CN105777625A - 一种制备4-（4-氨基-3-氟苯氧基）-n-甲基吡啶-2-甲酰胺的方法 - Google Patents
一种制备4-（4-氨基-3-氟苯氧基）-n-甲基吡啶-2-甲酰胺的方法 Download PDFInfo
- Publication number
- CN105777625A CN105777625A CN201410814308.XA CN201410814308A CN105777625A CN 105777625 A CN105777625 A CN 105777625A CN 201410814308 A CN201410814308 A CN 201410814308A CN 105777625 A CN105777625 A CN 105777625A
- Authority
- CN
- China
- Prior art keywords
- amino
- methanamide
- fluorophenoxy
- picoline
- preferred
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title abstract description 6
- ZQHJPIPGBODVTG-UHFFFAOYSA-N 4-(4-Amino-3-fluorophenoxy)-N-methyl-2-pyridinecarboxamide Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(N)=CC=2)=C1 ZQHJPIPGBODVTG-UHFFFAOYSA-N 0.000 title abstract description 3
- 238000000034 method Methods 0.000 claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- MNPLTKHJEAFOCA-UHFFFAOYSA-N 4-amino-3-fluorophenol Chemical compound NC1=CC=C(O)C=C1F MNPLTKHJEAFOCA-UHFFFAOYSA-N 0.000 claims abstract description 13
- BGVBBMZMEKXUTR-UHFFFAOYSA-N 4-chloro-n-methylpyridine-2-carboxamide Chemical compound CNC(=O)C1=CC(Cl)=CC=N1 BGVBBMZMEKXUTR-UHFFFAOYSA-N 0.000 claims abstract description 13
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 9
- 238000002425 crystallisation Methods 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical group CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 239000000376 reactant Substances 0.000 claims description 4
- NBJZEUQTGLSUOB-UHFFFAOYSA-N 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC(N=C=O)=CC=C1Cl NBJZEUQTGLSUOB-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 abstract description 5
- 238000000605 extraction Methods 0.000 abstract description 3
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 2
- 238000000926 separation method Methods 0.000 abstract 2
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 238000009413 insulation Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000003513 alkali Substances 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- -1 organic base potassium tert-butoxide Chemical class 0.000 description 2
- 238000005498 polishing Methods 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 239000003005 anticarcinogenic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- 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
- C07D213/60—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 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D9/0004—Crystallisation cooling by heat exchange
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01D—COMPOUNDS OF ALKALI METALS, i.e. LITHIUM, SODIUM, POTASSIUM, RUBIDIUM, CAESIUM, OR FRANCIUM
- C01D1/00—Oxides or hydroxides of sodium, potassium or alkali metals in general
- C01D1/04—Hydroxides
-
- 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
- C07D213/06—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/127—Preparation from compounds containing pyridine rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Materials Engineering (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Physics & Mathematics (AREA)
- Thermal Sciences (AREA)
- Crystallography & Structural Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明涉及一种制备4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺的方法，该方法包括使4-氯-N-甲基吡啶-2-甲酰胺与4-氨基-3-氟苯酚在无机碱的存在下进行反应。本发明选用无机碱取代现有技术中的叔丁醇钾，有效解决了叔丁醇钾在工业化生产中存在的安全隐患问题，而且，本发明在反应结束后，采用析晶法分离得到反应产物，相比于现有技术采用的萃取、浓缩、柱分离纯化等方法，操作更简单，成本更低，而且环境污染小，收率高，非常适合工业化生产。
Description
技术领域
本发明涉及一种医药中间体的制备方法，特别涉及一种4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺的制备方法。
背景技术
医药中间体4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺，CAS号：757251-39-1，其结构如下所示：
4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺为抗癌药瑞戈非尼的关键中间体，现有技术中有关其合成方法的报导，大致可分为两种，具体如下：
方法1：
美国专利US8637553B报道了以4-氯-N-甲基吡啶-2-甲酰胺，4-氨基-3-氟苯酚为原料以N,N-二甲基乙酰胺为溶剂，用有机碱叔丁醇钾作碱，反应制备得到4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺，反应流程式如下：
该方法采用叔丁醇钾做碱，在工业大规模生产中容易发生爆炸，存在一定的安全隐患；另外其后处理通过浓缩萃取等工序，给工业生产带来很大的不便，产生大量废水，尤其是该体系为深黑色，难以分清萃取分层界限，根据专利报道该法最高收率为77％。
方法2：
美国专利US20080090856A报道了首先将4-氨基-3-氟苯酚的氨基用酮(如2-甲基戊酮)进行保护，然后在有机碱叔丁醇钾的作用下与4-氯-N-甲基吡啶-2-甲酰胺反应，最后脱保护制备得到目标产物4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺，反应流程式如下：
该方法较方法1增加了上保护基团和脱保护步骤，使制备路线更加繁琐，尤其是其第二步反应收率只有78％左右。
鉴于现有技术中公开的4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺的合成过程中存在的种种缺陷，提供一条低成本，高收率的工艺路线来制备4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺，是该产品实现规模化生产亟待解决的问题。
发明内容
本发明提供了一种低成本，高收率，操作简便，安全性高的4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺的制备方法，从而克服了现有技术中存在的收率低、成本高、存在安全隐患等缺陷。
本发明采用的技术方案为：
一种制备下式的4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺的方法，
所述方法包括：
(a)在惰性气体保护下，使下式的4-氯-N-甲基吡啶-2-甲酰胺
与下式的4-氨基-3-氟苯酚
在无机碱的存在下进行反应。
其中，所述无机碱选自氢氧化钠或氢氧化钾，优选氢氧化钠。
其中，所述4-氯-N-甲基吡啶-2-甲酰胺，4-氨基-3-氟苯酚，无机碱的物质的量之比为1.0:0.9～1.5:0.9～1.5，优选为1.0:1.1～1.3:1.1～1.3。
其中，所述反应是在有机溶剂中进行的。所述有机溶剂选自N,N-二甲基乙酰胺，N,N-二甲基甲酰胺或N-甲基吡咯烷酮，优选为N,N-二甲基乙酰胺。
其中，所述反应的反应温度为40-160℃，优选为80-140℃，更优选为90-110℃。
其中，所述反应的反应时间为1～24h，优选为1～6h。
其中，所述方法进一步包括：
(b)反应结束后，加入适量的水至步骤(a)所得的反应液中，然后冷却至-20～20℃，优选为0～10℃进行结晶，得到4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺。
其中，步骤(b)中，加入的水与步骤(a)所得反应液的体积比为0.5～3:1，优选为1～2:1。
本发明还提供了一种瑞戈非尼的制备方法，所述方法包括：
(1)根据上述方法制备得到4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺；
(2)使步骤(1)所得4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺与4-氯-3-(三氟甲基)苯基异氰酸酯进行反应，得到瑞戈非尼。
其中，步骤(2)是在惰性有机溶剂中进行的，包括但不限于甲苯，丙酮，或它们的混合液。
与现有技术相比，本发明的有益效果主要体现在：一方面，本发明选用无机碱，例如氢氧化钠或氢氧化钾取代现有技术中的叔丁醇钾，有效解决了叔丁醇钾在工业化生产中存在的安全隐患问题，另一方面，采用本发明的方法，反应收率可提高到88％。而且，本发明在反应结束后，采用析晶法分离得到反应产物，相比于现有技术采用的萃取、浓缩、柱分离纯化等方法，操作更简单，成本更低，而且环境污染小，非常适合工业化生产。
具体实施方式
下面结合具体实施例对本发明进行进一步描述，但本发明的保护范围并不仅限于此。
实施例1：
氮气保护下，在反应罐中依次加入4-氨基-3-氟苯酚127g，4-氯-N-甲基吡啶-2-甲酰胺170g和N,N-二甲基乙酰胺170ml，搅拌溶清后加入氢氧化钠40g，升温至80℃，保温反应24小时。加入水510ml，将所得混合物冷却至-20℃，在此温度下搅拌析晶过夜，过滤并干燥，得到橙红色固体4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺211g。HPLC含量98.1％，mp：141.6-142.3℃，产率80.6％。
实施例2：
氮气保护下，在反应罐中依次加入4-氨基-3-氟苯酚190.5g，4-氯-N-甲基吡啶-2-甲酰胺170g和N,N-二甲基甲酰胺5100ml，搅拌溶清后加入氢氧化钾84g，升温至140℃，保温反应1小时。加入水2550ml，将所得混合物冷却至0℃，在此温度下搅拌析晶过夜，过滤并干燥，得到橙红色固体4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺213g。HPLC含量98.5％，mp：141.6-142.4℃，产率81.3％。
实施例3：
氮气保护下，在反应罐中依次加入4-氨基-3-氟苯酚165g，4-氯-N-甲基吡啶-2-甲酰胺170g和N-甲基吡咯烷酮1700ml，搅拌溶清后加入氢氧化钠52g，升温至100℃，保温反应6小时。加入水1700ml，将所得混合物冷却至20℃，在此温度下搅拌析晶过夜，过滤并干燥，得到橙红色固体4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺222g。HPLC含量99.1％，mp：141.5-142.5℃，产率85％。
实施例4：
氮气保护下，在反应罐中依次加入4-氨基-3-氟苯酚165g，4-氯-N-甲基吡啶-2-甲酰胺170g和N,N-二甲基乙酰胺1700ml，搅拌溶清后加入氢氧化钠52g，升温至100℃，保温反应3小时。加入水1700ml，将所得混合物冷却至10℃，在此温度下自然降温搅拌析晶过夜，过滤并干燥，得到橙红色固体4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺232g。HPLC含量99.2％，mp：141.5-142.5℃，产率88.6％。
实施例5：
氮气保护下，在反应罐中依次加入4-氨基-3-氟苯酚165g，4-氯-N-甲基吡啶-2-甲酰胺170g和N,N-二甲基乙酰胺1700ml，搅拌溶清后加入氢氧化钠52g，升温至40℃，保温反应3小时。加入水1700ml，将所得混合物冷却至10℃，在此温度下自然降温搅拌析晶过夜，过滤并干燥，得到橙红色固体4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺122g。HPLC含量95.2％，mp：141.5-142.5℃，产率46.5％。
实施例6：
氮气保护下，在反应罐中依次加入4-氨基-3-氟苯酚165g，4-氯-N-甲基吡啶-2-甲酰胺170g和N,N-二甲基乙酰胺1700ml，搅拌溶清后加入氢氧化钠52g，升温至160℃，保温反应3小时。加入水1700ml，将所得混合物冷却至10℃，在此温度下自然降温搅拌析晶过夜，过滤并干燥，得到橙红色固体4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺160g。HPLC含量99.2％，mp：141.5-142.5℃，产率61.2％。
实施例7：
氮气保护下，在装有搅拌器，温度计，滴加漏斗的反应罐中，加入171.5g的4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺和1200mL丙酮，40℃保温，然后慢慢滴加159.5g的4-氯-3-(三氟甲基)苯基异氰酸酯的600mL丙酮溶液(约2小时加毕)，保持温度再搅拌3小时，过滤得滤饼，真空烘干得白色或类白色固体瑞戈非尼269g。HPLC含量99.4％，mp：187-188℃，收率85％。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员，在不脱离本发明构思的前提下，还可以做出若干改进和润色，这些改进和润色也应视为本发明的保护范围内。
Claims (10)
1.一种制备下式的4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺的方法，
其特征在于，所述方法包括：
(a)在惰性气体保护下，使下式的4-氯-N-甲基吡啶-2-甲酰胺
与下式的4-氨基-3-氟苯酚
在无机碱的存在下进行反应。
2.根据权利要求1所述的方法，其特征在于，所述无机碱选自氢氧化钠或氢氧化钾，优选氢氧化钠。
3.根据权利要求1或2所述的方法，其特征在于，所述4-氯-N-甲基吡啶-2-甲酰胺，4-氨基-3-氟苯酚，无机碱的物质的量之比为1.0:0.9～1.5:0.9～1.5，优选为1.0:1.1～1.3:1.1～1.3。
4.根据权利要求1-3任一项所述的方法，其特征在于，所述反应是在有机溶剂中进行的。
5.根据权利要求4所述的方法，其特征在于，所述有机溶剂选自N,N-二甲基乙酰胺，N,N-二甲基甲酰胺或N-甲基吡咯烷酮，优选为N,N-二甲基乙酰胺。
6.根据权利要求1-5任一项所述的方法，其特征在于，所述反应的反应温度为40-160℃，优选为80-140℃，更优选为90-110℃。
7.根据权利要求1-6任一项所述的方法，其特征在于，所述反应的反应时间为1～24h，优选为1～6h。
8.根据权利要求1-7任一项所述的方法，其特征在于，所述方法进一步包括：
(b)反应结束后，加入适量的水至步骤(a)所得的反应液中，然后冷却至-20～20℃，优选为0～10℃进行结晶，得到4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺。
9.根据权利要求8所述的方法，其特征在于，步骤(b)中，加入的水与步骤(a)所得反应液的体积比为0.5～3:1，优选为1～2:1。
10.一种制备瑞戈非尼的方法，其特征在于，所述方法包括：
(1)根据权利要求1-9任一项所述方法制备得到4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺；
(2)使步骤(1)所得4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺与4-氯-3-(三氟甲基)苯基异氰酸酯进行反应，得到瑞戈非尼。
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410814308.XA CN105777625B (zh) | 2014-12-24 | 2014-12-24 | 一种制备4-（4-氨基-3-氟苯氧基）-n-甲基吡啶-2-甲酰胺的方法 |
| PCT/CN2015/094108 WO2016101714A1 (zh) | 2014-12-24 | 2015-11-09 | 一种制备4-(4-氨基-3-氟苯氧基)-n-甲基吡啶-2-甲酰胺的方法 |
| US15/532,374 US10081599B2 (en) | 2014-12-24 | 2015-11-09 | Preparation method of 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410814308.XA CN105777625B (zh) | 2014-12-24 | 2014-12-24 | 一种制备4-（4-氨基-3-氟苯氧基）-n-甲基吡啶-2-甲酰胺的方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105777625A true CN105777625A (zh) | 2016-07-20 |
| CN105777625B CN105777625B (zh) | 2020-05-22 |
Family
ID=56149200
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410814308.XA Active CN105777625B (zh) | 2014-12-24 | 2014-12-24 | 一种制备4-（4-氨基-3-氟苯氧基）-n-甲基吡啶-2-甲酰胺的方法 |
Country Status (3)
| Country | Link |
|---|---|
| US (1) | US10081599B2 (zh) |
| CN (1) | CN105777625B (zh) |
| WO (1) | WO2016101714A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106588760A (zh) * | 2016-12-20 | 2017-04-26 | 青岛辰达生物科技有限公司 | 一种瑞格菲尼中间体的制备工艺 |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1856469A (zh) * | 2003-07-23 | 2006-11-01 | 拜尔医药品股份有限公司 | 用于治疗和预防疾病和疾病症状的氟代ω－羧芳基二苯基脲 |
| CN101362718A (zh) * | 2008-09-28 | 2009-02-11 | 四川大学 | 4-(4-苯甲酰氨基苯氧基)-2-(甲基氨甲酰基)吡啶衍生物及其制备方法和用途 |
| WO2011113370A1 (zh) * | 2010-03-18 | 2011-09-22 | 苏州泽璟生物制药有限公司 | 氘代的ω-二苯基脲及其衍生物以及包含这些化合物的药物组合物 |
| WO2011113368A1 (zh) * | 2010-03-18 | 2011-09-22 | 苏州泽璟生物制药有限公司 | 含氟的氘代二苯基脲的合成方法 |
| WO2013036232A2 (en) * | 2011-09-08 | 2013-03-14 | Deciphera Pharmaceuticals, Llc | Methods and compositions for the treatment of myeloproliferative diseases and other proliferative diseases |
| CN104177292A (zh) * | 2014-08-08 | 2014-12-03 | 亿腾药业（泰州）有限公司 | 一种工业化生产甲苯磺酸索拉非尼多晶型ⅰ的方法 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3863553A (en) | 1973-12-20 | 1975-02-04 | Bryce L Koontz | Combination insulation stop and ventilation baffle |
| US7790756B2 (en) | 2006-10-11 | 2010-09-07 | Deciphera Pharmaceuticals, Llc | Kinase inhibitors useful for the treatment of myleoproliferative diseases and other proliferative diseases |
| CN104250226B (zh) | 2013-06-27 | 2019-04-26 | 常州方楠医药技术有限公司 | 一种制备瑞格菲尼中间体的方法 |
-
2014
- 2014-12-24 CN CN201410814308.XA patent/CN105777625B/zh active Active
-
2015
- 2015-11-09 WO PCT/CN2015/094108 patent/WO2016101714A1/zh active Application Filing
- 2015-11-09 US US15/532,374 patent/US10081599B2/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1856469A (zh) * | 2003-07-23 | 2006-11-01 | 拜尔医药品股份有限公司 | 用于治疗和预防疾病和疾病症状的氟代ω－羧芳基二苯基脲 |
| CN101362718A (zh) * | 2008-09-28 | 2009-02-11 | 四川大学 | 4-(4-苯甲酰氨基苯氧基)-2-(甲基氨甲酰基)吡啶衍生物及其制备方法和用途 |
| WO2011113370A1 (zh) * | 2010-03-18 | 2011-09-22 | 苏州泽璟生物制药有限公司 | 氘代的ω-二苯基脲及其衍生物以及包含这些化合物的药物组合物 |
| WO2011113368A1 (zh) * | 2010-03-18 | 2011-09-22 | 苏州泽璟生物制药有限公司 | 含氟的氘代二苯基脲的合成方法 |
| WO2013036232A2 (en) * | 2011-09-08 | 2013-03-14 | Deciphera Pharmaceuticals, Llc | Methods and compositions for the treatment of myeloproliferative diseases and other proliferative diseases |
| CN104177292A (zh) * | 2014-08-08 | 2014-12-03 | 亿腾药业（泰州）有限公司 | 一种工业化生产甲苯磺酸索拉非尼多晶型ⅰ的方法 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106588760A (zh) * | 2016-12-20 | 2017-04-26 | 青岛辰达生物科技有限公司 | 一种瑞格菲尼中间体的制备工艺 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105777625B (zh) | 2020-05-22 |
| US20170334856A1 (en) | 2017-11-23 |
| WO2016101714A1 (zh) | 2016-06-30 |
| US10081599B2 (en) | 2018-09-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111961018B (zh) | 一种高纯度丁苯酞的制备方法 | |
| CN106188116B (zh) | 一种合成吡唑‑4‑硼酸频那醇酯的方法 | |
| CN104017001B (zh) | 一种化学合成莫西克汀的方法 | |
| CN105968023A (zh) | 一种盐酸安非他酮的制备方法 | |
| CN105218440A (zh) | 一种高纯瑞戈非尼的制备方法 | |
| CN105017218A (zh) | 一种右兰索拉唑晶型及其制备方法 | |
| CN107674063B (zh) | Gs5816中间体及制备方法和应用 | |
| CN105777625A (zh) | 一种制备4-（4-氨基-3-氟苯氧基）-n-甲基吡啶-2-甲酰胺的方法 | |
| CN110845401A (zh) | 一种2-氟-3,6-二羟基吡啶的合成方法 | |
| CN104402813B (zh) | 一种索拉非尼的制备方法 | |
| CN110551052A (zh) | (r)-4-羟基-2-氧代-1-吡咯烷乙酸酯的制备方法 | |
| CN109678738B (zh) | 一种合成(2s,3s)-3-氨基-二环[2.2.2]辛烷-2-甲酸酯的方法 | |
| CN107573301B (zh) | 一种三环唑中间体的制备方法 | |
| CN105566296A (zh) | 一种制备达比加群酯酰胺化杂质的方法 | |
| CN106432059A (zh) | 一种3-羟基哌啶和其衍生物的制备方法及其中间体 | |
| CN103351312A (zh) | 一种用于苯二异氰酸酯的制备工艺 | |
| CN113956268B (zh) | 一种6-溴-1-氯苯并噻吩[2,3-c]吡啶及合成方法 | |
| CN115322191B (zh) | 一种莫西沙星盐酸盐的合成方法 | |
| CN107382640A (zh) | β‑芳基苯丙酮类化合物的合成方法 | |
| CN105753804A (zh) | 一种制备3-吗啉酮的方法 | |
| CN106831811A (zh) | 一种制备高含量尼莫克汀的方法 | |
| CN104370766B (zh) | 工业化生产间苯二甲酸衍生物的方法 | |
| CN118146182A (zh) | 一种3-苄氧基-4-氧代-4h-吡喃-2-羧酸的制备方法 | |
| CN105646154B (zh) | 一种新型含保护基的3-烯丙基苯酚衍生物的合成和脱保护的方法 | |
| CN115057767A (zh) | 一种邻苯二甲酸的制备方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A method for preparing 4 - (4-amino-3-fluorophenoxy) - n-methylpyridine-2-formamide Effective date of registration: 20201226 Granted publication date: 20200522 Pledgee: Industrial Commercial Bank of China Ltd. Taizhou Jiaojiang branch Pledgor: ZHEJIANG HISUN PHARMACEUTICAL Co.,Ltd. Registration number: Y2020330001302 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20210425 Granted publication date: 20200522 Pledgee: Industrial Commercial Bank of China Ltd. Taizhou Jiaojiang branch Pledgor: ZHEJIANG HISUN PHARMACEUTICAL Co.,Ltd. Registration number: Y2020330001302 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A method for preparing 4 - (4-amino-3-fluorophenoxy) - n-methylpyridine-2-formamide Effective date of registration: 20210729 Granted publication date: 20200522 Pledgee: Industrial Commercial Bank of China Ltd. Taizhou Jiaojiang branch Pledgor: ZHEJIANG HISUN PHARMACEUTICAL Co.,Ltd. Registration number: Y2021330000982 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20230130 Granted publication date: 20200522 Pledgee: Industrial Commercial Bank of China Ltd. Taizhou Jiaojiang branch Pledgor: ZHEJIANG HISUN PHARMACEUTICAL Co.,Ltd. Registration number: Y2021330000982 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A method for preparing 4 - (4-amino-3-fluorophenoxy) - N-methylpyridin-2-formamide Effective date of registration: 20230228 Granted publication date: 20200522 Pledgee: Industrial Commercial Bank of China Ltd. Taizhou Jiaojiang branch Pledgor: ZHEJIANG HISUN PHARMACEUTICAL Co.,Ltd. Registration number: Y2023330000447 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |