24 | 2019-10-25 | 南京普锐达医药科技有限公司 | Synthesis method of 2-methylthio-4, 6-dichloro-5-nitropyrimidine |
| CN110372605B (en) * | 2019-06-24 | 2022-05-13 | 南京普锐达医药科技有限公司 | Synthesis method of 2-methylthio-4, 6-dichloro-5-nitropyrimidine |
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