CN110128354A - A kind of preparation method of 5-fluoro-2-methylsulfonyl-4-aminopyrimidine - Google Patents
A kind of preparation method of 5-fluoro-2-methylsulfonyl-4-aminopyrimidine Download PDFInfo
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- CN110128354A CN110128354A CN201910536757.5A CN201910536757A CN110128354A CN 110128354 A CN110128354 A CN 110128354A CN 201910536757 A CN201910536757 A CN 201910536757A CN 110128354 A CN110128354 A CN 110128354A
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- RCUFOQUJXZMEBC-UHFFFAOYSA-N 5-fluoro-2-methylsulfonylpyrimidin-4-amine Chemical compound CS(=O)(=O)C1=NC=C(F)C(N)=N1 RCUFOQUJXZMEBC-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 11
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 238000004440 column chromatography Methods 0.000 claims abstract description 4
- 238000001953 recrystallisation Methods 0.000 claims abstract description 4
- AARYHVRMNPGMOJ-UHFFFAOYSA-N ClC1=NC(=NC=C1F)S(=O)(=O)C Chemical compound ClC1=NC(=NC=C1F)S(=O)(=O)C AARYHVRMNPGMOJ-UHFFFAOYSA-N 0.000 claims description 14
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 10
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 10
- 238000005576 amination reaction Methods 0.000 claims description 5
- 229910021529 ammonia Inorganic materials 0.000 claims description 5
- 238000000034 method Methods 0.000 abstract description 13
- 230000015572 biosynthetic process Effects 0.000 abstract 2
- 238000003786 synthesis reaction Methods 0.000 abstract 2
- LMVIXHUHBDGBBF-UHFFFAOYSA-N 4-fluoro-2-methylsulfonylpyrimidine Chemical compound CS(=O)(=O)C1=NC=CC(F)=N1 LMVIXHUHBDGBBF-UHFFFAOYSA-N 0.000 abstract 1
- 239000000908 ammonium hydroxide Substances 0.000 abstract 1
- 230000007812 deficiency Effects 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- 239000012535 impurity Substances 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 13
- 239000007787 solid Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- CZRAGHMJPYCHFG-UHFFFAOYSA-N 2-methylsulfonylpyrimidin-4-amine Chemical class CS(=O)(=O)C1=NC=CC(N)=N1 CZRAGHMJPYCHFG-UHFFFAOYSA-N 0.000 description 1
- UQWYZGXKPJZPLU-UHFFFAOYSA-N 4-chloro-5-fluoro-2-methylsulfanylpyrimidine Chemical compound CSC1=NC=C(F)C(Cl)=N1 UQWYZGXKPJZPLU-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000002830 appetite depressant Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- -1 pyrimidine compound Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
技术领域technical field
本发明涉及一种5-氟-2-甲磺酰基-4-氨基嘧啶的制备方法,属于精细化工中间体领域。The invention relates to a preparation method of 5-fluoro-2-methanesulfonyl-4-aminopyrimidine, which belongs to the field of fine chemical intermediates.
背景技术Background technique
5-氟-2-甲磺酰基-4-氨基嘧啶是一种重要的含氟农药和医药中间体，可用于合成具有抗肿瘤活性化合物及制备除草剂、杀菌剂、食欲抑制剂等，广泛得应用于医药卫生领域。该嘧啶类化合物具有良好的生物活性，能有效得抗菌并具有抗肿瘤活性。因此，该化合物在生物医药方面具有较高的应用价值。5-Fluoro-2-methylsulfonyl-4-aminopyrimidine is an important fluorine-containing pesticide and pharmaceutical intermediate, which can be used to synthesize compounds with antitumor activity and prepare herbicides, fungicides, appetite suppressants, etc. Applied in the field of medicine and health. The pyrimidine compound has good biological activity, can be effectively antibacterial and has antitumor activity. Therefore, the compound has high application value in biomedicine.
目前已有的合成5-氟-2-甲磺酰基-4-氨基嘧啶方法中，反应条件苛刻，反应过程中会产生大量的废液。在广泛文献调研的基础上，未见有用于制备5-氟-2-甲磺酰基-4-氨基的合适方法，因而需要开发一种制备该化合物的合成工艺路线。In the currently existing methods for synthesizing 5-fluoro-2-methanesulfonyl-4-aminopyrimidine, the reaction conditions are harsh, and a large amount of waste liquid will be generated during the reaction. On the basis of extensive literature research, there is no suitable method for preparing 5-fluoro-2-methanesulfonyl-4-amino, so it is necessary to develop a synthetic process route for preparing this compound.
发明内容Contents of the invention
为了解决上述缺陷，本发明提供一种5-氟-2-甲磺酰基-4-氨基嘧啶的制备方法，该方法合成路线简单，原料易得。In order to solve the above defects, the present invention provides a preparation method of 5-fluoro-2-methanesulfonyl-4-aminopyrimidine, which has a simple synthetic route and easy-to-obtain raw materials.
本发明技术方案如下：Technical scheme of the present invention is as follows:
一种5-氟-2-甲磺酰基-4-氨基嘧啶的制备方法，该方法是以4-氯-5-氟-2-甲磺酰基嘧啶与氨水为原料，以四氢呋喃为溶剂，在室温条件下经氨基化反应生成含5-氟-2-甲磺酰基-4-氨基嘧啶的混合物。A preparation method of 5-fluoro-2-methylsulfonyl-4-aminopyrimidine, the method is to use 4-chloro-5-fluoro-2-methylsulfonylpyrimidine and ammonia as raw materials, using tetrahydrofuran as a solvent, at room temperature Under the condition of amination reaction, a mixture containing 5-fluoro-2-methylsulfonyl-4-aminopyrimidine was generated.
所述氨基化反应过程为：将4-氯-5-氟-2-甲磺酰基嘧啶溶于四氢呋喃，在室温条件下滴加氨水，滴加完后搅拌3～10h，即生成含有5-氟-2-甲磺酰基-4-氨基嘧啶的混合物。The amination reaction process is as follows: dissolve 4-chloro-5-fluoro-2-methanesulfonylpyrimidine in tetrahydrofuran, add ammonia water dropwise at room temperature, stir for 3 to 10 hours after the addition, and generate 5-fluoro - Mixtures of 2-methylsulfonyl-4-aminopyrimidines.
将氨基化反应所得混合物通过重结晶及柱层析过程处理后，得到5-氟-2-甲磺酰基-4-氨基嘧啶，含量98％以上，收率65-80％。After the mixture obtained in the amination reaction is processed by recrystallization and column chromatography, 5-fluoro-2-methylsulfonyl-4-aminopyrimidine is obtained, the content is more than 98%, and the yield is 65-80%.
其中：4-氯-5-氟-2-甲磺酰基嘧啶的结构如式(1)所示，5-氟-2-甲磺酰基-4-氨基嘧啶的结构如式(2)所示。Wherein: the structure of 4-chloro-5-fluoro-2-methylsulfonylpyrimidine is shown in formula (1), and the structure of 5-fluoro-2-methylsulfonyl-4-aminopyrimidine is shown in formula (2).
本发明所述原料中，4-氯-5-氟-2-甲磺酰基嘧啶与氨水的摩尔比例为1:(2～4)；氨水中氨的含量为22％～25％。Among the raw materials of the present invention, the molar ratio of 4-chloro-5-fluoro-2-methanesulfonylpyrimidine to ammonia water is 1:(2-4); the content of ammonia in the ammonia water is 22%-25%.
本发明的优点及有益效果如下：Advantage of the present invention and beneficial effect are as follows:
1、本发明选用4-氯-5-氟-2-甲磺酰基嘧啶与氨水为原料，以四氢呋喃为溶剂“一锅法”合成5-氟-2-甲磺酰基-4-氨基嘧啶，合成工艺简单，操作方便。1. The present invention selects 4-chloro-5-fluoro-2-methylsulfonylpyrimidine and ammonia as raw materials, and uses tetrahydrofuran as a solvent to synthesize 5-fluoro-2-methylsulfonyl-4-aminopyrimidine in a "one-pot method". The process is simple and the operation is convenient.
2、本发明的主原料4-氯-5-氟-2-甲磺酰基嘧啶合成简单，反应完后得到的粗品不需要提纯直接用于下一步反应，合成的产品其气质分析反应过程中无异构体的出现，这样更有利于产品的分离及提纯。2. The main raw material 4-chloro-5-fluoro-2-methanesulfonylpyrimidine of the present invention is simple to synthesize, and the crude product obtained after the reaction does not need to be purified and is directly used in the next step reaction. The gaseous analysis reaction process of the synthesized product has no The appearance of isomers is more conducive to the separation and purification of products.
附图说明Description of drawings
图1是本发明制备的5-氟-2-甲磺酰基-4-氨基嘧啶产品的氢核磁谱图。Fig. 1 is the proton magnetic spectrum of the 5-fluoro-2-methanesulfonyl-4-aminopyrimidine product prepared by the present invention.
具体实施方式Detailed ways
下面通过具体实施例详述本发明，但不限制本发明的保护范围。如无特殊说明，本发明所采用的实验方法均为常规方法，所用实验器材、材料、试剂等均可从商业途径获得。The present invention is described in detail below through specific examples, but the protection scope of the present invention is not limited. Unless otherwise specified, the experimental methods used in the present invention are conventional methods, and the experimental equipment, materials, reagents, etc. used can be obtained from commercial sources.
本发明中主原料4-氯-5-氟-2-甲磺酰基嘧啶参考文献US20170226089A合成，即将4-氯-5-氟-2-甲硫基嘧啶溶于二氯甲烷中，在0℃左右加入mCPBA，0℃反应16h。In the present invention, the main raw material 4-chloro-5-fluoro-2-methylsulfonylpyrimidine is synthesized by referring to US20170226089A, that is, dissolving 4-chloro-5-fluoro-2-methylthiopyrimidine in dichloromethane at about 0°C Add mCPBA, react at 0°C for 16h.
实施例1Example 1
本实施例为5-氟-2-甲磺酰基-4-氨基嘧啶制备方法，按下述反应式：This embodiment is a preparation method of 5-fluoro-2-methanesulfonyl-4-aminopyrimidine, according to the following reaction formula:
具体实验过程如下：The specific experimental process is as follows:
使用三口烧瓶，加入新制备的4-氯-5-氟-2-甲磺酰基嘧啶4.21g(0.02mol，96％，1eq)，四氢呋喃20ml，室温下磁子搅拌滴加氨水3.09g(0.04mol，25％，2eq)，滴加完毕后反应3～5h，反应完毕减压除去溶剂四氢呋喃，釜残加入20mL水，冷却后有固体析出，过滤得到大量褐色固体，晾干后经重结晶和柱层析得到2.48g褐色固体产品5-氟-2-甲磺酰基-4-氨基嘧啶，GC：98％，收率65％。Using a three-necked flask, add 4.21g (0.02mol, 96%, 1eq) of newly prepared 4-chloro-5-fluoro-2-methanesulfonylpyrimidine, 20ml of tetrahydrofuran, and add 3.09g (0.04mol) of ammonia water dropwise with magnetic stirring at room temperature. , 25%, 2eq), after the completion of the dropwise reaction for 3 ~ 5h, after the reaction was completed, the solvent tetrahydrofuran was removed under reduced pressure, and 20mL of water was added to the residue of the kettle. After cooling, a solid precipitated out, and a large amount of brown solid was obtained by filtration. After drying, it was recrystallized and columnar. Chromatography gave 2.48 g of brown solid product 5-fluoro-2-methylsulfonyl-4-aminopyrimidine, GC: 98%, yield 65%.
实施例2Example 2
本实施例为5-氟-2-甲磺酰基-4-氨基嘧啶制备方法，按下述反应式：This embodiment is a preparation method of 5-fluoro-2-methanesulfonyl-4-aminopyrimidine, according to the following reaction formula:
具体实验过程如下：The specific experimental process is as follows:
使用三口烧瓶，加入新制备的4-氯-5-氟-2-甲磺酰基嘧啶4.21g(0.02mol，96％，1eq)，四氢呋喃20ml，室温下磁子搅拌滴加氨水4.63g(0.06mol，25％，3eq)，滴加完毕后反应3～5h，反应完毕减压除去溶剂四氢呋喃，釜残加入20mL水，冷却后有固体析出，过滤得到大量褐色固体，晾干后经重结晶和柱层析得到2.79g褐色固体产品5-氟-2-甲磺酰基-4-氨基嘧啶，GC：98％，收率73％。Using a three-necked flask, add 4.21g (0.02mol, 96%, 1eq) of newly prepared 4-chloro-5-fluoro-2-methanesulfonylpyrimidine, 20ml of tetrahydrofuran, and add ammonia water 4.63g (0.06mol , 25%, 3eq), after the completion of the dropwise reaction for 3 to 5 hours, the solvent THF was removed under reduced pressure after the reaction was completed, and 20 mL of water was added to the residue of the kettle. After cooling, solids were precipitated, and a large amount of brown solids were obtained by filtration. After drying, they were recrystallized and columnar. Chromatography gave 2.79 g of brown solid product 5-fluoro-2-methanesulfonyl-4-aminopyrimidine, GC: 98%, yield 73%.
实施例3Example 3
本例为4-氯-5-氟-2-甲磺酰基嘧啶制备方法，按下述反应式：This example is the preparation method of 4-chloro-5-fluoro-2-methylsulfonyl pyrimidine, according to the following reaction formula:
具体实验过程如下：The specific experimental process is as follows:
使用三口烧瓶，加入新制备的4-氯-5-氟-2-甲磺酰基嘧啶4.21g(0.02mol，96％，1eq)，四氢呋喃20ml，室温下磁子搅拌滴加氨水4.63g(0.06mol，25％，3eq)，滴加完毕后反应8～10h，反应完毕减压除去溶剂四氢呋喃，釜残加入20mL水，冷却后有固体析出，过滤得到大量褐色固体，晾干后经重结晶和柱层析得到3.06g褐色固体产品5-氟-2-甲磺酰基-4-氨基嘧啶，GC：98％，收率80％。Using a three-necked flask, add 4.21g (0.02mol, 96%, 1eq) of newly prepared 4-chloro-5-fluoro-2-methanesulfonylpyrimidine, 20ml of tetrahydrofuran, and add ammonia water 4.63g (0.06mol , 25%, 3eq), after the dropwise addition, react for 8-10h, remove the solvent tetrahydrofuran under reduced pressure after the reaction is completed, add 20mL water to the residue of the kettle, after cooling, solids are precipitated, and a large amount of brown solids are obtained by filtration, after drying, recrystallization and column Chromatography gave 3.06 g of brown solid product 5-fluoro-2-methanesulfonyl-4-aminopyrimidine, GC: 98%, yield 80%.
根据实施例1、2，增加氨水的摩尔量，产品的收率由60％提升至73％；根据实施例2、3，延长反应时间，产品的收率由73％提升至80％。According to embodiment 1,2, increase the molar weight of ammoniacal liquor, the yield of product is promoted to 73% by 60%; According to embodiment 2,3, prolong reaction time, the yield of product is promoted to 80% by 73%.
以上所述，仅为本发明创造较佳的具体实施方式，但本发明创造的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明创造披露的技术范围内，根据本发明创造的技术方案及其发明构思加以等同替换或改变，都应涵盖在本发明创造的保护范围之内。The above is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto, any person familiar with the technical field within the technical scope of the disclosure of the present invention, according to the present invention Any equivalent replacement or change of the created technical solution and its inventive concept shall be covered within the scope of protection of the present invention.
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| CN103923019A (en) * | 2014-03-20 | 2014-07-16 | 蚌埠中实化学技术有限公司 | Preparation method of 2-hydroxy-4-amino-5-fluoropyrimidine |
| CN106795144A (en) * | 2014-10-13 | 2017-05-31 | 株式会社柳韩洋行 | Compound and composition for adjusting EGFR mutant kinase activities |
| CN109071488A (en) * | 2016-02-10 | 2018-12-21 | 詹森药业有限公司 | Substituted 1,2,3- triazole is as NR2B- selective NMDA regulator |
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