CN110818618A - 一种吡咯替尼中间体2-[(2-氯-4-硝基苯氧基)甲基]吡啶的合成方法 - Google Patents
一种吡咯替尼中间体2-[(2-氯-4-硝基苯氧基)甲基]吡啶的合成方法 Download PDFInfo
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- GWYKHOLLVPAQFF-UHFFFAOYSA-N 2-[(2-chloro-4-nitrophenoxy)methyl]pyridine Chemical compound ClC1=CC([N+](=O)[O-])=CC=C1OCC1=CC=CC=N1 GWYKHOLLVPAQFF-UHFFFAOYSA-N 0.000 title claims description 23
- 238000010189 synthetic method Methods 0.000 title claims description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 12
- OFPWMRMIFDHXFE-UHFFFAOYSA-N 2-(bromomethyl)pyridine Chemical compound BrCC1=CC=CC=N1 OFPWMRMIFDHXFE-UHFFFAOYSA-N 0.000 claims abstract description 11
- BOFRXDMCQRTGII-UHFFFAOYSA-N 619-08-9 Chemical compound OC1=CC=C([N+]([O-])=O)C=C1Cl BOFRXDMCQRTGII-UHFFFAOYSA-N 0.000 claims abstract description 9
- 230000002194 synthesizing effect Effects 0.000 claims abstract 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
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- -1 2-chloro-4-nitrophenoxy Chemical group 0.000 abstract 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 7
- 239000003651 drinking water Substances 0.000 description 6
- 235000020188 drinking water Nutrition 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 4
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 229940043275 anti-HER2 drug Drugs 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
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- 230000002427 irreversible effect Effects 0.000 description 2
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- 210000004881 tumor cell Anatomy 0.000 description 2
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- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 2
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 2
- DPHCXXYPSYMICK-UHFFFAOYSA-N 2-chloro-1-fluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C(Cl)=C1 DPHCXXYPSYMICK-UHFFFAOYSA-N 0.000 description 1
- 101100067974 Arabidopsis thaliana POP2 gene Proteins 0.000 description 1
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- 101710100963 Receptor tyrosine-protein kinase erbB-4 Proteins 0.000 description 1
- 101100123851 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) HER1 gene Proteins 0.000 description 1
- 238000012338 Therapeutic targeting Methods 0.000 description 1
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- 239000000710 homodimer Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 1
- 229960004891 lapatinib Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229950008835 neratinib Drugs 0.000 description 1
- ZNHPZUKZSNBOSQ-BQYQJAHWSA-N neratinib Chemical compound C=12C=C(NC\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 ZNHPZUKZSNBOSQ-BQYQJAHWSA-N 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- SHNUBALDGXWUJI-UHFFFAOYSA-N pyridin-2-ylmethanol Chemical compound OCC1=CC=CC=N1 SHNUBALDGXWUJI-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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Abstract
本发明公开了一种吡咯替尼中间体2‑[(2‑氯‑4‑硝基苯氧基)甲基]吡啶的合成方法。该方法由2‑溴甲基吡啶和2‑氯‑4‑硝基苯酚在碱性条件下温和反应得到2‑[(2‑氯‑4‑硝基苯氧基)甲基]吡啶。本发明反应条件温和，后处理简单，产品纯度高(收率≥95％)和收率高(纯度≥99.5％)，适宜于工业化生产。
Description
技术领域
本发明涉及一种吡咯替尼中间体2-[(2-氯-4-硝基苯氧基)甲基]吡啶的合成方法，属于医药技术领域。
背景技术
吡咯替尼是新一代抗HER2治疗靶向药，其机制是泛-ErbB受体的、小分子、不可逆酪氨酸激酶抑制剂(TKI)，与HER1、HER2和HER4的胞内激酶区ATP结合位点共价结合，阻止HER家族同/异源二聚体形成，抑制自身磷酸化，阻断下游信号通路的激活，抑制肿瘤细胞生长，具有全能、强效的抗肿瘤作用。与上一代抗HER2药物如曲妥珠单抗相比，吡咯替尼可直接作用于HER2通路的酪氨酸激酶区，全面阻断包括曲妥珠单抗无法阻断的HER2异源二聚体在内的所有二聚体下游通路；与其他小分子抗HER2药物如拉帕替尼相比，吡咯替尼靶点更全面，且对靶点造成不可逆抑制，更强效地抑制肿瘤生长；与另一小分子抗HER2药物来那替尼相比，吡咯替尼生物利用度更高，因此对肿瘤细胞的抑制强度更高，且安全性更好。也就是说，无论在药物机制或疗效上，吡咯替尼都优于目前其他已上市的HER2药物。
2-[(2-氯-4-硝基苯氧基)甲基]吡啶是吡咯替尼合成过程中的一个重要的中间体，由于吡咯替尼是一种新研发的药品，关于吡咯替尼中间体2-[(2-氯-4-硝基苯氧基)甲基]吡啶的研究报道较少，根据文献报道只有一种合成方法，合成路线如下所示。
该路线是以乙腈为溶剂，在碱性条件下(采用KOH)，由2-羟甲基吡啶与2-氯-4-硝基氟苯进行反应得到。该合成方法在生产过程中反应时间较长，且产品收率偏低，不适宜于工业化生产。
发明内容
本发明克服了现有技术的不足，提供了一种吡咯替尼中间体2-[(2-氯-4-硝基苯氧基)甲基]吡啶的新的合成方法。该合成方法是由2-溴甲基吡啶和2-氯-4-硝基苯酚在碱性条件下温和反应得到2-[(2-氯-4-硝基苯氧基)甲基]吡啶。其反应条件温和，后处理简单，产品纯度高，收率高，适宜于工业化生产。
本发明的技术方案是：一种吡咯替尼中间体2-[(2-氯-4-硝基苯氧基)甲基]吡啶的合成方法，其特征是，向反应容器中加入2-溴甲基吡啶、2-氯-4-硝基苯酚、反应溶剂和碳酸钠，10-30℃下反应4-6小时；反应完成后加水使2-[(2-氯-4-硝基苯氧基)甲基]吡啶析出，过滤，水洗滤饼，烘干，得类白色固体2-[(2-氯-4-硝基苯氧基)甲基]吡啶。
反应方程式如下所示：
优选的，所述反应温度为20-30℃，反应完成后加水(水与反应溶剂的体积比为1.5～2：1)，搅拌，然后降温至8-12℃继续搅拌使2-[(2-氯-4-硝基苯氧基)甲基]吡啶析出，过滤。
所述反应溶剂为乙腈、纯化水、醇类(甲醇、乙醇、异丁醇)，优选乙腈。
所述烘干温度优选为60-65℃。
所述2-溴甲基吡啶和2-氯-4-硝基苯酚的摩尔比为1：0.9～1.5。
所述2-溴甲基吡啶和碳酸钠的摩尔比为1：0.9～1.5。
本发明的有益效果是：本发明反应条件温和，后处理简单，产品纯度高(纯度≥99.5％)和收率高(收率≥95％)，适宜于工业化生产。
具体实施方式
以下实例是对本发明的进一步说明，但是本发明并不局限于此。
实施例1：
向1000ml三口瓶中加入40g 2-溴甲基吡啶、44g 2-氯-4-硝基苯酚，加入300ml乙腈和24.6g碳酸钠，开启搅拌，控制反应瓶内温度为25℃搅拌反应5小时，然后加入饮用水500ml，搅拌10分钟后降温至10℃搅拌30分钟，过滤，用200ml饮用水洗涤滤饼，所得湿品固体置于热风循环烘箱，控温60-65℃烘干6小时，得类白色固体59.68g，收率96.98％，纯度99.83％。
实施例2：
向1000ml三口瓶中加入40g 2-溴甲基吡啶、45.0g 2-氯-4-硝基苯酚，加入300ml乙腈和25.0g碳酸钠，开启搅拌，控制反应瓶内温度为25℃搅拌反应5小时，然后加入饮用水500ml，搅拌12分钟后降温至10℃搅拌35分钟，过滤，用200ml饮用水洗涤滤饼，所得湿品固体置于热风循环烘箱，控温60-65℃烘干6小时，得类白色固体59.25g，收率96.28％，纯度99.61％。
实施例3：
向1000ml三口瓶中加入40g 2-溴甲基吡啶、43.0g 2-氯-4-硝基苯酚，加入300ml乙腈和24.0g碳酸钠，开启搅拌，控制反应瓶内温度为25℃搅拌反应6小时，然后加入饮用水500ml，搅拌10分钟后降温至10℃搅拌25分钟，过滤，用200ml饮用水洗涤滤饼，所得湿品固体置于热风循环烘箱，控温60-65℃烘干6小时，得类白色固体58.73g，收率95.43％，纯度99.85％。
Claims (7)
1.一种吡咯替尼中间体2-[(2-氯-4-硝基苯氧基)甲基]吡啶的合成方法，其特征是，向反应容器中加入2-溴甲基吡啶、2-氯-4-硝基苯酚、反应溶剂和碳酸钠，10-30℃下反应4-6小时；反应完成后加水使2-[(2-氯-4-硝基苯氧基)甲基]吡啶析出，过滤，水洗滤饼，烘干，得2-[(2-氯-4-硝基苯氧基)甲基]吡啶。
2.如权利要求1所述的一种吡咯替尼中间体2-[(2-氯-4-硝基苯氧基)甲基]吡啶的合成方法，其特征是，所述使2-[(2-氯-4-硝基苯氧基)甲基]吡啶析出具体为：20-30℃下反应，反应完成后加水，水与反应溶剂的体积比为1.5～2：1，搅拌，然后降温至8-12℃继续搅拌使2-[(2-氯-4-硝基苯氧基)甲基]吡啶析出。
3.如权利要求1或2所述的一种吡咯替尼中间体2-[(2-氯-4-硝基苯氧基)甲基]吡啶的合成方法，其特征是，所述反应溶剂为乙腈、纯化水、醇类。
4.如权利要求3所述的一种吡咯替尼中间体2-[(2-氯-4-硝基苯氧基)甲基]吡啶的合成方法，其特征是，所述醇类为甲醇、乙醇或者异丁醇。
5.如权利要求1或2所述的一种吡咯替尼中间体2-[(2-氯-4-硝基苯氧基)甲基]吡啶的合成方法，其特征是，所述烘干温度为60-65℃。
6.如权利要求1或2所述的一种吡咯替尼中间体2-[(2-氯-4-硝基苯氧基)甲基]吡啶的合成方法，其特征是，所述2-溴甲基吡啶和2-氯-4-硝基苯酚的摩尔比为1：0.9～1.5。
7.如权利要求1或2所述的一种吡咯替尼中间体2-[(2-氯-4-硝基苯氧基)甲基]吡啶的合成方法，其特征是，所述2-溴甲基吡啶和碳酸钠的摩尔比为1：0.9～1.5。
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