CN115433122A - 一种6-氟烟酸的制备方法 - Google Patents
一种6-氟烟酸的制备方法 Download PDFInfo
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- UJDLCTNVHJEBDG-UHFFFAOYSA-N 6-fluoropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=C(F)N=C1 UJDLCTNVHJEBDG-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- IUYHWZFSGMZEOG-UHFFFAOYSA-M isopropylmagnesium chloride Substances [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims abstract description 20
- ZHXUWDPHUQHFOV-UHFFFAOYSA-N 2,5-dibromopyridine Chemical compound BrC1=CC=C(Br)N=C1 ZHXUWDPHUQHFOV-UHFFFAOYSA-N 0.000 claims abstract description 17
- MOVBJUGHBJJKOW-UHFFFAOYSA-N methyl 2-amino-5-methoxybenzoate Chemical compound COC(=O)C1=CC(OC)=CC=C1N MOVBJUGHBJJKOW-UHFFFAOYSA-N 0.000 claims abstract description 15
- JDJBRMNTXORYEN-UHFFFAOYSA-N 6-bromopyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=C(Br)N=C1 JDJBRMNTXORYEN-UHFFFAOYSA-N 0.000 claims abstract description 13
- 230000007062 hydrolysis Effects 0.000 claims abstract description 13
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 11
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- 238000003682 fluorination reaction Methods 0.000 claims abstract description 4
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- NFLROFLPSNZIAH-UHFFFAOYSA-N methyl 6-bromopyridine-3-carboxylate Chemical group COC(=O)C1=CC=C(Br)N=C1 NFLROFLPSNZIAH-UHFFFAOYSA-N 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
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- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
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- 235000001968 nicotinic acid Nutrition 0.000 description 3
- 239000011664 nicotinic acid Substances 0.000 description 3
- 239000012286 potassium permanganate Substances 0.000 description 3
- UEYQJQVBUVAELZ-UHFFFAOYSA-M 2-oxo-1h-pyridine-3-carboxylate Chemical compound [O-]C(=O)C1=CC=CNC1=O UEYQJQVBUVAELZ-UHFFFAOYSA-M 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- ULYZAYCEDJDHCC-UHFFFAOYSA-N isopropyl chloride Chemical compound CC(C)Cl ULYZAYCEDJDHCC-UHFFFAOYSA-N 0.000 description 2
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- 150000003839 salts Chemical class 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- GBAJDPJECJPPSP-UHFFFAOYSA-N tert-butyl 5-bromopyridine-2-carboxylate Chemical compound CC(C)(C)OC(=O)C1=CC=C(Br)C=N1 GBAJDPJECJPPSP-UHFFFAOYSA-N 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- JVSWJIKNEAIKJW-UHFFFAOYSA-N 2-Methylheptane Chemical compound CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 1
- AOSOZARHUJMBLZ-UHFFFAOYSA-N 2-fluoro-5-methylpyridine Chemical compound CC1=CC=C(F)N=C1 AOSOZARHUJMBLZ-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 1
- MVJPVDSRSXLJNQ-UHFFFAOYSA-N ethyl 5-bromopyridine-2-carboxylate Chemical compound CCOC(=O)C1=CC=C(Br)C=N1 MVJPVDSRSXLJNQ-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000010814 metallic waste Substances 0.000 description 1
- JEURNBCYNWNADN-UHFFFAOYSA-N methyl 5-bromopyridine-2-carboxylate Chemical compound COC(=O)C1=CC=C(Br)C=N1 JEURNBCYNWNADN-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
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- 229960003512 nicotinic acid Drugs 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000005406 washing Methods 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
- C07D213/60—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
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- 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
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
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- Pyridine Compounds (AREA)
Abstract
本发明公开了一种6‑氟烟酸的制备方法，属于医药中间体技术领域。以2,5‑二溴吡啶为原料，在催化剂存在下，经异丙基氯化镁格氏试剂催化剂交换后，与氯甲酸酯或Boc2O反应高选择性生成6‑溴烟酸酯；接着6‑溴烟酸酯与四甲基氟化铵进行氟化反应，再经水解制得6‑氟烟酸。该制备方法环境友好、成本低、操作条件易于控制，适合工业化生产。
Description
技术领域
本发明属于医药中间体技术领域，具体涉及一种6-氟烟酸的制备方法。
背景技术
6-氟烟酸，英文名：6-Fluoronicotinic acid，CAS：403-45-2，白色固体，是制备含氟吡啶环类抗菌药物的重要中间体。
该化合物的制备方法目前文献报道较少，主要是以2-氟-5-甲基吡啶为原料，采用高锰酸钾高温氧化得到6-氟烟酸(参考Journal of Med Chem,1990,33,1667-1675、US2002/10185、US5583148)。该方法需要加入大量水溶解高锰酸钾，反应收率仅有45％左右，且产生大量重金属废固(二氧化锰)，存在三废多、产能低、安全风险大等问题，不利于工业化生产。
发明内容：
为了克服以上问题，本发明公开了一种6-氟烟酸的改进制备方法。以2,5-二溴吡啶为原料，在催化剂存在下，经异丙基氯化镁格氏试剂催化剂交换后，与氯甲酸酯反应高选择性生成6-溴烟酸酯；接着6-溴烟酸酯与四甲基氟化铵进行氟化反应，再经水解制得6-氟烟酸。该制备方法环境友好、成本低、操作条件易于控制，适合工业化生产。
本发明提供的一种6-氟烟酸的制备方法，包括如下操作步骤：
第一步，将有机溶剂A、催化剂和2,5-二溴吡啶混合，与异丙基氯化镁溶液选择性格氏交换后，与氯甲酸酯或Boc2O反应得到6-溴烟酸酯；
第二步，向无水四甲基氟化铵加入有机溶剂B和6-溴烟酸酯，升温至40-50℃反应，减压蒸出有机溶剂B，滴加酸性或碱性溶液，处理得到6-氟烟酸。
采用方程式表示如下：
进一步地，所述第一步中，有机溶剂A选自四氢呋喃、2-甲基四氢呋喃或环戊基甲基醚。
进一步地，所述第一步中，催化剂选自溴化亚铜或碘化亚铜。
进一步地，所述第一步中，2,5-二溴吡啶、异丙基氯化镁、催化剂与氯甲酸酯/Boc2O摩尔比为1:1.2-1.4:0.03-0.05:1.1-1.4。
进一步地，所述第一步中，氯甲酸酯选自氯甲酸甲酯、氯甲酸乙酯、氯甲酸异丙酯、氯甲酸叔丁酯。
进一步地，所述第二步中，6-溴烟酸酯与四甲基氟化铵摩尔比为1.0:2.0-2.2。
进一步地，所述第二步中，当6-溴烟酸酯为6-溴烟酸甲酯、6-溴烟酸乙酯或6-溴烟酸异丙酯，滴加碱性水溶液进行水解，其中碱性溶液选自氢氧化钾溶液或氢氧化钠溶液，滴毕，室温搅拌3-4小时，中控水解完全，滴加盐酸调pH＝3-4，过滤得到白色固体6-氟烟酸。
进一步地，所述第二步中，当6-溴烟酸酯为6-溴烟酸叔丁酯，滴加盐酸进行水解，滴毕，室温搅拌5-6小时，中控水解完全，过滤得到白色固体6-氟烟酸。
进一步地，所述第二步中，有机溶剂B选自DMF或DMSO。
第一步地，所述第二步中，无水四甲基氟化铵操作为，将四甲基氟化铵加入甲苯，所得溶液加热至回流，利用分水器常压分出氟化试剂中水分，直至混合液含水＜300ppm，降温，减压蒸出甲苯。
本发明具有以下优势：
1、所用物料廉价易得，避免了使用高锰酸钾氧化时产生大量二氧化锰重金属废固。
2、采用2,5-二溴吡啶与异丙基格氏试剂交换后，与氯甲酸酯在催化剂作用下可高选择性的得到6-溴烟酸酯。
3、该方法反应条件温和，操作简便，安全可控；具有成本和路线优势、产能高、质量稳定，适合工业化放大生产。
附图说明
图1为实施例1中6-氟烟酸的氢谱核磁谱图；
具体实施例
实施例1
第一步，氮气保护下，向反应瓶中加入400mL四氢呋喃和2,5-二溴吡啶(59.2g，0.25mol)，控温-10～0℃下滴加异丙基氯化镁的四氢呋喃溶液(2.0M，150mL，0.30mol)，滴毕保温反应3小时，HPLC中控原料2,5-二溴吡啶＜0.5％，保温下继续加入碘化亚铜(1.43g，7.5mmol)，然后滴加氯甲酸甲酯(28.4g，0.30mol)，滴毕，室温搅拌1小时，HPLC中控中间体反应完全，6-溴烟酸甲酯88.6％、异构体5-溴吡啶-2-羧酸甲酯7.2％，0～10℃下滴加3MHCl调体系pH＝3-4，加入乙酸乙酯萃取(200mL×3)，有机层合并，饱和食盐水洗，有机层减压浓缩，加入100mL正庚烷/甲基叔丁基醚(体积比6/1)打浆，过滤得类白色固体6-溴烟酸甲酯42.9g，HPLC:97.1％，收率79.3％，LC-MS(m/z)217.0(M+H+)。
第二步，向反应瓶中加入200mL甲苯和四甲基氟化铵(37.2g，0.40mol)，加热至回流，利用分水器分出少量水至反应瓶内液体含水＜300ppm，降温，减压浓缩出甲苯。加入6-溴烟酸甲酯(42.9g，0.20mol)和300mL DMF，升温至40-50℃反应16小时，HPLC中控原料反应完全，降至室温，减压蒸出DMF，20-30℃下滴加60g 30％NaOH溶液，滴毕，室温搅拌3小时，HPLC中控水解完全，6-氟烟酸钠94.6％、6-羟基烟酸钠5.0％，滴加20％盐酸调pH＝3-4，过滤，滤饼用60mL水淋洗，真空干燥得白色固体6-氟烟酸24.1g，HPLC:98.0％，收率85.6％，mp:146.1-148.2℃，LC-MS(m/z)142.1(M+H+)。1H-NMR表征图谱如图1所示。
实施例2
第一步，氮气保护下，向反应瓶中加入400mL2-甲基四氢呋喃和2,5-二溴吡啶(59.2g，0.25mol)，控温-10～0℃下滴加异丙基氯化镁的四氢呋喃溶液(2.0M，162.5mL，0.32mol)，滴毕保温反应3小时，HPLC中控原料2,5-二溴吡啶＜0.5％，保温下加入溴化亚铜(1.79g，12.5mmol)，然后滴加氯甲酸乙酯(34.7g，0.32mol)，滴毕，室温搅拌1小时，HPLC中控中间体反应完全，6-溴烟酸乙酯89.4％、异构体5-溴吡啶-2-羧酸乙酯6.6％，0～10℃下滴加3M HCl调体系pH＝3-4，加入乙酸乙酯萃取(200mL×3)，有机层合并，饱和食盐水洗，有机层减压浓缩，加入100mL正庚烷/甲基叔丁基醚(体积比6/1)打浆，过滤得类白色固体6-溴烟酸乙酯45.9g，HPLC:97.3％，收率79.9％，LC-MS(m/z)231.0(M+H+)。
第二步，向反应瓶中加入200mL甲苯和四甲基氟化铵(41.0g，0.44mol)，加热至回流，利用分水器分出少量水至反应瓶内液体含水＜300ppm，降温，减压浓缩出甲苯。加入6-溴烟酸乙酯(45.9g，0.20mol)和300mL DMF，40-50℃反应16小时，HPLC中控原料反应完全，降至室温，减压蒸出DMF，20-30℃下滴加60g 30％NaOH溶液，滴毕，室温搅拌3小时，HPLC中控水解完全，6-氟烟酸钠94.1％、6-羟基烟酸钠5.7％，滴加20％盐酸调pH＝3-4，过滤，滤饼用60mL水淋洗，真空干燥得白色固体6-氟烟酸23.7g，HPLC:97.7％，收率84.1％，mp:146.5-148.9℃，LC-MS(m/z)142.1(M+H+)。1H-NMR(DMSO-d6,400MHz)与标准图谱一致。
实施例3
第一步，氮气保护下，向反应瓶中加入400mL环戊基甲基醚和2,5-二溴吡啶(59.2g，0.25mol)，控温-10～0℃下滴加异丙基氯化镁的四氢呋喃溶液(2.0M，175mL，0.35mol)，滴毕保温反应3小时，HPLC中控原料2,5-二溴吡啶＜0.5％，保温下加入溴化亚铜(1.79g，12.5mmol)，然后滴加氯甲酸异丙酯(42.9g，0.35mol)，滴毕，室温搅拌1小时，HPLC中控中间体反应完全，6-溴烟酸异丙酯91.5％、异构体5-溴吡啶-2-羧酸异丙酯4.7％，0～10℃下滴加3M HCl调体系pH值3-4，加入乙酸乙酯萃取(200mL×3)，有机层合并，饱和食盐水洗，有机层减压浓缩，加入100mL正庚烷/甲基叔丁基醚(体积比6/1)打浆，过滤得类白色固体6-溴烟酸异丙酯50.8g，HPLC:98.2％，收率83.3％，LC-MS(m/z)245.0(M+H+)。
第二步，向反应瓶中加入200mL甲苯和四甲基氟化铵(40.7g，0.437mol)，加热至回流，利用分水器分出少量水至反应瓶内液体含水＜300ppm，降温减压浓缩甲苯。加入6-溴烟酸异丙酯(50.8g，0.208mol)和300mL DMF，升温至40-50℃反应16小时，HPLC中控原料反应完全，降至室温，减压蒸出DMF，20-30℃下滴加60g 30％NaOH溶液，滴毕，室温搅拌4小时，HPLC中控水解完全，6-氟烟酸钠90.1％、6-羟基烟酸钠8.7％，滴加20％盐酸调pH＝3-4，过滤，滤饼用60mL水淋洗，真空干燥得白色固体6-氟烟酸23.0g，HPLC:96.9％，收率78.5％，mp:146.5-148.9℃，LC-MS(m/z)142.1(M+H+)。1H-NMR(DMSO-d6,400MHz)与标准图谱一致。
实施例4
第一步，氮气保护下，向反应瓶中加入400mL四氢呋喃和2,5-二溴吡啶(59.2g，0.25mol)，控温-10～0℃下滴加异丙基氯化镁的四氢呋喃溶液(2.0M，162.5mL，0.325mol)，滴毕保温反应3小时，HPLC中控原料2,5-二溴吡啶＜0.5％，保温下加入碘化亚铜(1.43g，7.5mmol)，然后滴加Boc2O(60.0g，0.275mol)的四氢呋喃溶液60mL，滴毕，室温搅拌1小时，HPLC中控中间体反应完全，6-溴烟酸叔丁酯93.7％、异构体5-溴吡啶-2-羧酸叔丁酯2.9％，0～10℃下滴加3M HCl调体系pH＝3-4，加入乙酸乙酯萃取(200mL×3)，有机层合并，饱和食盐水洗，有机层减压浓缩，加入100mL正庚烷/甲基叔丁基醚(体积比6/1)打浆，过滤得类白色固体6-溴烟酸叔丁酯55.1g，HPLC:98.8％，收率85.4％，LC-MS(m/z)259.1(M+H+)。
第二步，向反应瓶中加入200mL甲苯和四甲基氟化铵(39.7g，0.426mol)，加热至回流，利用分水器分出少量水至反应瓶内液体含水＜300ppm，降温，减压浓缩出甲苯。加入6-溴烟酸叔丁酯(55.1g，0.213mol)和300mL DMF，升温至40-50℃反应16小时，HPLC中控原料反应完全，降至室温，减压蒸出DMF，20-30℃下滴加50g 20％HCl溶液调pH＝1-2，滴毕，室温搅拌5小时，HPLC中控水解完全，6-氟烟酸98.0％，过滤，滤饼用60mL水淋洗，真空干燥得白色固体6-氟烟酸27.2g，HPLC:99.4％，收率90.6％，mp:146.1-147.3℃，LC-MS(m/z)142.1(M+H+)。1H-NMR(DMSO-d6,400MHz)与标准图谱一致。
实施例5
第一步，氮气保护下，向反应瓶中加入400mL四氢呋喃和2,5-二溴吡啶(59.2g，0.25mol)，控温-10～0℃下滴加异丙基氯化镁的四氢呋喃溶液(2.0M，162.5mL，0.325mol)，滴毕保温反应3小时，HPLC中控原料2,5-二溴吡啶＜0.5％，保温下滴加Boc2O(60.0g，0.275mol)的四氢呋喃溶液，滴毕，室温搅拌1小时，HPLC中控中间体反应完全，6-溴烟酸叔丁酯75.9％、异构体5-溴吡啶-2-羧酸叔丁酯20.3％，0～10℃下滴加3M HCl调体系pH＝3-4，加入乙酸乙酯萃取(200mL×3)，有机层合并，饱和食盐水洗，有机层减压浓缩，加入100mL正庚烷/甲基叔丁基醚(体积比6/1)打浆，过滤得类白色固体6-溴烟酸叔丁酯41.0g，HPLC:95.3％，收率63.6％，LC-MS(m/z)259.1(M+H+)。
第二步，向反应瓶中加入200mL甲苯和四甲基氟化铵(29.6g，0.318mol)，加热至回流，利用分水器分出少量水至反应瓶内液体含水＜300ppm，降温，减压浓缩出甲苯。加入上步所得6-溴烟酸叔丁酯(41.0g，0.159mol)和300mL DMF，升温至40-50℃反应16小时，HPLC中控原料反应完全，降至室温，减压蒸出DMF，20-30℃下滴加36g20％HCl溶液调pH＝1-2，滴毕，室温搅拌5小时，HPLC中控水解完全，6-氟烟酸96.1％，过滤，滤饼用60mL水淋洗，真空干燥得白色固体6-氟烟酸19.9g，HPLC:98.5％，收率88.7％，mp:146.1-147.3℃，LC-MS(m/z)142.1(M+H+)。1H-NMR(DMSO-d6,400MHz)与标准图谱一致。
以上显示和描述了本发明的基本原理和主要特征和本发明的优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明精神和范围的前提下，本发明还会有各种变化和改进，这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (10)
1.一种6-氟烟酸的制备方法，其特征在于，包括如下步骤：
第一步，将有机溶剂A、催化剂和2,5-二溴吡啶混合，与异丙基氯化镁溶液选择性格氏交换后，与氯甲酸酯或Boc2O反应得到6-溴烟酸酯；
第二步，向无水四甲基氟化铵加入有机溶剂B和6-溴烟酸酯，升温至40-50℃反应，减压蒸出有机溶剂B，滴加酸性或碱性溶液，处理得到6-氟烟酸。
2.根据权利要求1所述6-氟烟酸的制备方法，其特征在于：所述第一步中，有机溶剂A选自四氢呋喃、2-甲基四氢呋喃或环戊基甲基醚。
3.根据权利要求1所述6-氟烟酸的制备方法，其特征在于：所述第一步中，催化剂选自溴化亚铜或碘化亚铜。
4.根据权利要求1所述6-氟烟酸制备方法，其特征在于：所述第一步中，2,5-二溴吡啶、异丙基氯化镁、催化剂与氯甲酸酯/Boc2O摩尔比为1:1.2-1.4:0.03-0.05:1.1-1.4。
5.根据权利要求1所述6-氟烟酸的制备方法，其特征在于：所述第一步中，氯甲酸酯选自氯甲酸甲酯、氯甲酸乙酯、氯甲酸异丙酯或氯甲酸叔丁酯。
6.根据权利要求1所述6-氟烟酸的制备方法，其特征在于：所述第二步中，6-溴烟酸酯与四甲基氟化铵摩尔比为1.0:2.0-2.2。
7.根据权利要求1所述6-氟烟酸的制备方法，其特征在于：所述第二步中，所述6-溴烟酸酯选自6-溴烟酸甲酯、6-溴烟酸乙酯或6-溴烟酸异丙酯，滴加碱性水溶液进行水解，其中碱性水溶液选自氢氧化钾溶液或氢氧化钠溶液，滴毕，室温搅拌3-4小时，中控水解完全，滴加盐酸调pH＝3-4，过滤得到6-氟烟酸。
8.根据权利要求1所述6-氟烟酸的制备方法，其特征在于：所述第二步中，所述6-溴烟酸酯选自6-溴烟酸叔丁酯，滴加盐酸进行水解，滴毕，室温搅拌5-6小时，中控水解完全，过滤得到6-氟烟酸。
9.根据权利要求1所述6-氟烟酸的制备方法，其特征在于：所述第二步中，有机溶剂B选自DMF或DMSO。
10.根据权利要求1-9任意一项所述6-氟烟酸的制备方法，其特征在于：所述第二步中，无水四甲基氟化铵操作为，将四甲基氟化铵加入甲苯，所得溶液加热至回流，利用分水器常压分出氟化试剂中水分，直至混合液含水＜300ppm，降温，减压蒸出甲苯。
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108026042A (zh) * | 2015-08-04 | 2018-05-11 | 美国陶氏益农公司 | 用于使化合物氟化的方法 |
| CN112088157A (zh) * | 2017-12-22 | 2020-12-15 | 拉文纳制药公司 | 作为磷脂酰肌醇磷酸激酶抑制剂的芳基-联吡啶胺衍生物 |
-
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108026042A (zh) * | 2015-08-04 | 2018-05-11 | 美国陶氏益农公司 | 用于使化合物氟化的方法 |
| CN112088157A (zh) * | 2017-12-22 | 2020-12-15 | 拉文纳制药公司 | 作为磷脂酰肌醇磷酸激酶抑制剂的芳基-联吡啶胺衍生物 |
Non-Patent Citations (2)
| Title |
|---|
| HONGMEI LI等: "Highly selective and efficient conversion of aryl bromides to t-butyl benzoates with di-t-butyl dicarbonate", TETRAHEDRON LETTERS, vol. 49, pages 2034 - 2037, XP022492104, DOI: 10.1016/j.tetlet.2007.12.134 * |
| SYDONIE D. SCHIMLER等: "Anhydrous Tetramethylammonium Fluoride for Room-Temperature SNAr Fluorination", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 80, pages 12137 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| CN117486728B (zh) * | 2023-12-28 | 2024-05-17 | 山东国邦药业有限公司 | 一种高效循环的氟化试剂及其制备方法与应用 |
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