CN113801152A - 3-羧基-5-羟基苯硼酸的合成方法 - Google Patents
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- 238000000034 method Methods 0.000 title claims abstract description 17
- 230000002194 synthesizing effect Effects 0.000 title claims description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 22
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 16
- 239000007864 aqueous solution Substances 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 9
- 238000005271 boronizing Methods 0.000 claims abstract description 8
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims abstract description 8
- 239000004327 boric acid Substances 0.000 claims abstract description 7
- QLIWJQBBIUBTOY-UHFFFAOYSA-M sodium;benzoate;dihydrate Chemical compound O.O.[Na+].[O-]C(=O)C1=CC=CC=C1 QLIWJQBBIUBTOY-UHFFFAOYSA-M 0.000 claims abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 4
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- TYMXGALTCIVHQY-UHFFFAOYSA-N ethyl 3,5-dibromobenzoate Chemical compound CCOC(=O)C1=CC(Br)=CC(Br)=C1 TYMXGALTCIVHQY-UHFFFAOYSA-N 0.000 claims abstract description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- HXITXNWTGFUOAU-UHFFFAOYSA-N dihydroxy-phenylborane Natural products OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 9
- SFTFNJZWZHASAQ-UHFFFAOYSA-N 3,5-dibromobenzoic acid Chemical compound OC(=O)C1=CC(Br)=CC(Br)=C1 SFTFNJZWZHASAQ-UHFFFAOYSA-N 0.000 claims description 8
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 8
- GSMAWUZTAIOCPL-UHFFFAOYSA-N methyl 3,5-dibromobenzoate Chemical group COC(=O)C1=CC(Br)=CC(Br)=C1 GSMAWUZTAIOCPL-UHFFFAOYSA-N 0.000 claims description 5
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 4
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 3
- LGQXXHMEBUOXRP-UHFFFAOYSA-N tributyl borate Chemical compound CCCCOB(OCCCC)OCCCC LGQXXHMEBUOXRP-UHFFFAOYSA-N 0.000 claims description 3
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical group COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 claims description 3
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 claims description 3
- CWBLIPMCDMSOFX-UHFFFAOYSA-N 3-borono-5-bromobenzoic acid Chemical compound OB(O)C1=CC(Br)=CC(C(O)=O)=C1 CWBLIPMCDMSOFX-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000012973 diazabicyclooctane Substances 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract description 4
- 238000010511 deprotection reaction Methods 0.000 abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 3
- 238000010189 synthetic method Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 238000001816 cooling Methods 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- CJSWOALHLRQFNX-UHFFFAOYSA-N (3-bromo-5-methoxycarbonylphenyl)boronic acid Chemical compound COC(=O)C1=CC(Br)=CC(B(O)O)=C1 CJSWOALHLRQFNX-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- ALMQNZNREIHKET-UHFFFAOYSA-N benzoic acid;dihydrate Chemical compound O.O.OC(=O)C1=CC=CC=C1 ALMQNZNREIHKET-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- -1 phenylboronic acid compound Chemical class 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- DKSMCEUSSQTGBK-UHFFFAOYSA-M bromite Chemical compound [O-]Br=O DKSMCEUSSQTGBK-UHFFFAOYSA-M 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- KNUQTRXBSGKILE-UHFFFAOYSA-N (3-bromo-5-ethoxycarbonylphenyl)boronic acid Chemical compound CCOC(=O)C1=CC(Br)=CC(B(O)O)=C1 KNUQTRXBSGKILE-UHFFFAOYSA-N 0.000 description 1
- OWIKHYCFFJSOEH-UHFFFAOYSA-N Isocyanic acid Chemical compound N=C=O OWIKHYCFFJSOEH-UHFFFAOYSA-N 0.000 description 1
- 238000003109 Karl Fischer titration Methods 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- MLJXWZIVGBBOQZ-UHFFFAOYSA-N bromoimino(oxo)methane Chemical compound BrN=C=O MLJXWZIVGBBOQZ-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000007336 electrophilic substitution reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
本发明公开了一种3‑羧基‑5‑羟基苯硼酸的合成方法,属于医药中间体技术领域。采用3,5‑二溴苯甲酸甲或乙酯为原料与硼化试剂和正丁基锂反应得到3‑溴‑5‑甲/乙氧羰基苯硼酸;接着与无机碱水解得到3‑溴‑5‑硼酸苯甲酸钠二水合物;最后在催化剂作用下与碳酸钠水溶液反应得到3‑羧基‑5‑羟基苯硼酸。本工艺路线原料易得,避免对各个基团的保护与脱保护,反应步骤短,收率高,产品纯度高达99.8%。
Description
技术领域
本发明涉及3-羧基-5-羟基苯硼酸的合成方法,属于有机合成技术领域。
背景技术
苯硼酸类化合物是一种重要的有机中间体,主要用于Suzuki偶联反应来合成含C-O键、C-N键、C-S键结构的联芳烃化合物,该类化合物是许多催化剂配体、功能材料、精细化工品以及医药中间体的重要组成单元,其发挥越来越重要的作用,具有广泛应用的价值。
其中3-羧基-5-羟基苯硼酸是苯硼酸的一个重要的衍生物,是近年来发现的重要医药中间体。目前关于3-羧基-5-羟基苯硼酸的合成方法未见报道。
本申请开发了合理的工艺路线,以适合工业化放大规模的方法。
发明内容
为了克服上述技术缺陷,本发明公开了一种3-羧基-5-羟基苯硼酸的合成方法。采用3,5-二溴苯甲酸酯为原料与硼化试剂和正丁基锂在深冷条件下一锅法得到3-溴-5-甲/乙氧羰基苯硼酸。随后与无机碱水解得到3-溴-5-硼酸苯甲酸钠二水合物。最后在催化剂催化作用下与碳酸钠水溶液反应得到3-羧基-5-羟基苯硼酸。本工艺路线原料易得,避免对各个基团的保护与脱保护,反应步骤短,收率高,产品纯度高达99.8%。
本发明所述一种3-羧基-5-羟基苯硼酸的合成方法,包括如下步骤:
第一步、采用3,5-二溴苯甲酸酯为原料与硼化试剂和正丁基锂反应得到3-溴-5-甲/乙氧羰基苯硼酸;
第二步、3-溴-5-烷氧羰基苯硼酸与无机碱水解得到3-溴-5-硼酸苯甲酸钠二水合物;
第三步、3-溴-5-硼酸苯甲酸钠二水合物在催化剂催化作用下与碳酸钠水溶液反应得到3-羧基-5-羟基苯硼酸。
反应方程式如下:
进一步地,在上述技术方案中,3,5-二溴苯甲酸酯选自3,5-二溴苯甲酸甲酯或3,5-二溴苯甲酸乙酯;硼化试剂选自硼酸三甲酯、硼酸三异丙酯或硼酸三正丁酯,R1选自甲基或乙基,R2选自甲基、异丙基与正丁基。
进一步地,在上述技术方案中,第一步反应,所述3,5-二溴苯甲酸酯、硼化试剂与正丁基锂摩尔比为1:1.1-1.2:1.05-1.10。
进一步地,在上述技术方案中,第二步反应,所述无机碱选自氢氧化钠或氢氧化锂。
进一步地,在上述技术方案中,第二步反应,3-溴-5-甲/乙氧羰基)苯基硼酸与无机碱摩尔比为1:1.0-1.05。
进一步地,在上述技术方案中,第三步反应,所述催化剂选自DABCO三乙烯二胺与溴化亚铜或者反式环己二甲胺与溴化亚铜组合。
进一步地,在上述技术方案中,第三步反应,所述3-溴-5-羧基苯硼酸、碳酸钠与催化剂摩尔比为1:1.5-1.6:0.02:0.05。
发明有益效果
本发明中采用市场上常见原料3,5-二溴苯甲酸酯,采用正丁基锂选择性拔除一个溴,相比较苯环上的羰基与溴,正丁基锂率先与溴核取代,采用一锅法大大减少了与羰基反应的情况,从而合成硼酸收率更高(70%-80%)。采用配体方法对溴进行亲电取代,避免溴在碱性条件下脱离,并且大大减少反应时间。避免在硼化时对各个基团的保护及最后脱保护,步骤短,反应连续。
具体实施例
实施例1
氮气保护下,反应瓶内投入3,5-二溴苯甲酸甲酯30g(0.102mol)、硼酸三甲酯12.7g(0.122mol)和四氢呋喃160mL。降温至-78℃,滴加2.5M正丁基锂/正已烷溶液45mL,滴加结束后升温至-70~-60℃反应2小时,自然升温至0℃,加入5%盐酸水溶液淬灭,分层,保留有机相,水相用100mL乙酸乙酯萃取,有机相合并,35-45℃减压浓缩至不流液,加入80mL正庚烷,降温至10-15℃,析出大量固体,过滤,滤饼烘干得到3-溴-5-甲氧羰基苯硼酸18.9g,HPLC 95.3%,收率71.7%。1HNMR(400MHz,DMSO-d6)δ:3.89(s,3H),6.10(s,2H),7.71(s,1H),7.98(s,1H),8.19(s,1H).
实施例2
氮气保护下,反应瓶内投入3,5-二溴苯甲酸甲酯30g(0.102mol)、硼酸三异丙酯22.1g(0.117mol)和四氢呋喃160mL。降温至-78℃,滴加2.5M正丁基锂溶液45mL,滴加结束后升温至-70~-60℃反应2小时,自然升温至0℃,加入5%盐酸水溶液淬灭,分层,保留有机相,水相用100mL乙酸乙酯萃取,有机相合并,35-45℃减压浓缩至不流液,加入80mL正庚烷,降温至10-15℃,析出大量固体,过滤滤饼烘干得到3-溴-5-甲氧羰基苯硼酸20.6g,HPLC97.4%,收率77.8%。
实施例3
氮气保护下,反应瓶内投入3,5-二溴苯甲酸甲酯30g(0.097mol)、硼酸三正丁酯24.7g(0.107mol)和四氢呋喃160mL。降温至-78℃,滴加2.5M正丁基锂溶液41mL,滴加结束后升温至-70~-60℃反应2小时,自然升温至0℃,加入5%盐酸水溶液淬灭,分层,保留有机相,水相用100mL乙酸乙酯萃取,有机相合并,35-45℃减压浓缩至不流液,加入80mL正庚烷,降温至10-15℃,析出大量固体,过滤,滤饼烘干得到3-溴-5-乙氧羰基苯硼酸20.6g,HPLC98.2%,收率80.1%。1HNMR(400MHz,DMSO-d6)δ:1.30(m,3H),4.30(m,2H),6.07(s,2H),7.70(s,1H),7.97(s,1H),8.19(s,1H).
实施例4
氮气保护下,反应瓶内投入3-溴-5-甲氧羰基苯硼酸25.9g(0.1mol)和甲醇80g。控制温度在15-20℃范围内滴加20%氢氧化锂水溶液12.6g(0.105mol),反应6小时,TLC原料无剩余,35-45℃减压浓缩至不流液,加入30mL丙酮,降温至0-5℃,大量固体析出,过滤,滤饼烘干得到3-溴-5-硼酸苯甲酸钠二水合物28.2g(采用卡尔费休滴定含水判断),HPLC98.9%,收率93.1%。1HNMR(400MHz,DMSO-d6)δ:5.89(s,2H),7.84(s,1H),8.14(s,1H),8.35(s,1H).
实施例5
氮气保护下,反应瓶内投入3-溴-5-甲氧羰基苯硼酸25.9g(0.1mol)和乙醇80g。控制温度在15-20℃范围内滴加30%氢氧化钠水溶液13.4g(0.1mol),反应6小时,TLC原料几乎无剩余,35-45℃减压浓缩至不流液,加入30mL丙酮,降温至0-5℃,有大量固体,过滤,滤饼烘干得到3-溴-5-硼酸苯甲酸钠二水合物27.4g,HPLC 99.1%,收率90.4%。
实施例6
氮气保护下,反应瓶内投入3-溴-5-硼酸苯甲酸钠二水合物30.3g(0.1mol)和120g去离子水。控制温度在15-20℃范围内滴加20%碳酸钠水溶液79.5g(0.15mol),物料完全溶解后,加入溴化亚酮0.72g(0.005mol)和三乙烯二胺0.56g(0.005mol),升温至80-83℃,反应14小时,HPLC原料剩余0.5%,降温至20℃,滴加浓盐酸调节pH=1.0,加入180mL乙酸乙酯萃取,分层,水相再用100mL乙酸乙酯萃取,合并有机相,减压浓缩至不流液,加入正庚烷,降温过滤,滤饼重新投入反应瓶内,加入40%甲醇水溶液升温至回流并溶清,加入1.5g活性炭,搅拌2小时,趁热过滤,滤液缓慢降温至10-15℃,过滤,滤饼用冷的20%甲醇水溶液漂洗,得到3-羧基-5-羟基苯硼酸14.6g,HPLC99.8%,收率80.3%。1HNMR(400MHz,DMSO-d6)δ:5.93(s,2H),7.14(s,1H),7.52(s,1H),7.76(s,1H),9.45(s,1H),12.74(s,1H).
实施例7
氮气保护下,反应瓶内投入3-溴-5-硼酸苯甲酸钠二水合物30.3g(0.1mol)和120g去离子水。控制温度在15-20℃范围内滴加20%碳酸钠水溶液79.5g(0.15mol),物料完全溶解后,加入溴化亚酮0.29g(0.002mol)和反式环已二甲胺0.29g(0.002mol),升温至7075℃,反应9小时,HPLC原料剩余0.6%,降温至20℃,滴加浓盐酸调节pH=1.0,加入180mL乙酸乙酯萃取,分层,水相再用100mL乙酸乙酯萃取,合并有机相,减压浓缩至不流液,加入正庚烷,降温过滤,滤饼重新投入反应瓶内,加入40%甲醇水溶液升温至回流并溶清,加入1.5g活性炭,搅拌2小时,趁热过滤,滤液缓慢降温至10-15℃,过滤,滤饼用冷的20%甲醇水溶液漂洗,得到3-羧基-5-羟基苯硼酸15.4g,HPLC99.8%,收率84.8%。
以上所述,仅为本发明较佳的具体实施方式,但本发明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披露的技术范围内,根据本发明的技术方案及其发明构思加以等同替换或改变,都应涵盖在本发明的保护范围之内。
Claims (7)
1.一种3-羧基-5-羟基苯硼酸的合成方法,其特征在于,包括如下步骤:
第一步、采用3,5-二溴苯甲酸酯为原料与硼化试剂和正丁基锂反应得到3-溴-5-甲/乙氧羰基苯硼酸;
第二步、3-溴-5-烷氧羰基苯硼酸与无机碱水解得到3-溴-5-硼酸苯甲酸钠二水合物;
第三步、3-溴-5-硼酸苯甲酸钠二水合物在催化剂催化作用下与碳酸钠水溶液反应得到3-羧基-5-羟基苯硼酸。
2.根据权利要求1所述3-羧基-5-羟基苯硼酸的合成方法,其特征在于:所述3,5-二溴苯甲酸酯选自3,5-二溴苯甲酸甲酯或3,5-二溴苯甲酸乙酯;硼化试剂选自硼酸三甲酯、硼酸三异丙酯或硼酸三正丁酯。
3.根据权利要求1所述3-羧基-5-羟基苯硼酸的合成方法,其特征在于:第一步反应,所述3,5-二溴苯甲酸酯、硼化试剂与正丁基锂摩尔比为1:1.1-1.2:1.05-1.10。
4.根据权利要求1所述3-羧基-5-羟基苯硼酸的合成方法,其特征在于:第二步反应,所述无机碱选自氢氧化钠或氢氧化锂。
5.根据权利要求1所述3-羧基-5-羟基苯硼酸的合成方法,其特征在于:第二步反应,3-溴-5-甲/乙氧羰基)苯基硼酸与无机碱摩尔比为1:1.0-1.05。
6.根据权利要求1所述3-羧基-5-羟基苯硼酸的合成方法,其特征在于:第三步反应,所述催化剂选自DABCO三乙烯二胺与溴化亚铜或者反式环己二甲胺与溴化亚铜组合。
7.根据权利要求1所述3-羧基-5-羟基苯硼酸的合成方法,其特征在于:第三步反应,所述3-溴-5-羧基苯硼酸、碳酸钠与催化剂摩尔比为1:1.5-1.6:0.02:0.05。
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Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050267071A1 (en) * | 2003-10-31 | 2005-12-01 | Fulcrum Pharmaceuticals, Inc. | Inhibitors of coronavirus protease and methods of use thereof |
CN101092333A (zh) * | 2007-07-05 | 2007-12-26 | 江苏工业学院 | 一种间苯二酚的制备方法 |
US20080280891A1 (en) * | 2006-06-27 | 2008-11-13 | Locus Pharmaceuticals, Inc. | Anti-cancer agents and uses thereof |
CN101541732A (zh) * | 2006-11-28 | 2009-09-23 | 纳幕尔杜邦公司 | 合成2,5-二羟基对苯二甲酸的方法 |
CN101541735A (zh) * | 2006-11-28 | 2009-09-23 | 纳幕尔杜邦公司 | 合成2,5-二羟基对苯二甲酸的方法 |
US20100093698A1 (en) * | 2008-09-08 | 2010-04-15 | Sogole Bahmanyar | Aminotriazolopyridines, compositions thereof, and methods of treatment therewith |
CN103254039A (zh) * | 2013-06-08 | 2013-08-21 | 济南卡博唐生物科技有限公司 | 一种邻甲酚的制备方法 |
CN111171062A (zh) * | 2020-01-07 | 2020-05-19 | 大连双硼医药化工有限公司 | 一种合成2-羧基苯硼酸钠的方法 |
CN111978139A (zh) * | 2020-09-04 | 2020-11-24 | 许昌学院 | 一种水相中光催化一锅法合成苯酚或其衍生物的方法 |
-
2021
- 2021-08-30 CN CN202111006565.7A patent/CN113801152B/zh active Active
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050267071A1 (en) * | 2003-10-31 | 2005-12-01 | Fulcrum Pharmaceuticals, Inc. | Inhibitors of coronavirus protease and methods of use thereof |
US20080280891A1 (en) * | 2006-06-27 | 2008-11-13 | Locus Pharmaceuticals, Inc. | Anti-cancer agents and uses thereof |
CN101541732A (zh) * | 2006-11-28 | 2009-09-23 | 纳幕尔杜邦公司 | 合成2,5-二羟基对苯二甲酸的方法 |
CN101541735A (zh) * | 2006-11-28 | 2009-09-23 | 纳幕尔杜邦公司 | 合成2,5-二羟基对苯二甲酸的方法 |
CN101092333A (zh) * | 2007-07-05 | 2007-12-26 | 江苏工业学院 | 一种间苯二酚的制备方法 |
US20100093698A1 (en) * | 2008-09-08 | 2010-04-15 | Sogole Bahmanyar | Aminotriazolopyridines, compositions thereof, and methods of treatment therewith |
CN103254039A (zh) * | 2013-06-08 | 2013-08-21 | 济南卡博唐生物科技有限公司 | 一种邻甲酚的制备方法 |
CN111171062A (zh) * | 2020-01-07 | 2020-05-19 | 大连双硼医药化工有限公司 | 一种合成2-羧基苯硼酸钠的方法 |
CN111978139A (zh) * | 2020-09-04 | 2020-11-24 | 许昌学院 | 一种水相中光催化一锅法合成苯酚或其衍生物的方法 |
Non-Patent Citations (1)
Title |
---|
MANOJ M. JADHAV 等: "Unfolding ESIPT in Bis-2, 5-(2-benzoxazolyl) Hydroquinone and 2, 5-Bis(benzo[d]oxazol-2-yl)-4-methoxyphenol:a Comprehensive Computational Approach", 《J FLUORESC》, vol. 26, pages 1296 * |
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