CN115124410A - 一种2-氟-4-羟基苯甲醛的制备方法 - Google Patents
一种2-氟-4-羟基苯甲醛的制备方法 Download PDFInfo
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- ONRPXRPUBXXCCM-UHFFFAOYSA-N 2-fluoro-4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C(F)=C1 ONRPXRPUBXXCCM-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 14
- SJTBRFHBXDZMPS-UHFFFAOYSA-N 3-fluorophenol Chemical compound OC1=CC=CC(F)=C1 SJTBRFHBXDZMPS-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000005893 bromination reaction Methods 0.000 claims abstract description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 7
- 230000031709 bromination Effects 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- AKLUAOGEXFDAFW-UHFFFAOYSA-N 1-bromo-2-fluoro-4-propan-2-yloxybenzene Chemical compound CC(C)OC1=CC=C(Br)C(F)=C1 AKLUAOGEXFDAFW-UHFFFAOYSA-N 0.000 claims description 10
- INDGWZOOYLDIPO-UHFFFAOYSA-N 1-fluoro-3-propan-2-yloxybenzene Chemical compound CC(C)OC1=CC=CC(F)=C1 INDGWZOOYLDIPO-UHFFFAOYSA-N 0.000 claims description 10
- RJOOMVDJWKWFDU-UHFFFAOYSA-N 2-fluoro-4-propan-2-yloxybenzaldehyde Chemical compound CC(C)OC1=CC=C(C=O)C(F)=C1 RJOOMVDJWKWFDU-UHFFFAOYSA-N 0.000 claims description 9
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 claims description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical group ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 6
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- SFLXUZPXEWWQNH-UHFFFAOYSA-K tetrabutylazanium;tribromide Chemical group [Br-].[Br-].[Br-].CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC SFLXUZPXEWWQNH-UHFFFAOYSA-K 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 4
- JQRYUMGHOUYJFW-UHFFFAOYSA-N pyridine;trihydrobromide Chemical compound [Br-].[Br-].[Br-].C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1 JQRYUMGHOUYJFW-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 2
- 239000002994 raw material Substances 0.000 abstract description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 9
- 238000010511 deprotection reaction Methods 0.000 abstract description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 abstract description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 abstract description 5
- 125000006239 protecting group Chemical group 0.000 abstract description 5
- 238000000746 purification Methods 0.000 abstract description 4
- 238000012216 screening Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 150000001299 aldehydes Chemical class 0.000 abstract description 3
- 239000007818 Grignard reagent Substances 0.000 abstract description 2
- 150000004795 grignard reagents Chemical group 0.000 abstract description 2
- 239000012074 organic phase Substances 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 239000005457 ice water Substances 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 229940060037 fluorine Drugs 0.000 description 4
- 235000019000 fluorine Nutrition 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- UWWCZZMOTBWUAB-UHFFFAOYSA-N 1-ethoxy-3-fluorobenzene Chemical compound CCOC1=CC=CC(F)=C1 UWWCZZMOTBWUAB-UHFFFAOYSA-N 0.000 description 2
- MFJNOXOAIFNSBX-UHFFFAOYSA-N 1-fluoro-3-methoxybenzene Chemical compound COC1=CC=CC(F)=C1 MFJNOXOAIFNSBX-UHFFFAOYSA-N 0.000 description 2
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- XANVIFOBBVAKCY-UHFFFAOYSA-N 1-bromo-2-fluoro-4-methoxybenzene Chemical compound COC1=CC=C(Br)C(F)=C1 XANVIFOBBVAKCY-UHFFFAOYSA-N 0.000 description 1
- ZLECMIQMTYRKRG-UHFFFAOYSA-N 1-bromo-4-ethoxy-2-fluorobenzene Chemical compound CCOC1=CC=C(Br)C(F)=C1 ZLECMIQMTYRKRG-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229940123502 Hormone receptor antagonist Drugs 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102000029828 Melanin-concentrating hormone receptor Human genes 0.000 description 1
- 108010047068 Melanin-concentrating hormone receptor Proteins 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- OZQXEOSNFMMMRD-UHFFFAOYSA-M [Cl-].CC(C)[Mg+].C1CCOC1 Chemical compound [Cl-].CC(C)[Mg+].C1CCOC1 OZQXEOSNFMMMRD-UHFFFAOYSA-M 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 description 1
- 229940008406 diethyl sulfate Drugs 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- RKSOPLXZQNSWAS-UHFFFAOYSA-N tert-butyl bromide Chemical compound CC(C)(C)Br RKSOPLXZQNSWAS-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/004—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with organometalhalides
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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
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic System
- C07F3/02—Magnesium 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
Abstract
本发明公开了一种2‑氟‑4‑羟基苯甲醛的制备方法，属于有机合成技术领域。以3‑氟苯酚为原料将羟基保护，接着与溴化试剂进行溴代，随后格氏试剂交换与DMF反应生成相应醛，最后脱保护，纯化得到2‑氟‑4‑羟基苯甲醛。本发明原料易得，成本低廉，反应条件温和且连续，对设备要求低，产品纯度高达99.5％，并通过筛选不同酚羟基保护基团，最后选择异丙基为保护基团，从而优化得到最终工艺。
Description
技术领域
本发明涉及一种2-氟-4-羟基苯甲醛的制备方法，属于有机合成技术领域。
背景技术
2-氟-4-羟基苯甲醛，英文名称：2-fluoro-4-hydroxybenzaldehyde，CAS 348-27-6，2-氟-4-羟基苯甲醛主要应用于医药或农药等生理活性化合物的中间体，是广泛的有机砌块化合物，其结构含氟、醛基、酚羟基均可增加或替换其它官能团。
目前含氟医药的开发最为活跃，已经商品化或正在开发的产品百余种。文献[Bioorganic and Medicinal Chemistry Letters,2010,20,153-156]通过2-氟-4-羟基苯甲醛为中间体合成有效JAK2激酶抑制剂；文献[RSC Advances,2016,6,95177-95188]通过2-氟-4-羟基苯甲醛为中间体合成金刚烷取代咪唑并[1,2-a]吡啶衍生物；文献[Journalof Medi cinal Chemistry,2016,59,2497-2511]通过2-氟-4-羟基苯甲醛为中间体合成新型黑色素浓缩激素受体拮抗剂。WO2016/22742,2016,A1同样用2-氟-4-羟基苯甲醛为中间体合成含咪唑稠合三环药物。
然而2-氟-4-羟基苯甲醛合成的方法并不多，其中[Journal ofFluo rineChemistry,1995,70,39-44]报道采用3-氟苯酚与叔丁基二甲基氯硅烷反应保护羟基，随后仲丁基锂超低温拔氢后与DMF反应生成醛，随后在酸性条件下脱保护得到2-氟-4-羟基苯甲醛。反应方程式如下：
该路线步骤短，总收率达到68.4％，但所用试剂价格均贵，需要超低温反应，对设备要求高，不利于规模性生产。
通常路线均为采用3-氟苯酚羟基上保护，随后丁基锂/DMF上醛基，随后脱保护从而得到2-氟-4-羟基苯甲醛。通过实验优化本发明筛选出价格低廉并易脱除保护基团，并且其位阻适中，有利于氟邻位溴代，其反应条件温和且连续，不需要超低温，对设备要求低，质量高，适合工业化生产，以满足日益增长的市场需求。
发明内容
为了克服上述技术缺陷，本发明提供了一种2-氟-4-羟基苯甲醛的制备方法。以3-氟苯酚为原料将羟基保护，接着与溴化试剂进行溴代，随后格氏试剂交换与DMF反应生成相应醛，最后脱酚羟基保护，进而纯化得到2-氟-4-羟基苯甲醛。本发明原料易得，成本低廉，反应条件温和且连续，对设备要求低，产品纯度高达99.5％，并通过筛选不同酚羟基保护基团，最后选择异丙基为保护基团，从而优化得到最终工艺。
本发明所述一种2-氟-4-羟基苯甲醛的制备方法，反应方程式如下：
包括如下步骤：
第一步：将3-氟苯酚、碳酸钾和2-溴丙烷在有机溶剂中混合，升温反应1-氟-3-异丙氧基苯；
第二步：将1-氟-3-异丙氧基苯溶于有机溶剂中，与溴代试剂反应得到1-溴-2-氟-4-异丙氧基苯；
第三步：将1-溴-2-氟-4-异丙氧基苯溶于四氢呋喃中，-10℃至0℃滴加异丙基氯化镁/四氢呋喃溶液，格氏交换后加入DMF反应得到2-氟-4-异丙氧基苯甲醛；
第四步：将2-氟-4-异丙氧基苯甲醛与三氯化硼反应，脱保护得到2-氟-4-羟基苯甲醛。
进一步地，在上述技术方案中，第一步所述有机溶剂选自乙腈、丙酮、四氢呋喃或DMF。
进一步地，在上述技术方案中，第一步所述3-氟苯酚、碳酸钾与2-溴丙烷摩尔比为1：1.80-2.30：1.20-1.40。
进一步地，在上述技术方案中，第二步所述溴代试剂选自四丁基三溴化铵或吡啶鎓三溴化物。
进一步地，在上述技术方案中，第二步所述有机溶剂选自1,2-二氯乙烷或二氯甲烷。
进一步地，在上述技术方案中，第二步所述1-氟-3-异丙氧基苯与溴代试剂摩尔比例为1：0.98-1.05。
进一步地，在上述技术方案中，第三步所述1-溴-2-氟-4-异丙氧基苯、异丙基氯化镁和DMF摩尔比为1：1.15-1.20：1.25-1.35。
进一步地，在上述技术方案中，第四步所述2-氟-4-异丙氧基苯甲醛与三氯化硼摩尔比为1：2-5.5。
发明有益效果
1、通过酚羟基保护基团筛选，从甲基、乙基、异丙基、叔丁基和THP(2-四氢吡喃)的保护基进行溴代，甲基、乙基保护基团溴代时异构体较多，叔丁基保护基团溴代异构体最少，但叔丁基溴价格较贵，且不易上保护，THP在溴代反应时易脱保护，通过不同的溴代试剂筛选，对不同的酚羟基保护基团溴代反应，发现二溴海因、四丁基三溴化铵或吡啶鎓三溴化物的异构体少，优选四丁基三溴化铵。采用在低温下用三氯化硼脱保护，异构体可重结晶纯化。综上，2-溴丙烷价格相对较低，异丙基保护基溴代时异构体相对少，且在脱保护时采用三氯化硼，条件更加温合，收率更高。
2、整个工艺中避免了超低温反应，反应条件温和，通过对杂质的性质分析，中间体可无需纯化，最后得到产品通过异丙醚重结晶得到纯度高达99.5％以上。
具体实施例
下面通过具体实例对本发明进行进一步说明。这些实施例应理解为仅用于说明本发明而不用于限制本发明的保护范围。在阅读了本发明记载的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等效变化和修改同样落入本发明权利要求所限定的范围。
实施例1
将5.6g(0.05mol,1eq)3-氟苯酚、20.7g(0.15mol,3eq)研磨碳酸钾和60mL乙腈混合，30-35℃缓慢滴8.8g(0.07mol,1.4eq)硫酸二甲酯，随后升温至80-82℃反应4小时，HPLC检测原料剩余2％，降至室温加入水和乙酸乙酯，分出有机相，有机相用水和饱和氯化钠洗涤，无水硫酸钠干燥，有机相浓缩得到1-氟-3-甲氧基苯6.03g。HPLC 94.5％，收率95.6％。1HNMR(400MHz,CDCl3):7.73-7.69(m,1H),7.45-7.41(m,1H),7.15-7.11(m,1H),6.71-6.68(m,1H),3.81(s,3H).
氮气保护下，将5.0g(0.04mol,1eq)1-氟-3-甲氧基苯与50mL二氯甲烷混合，降温至10℃，缓慢滴加含6.4g(0.04mol,1eq)溴素/5mL二氯甲烷溶液，HPLC检测原料剩余3％，加入冰水，分批加入碳酸钠固体调节pH＝8-9，分层，水相用二氯甲烷萃取，合并有机相，有机相用水和饱和氯化钠各洗涤，无水硫酸钠干燥，有机相浓缩，HPLC 52％，柱层析乙酸乙酯：正庚烷＝1：10-1：5洗脱得到1-溴-2-氟-4-甲氧基苯3.7g，收率44.9％，HPLC 97.3％。1HNMR(400MHz,CDCl3):7.45-7.40(m,1H),7.01-6.97(m,1H),6.64-6.60(m,1H),3.78(s,3H).
实施例2
将5.6g(0.05mol,1eq)3-氟苯酚、20.7g(0.15mol,3eq)研磨碳酸钾和60mL乙腈混合，30-35℃缓慢滴10.8g(0.07mol,1.4eq)硫酸二乙酯，随后升温至80-82℃反应6小时，HPLC检测原料剩余2％，降至室温加入水和乙酸乙酯，分出有机相，有机相水和饱和氯化钠洗涤，无水硫酸钠干燥，有机相浓缩得到1-氟-3-乙氧基苯6.7g，HPLC 93.7％，收率96.0％。1HNMR(400MHz,CDCl3):7.71-7.68(m,1H),7.44-7.40(m,1H),7.14-7.10(m,1H),6.63-6.60(m,1H),4.02-3.99(m,2H),1.38-1.34(m,3H).
氮气保护下，将5.6g(0.04mol,1eq)1-氟-3-乙氧基苯与50mL二氯甲烷混合，降温至10℃，分批加入7.1g(0.04mol,1eq)NBS，HPLC检测原料剩余3％，加入冰水，分批加入碳酸钠固体调节pH＝8-9分层，水相二氯甲烷萃取，合并有机相，有机相水和饱和氯化钠洗，无水硫酸钠干燥，有机相浓缩，HPLC 71％，柱层析乙酸乙酯/正庚烷＝1/10洗脱得到1-溴-2-氟-4-乙氧基苯5.3g，收率60.3％，HPLC 96.8％。1H NMR(400MHz,CDCl3):7.44-7.38(m,1H),6.91-6.87(m,1H),6.60-6.58(m,1H),4.01-3.98(m,2H),1.40-1.37(m,3H).
实施例3
将5.6g(0.05mol,1eq)3-氟苯酚、15.9g(0.115mol,2.3eq)研磨碳酸钾和60mL乙腈混合，30-35℃缓慢滴8.7g(0.07mol,1.4eq)2-溴丙烷，随后升温至80-82℃反应14小时，HPLC检测原料剩余2％，降温至室温加入水和乙酸乙酯，分出有机相，有机相用水和饱和氯化钠洗涤，无水硫酸钠干燥，有机相浓缩得到1-氟-3-异丙氧基苯7.5g，HPLC 95.7％，收率97.1％。1HNMR(400MHz,CDCl3):7.64-7.60(m,1H),7.40-7.35(m,1H),7.10-7.06(m,1H),6.59-6.55(m,1H),4.51-4.46(m,1H),1.37-1.33(m,6H).
氮气保护下，将5.6g(0.04mol,1eq)1-氟-3-异丙氧基苯与50mL二氯甲烷混合，降温至10℃，分批加入11.4g(0.04mol,1eq)二溴海因，HPLC检测原料剩余2％，加入冰水，分批加入碳酸钠固体调节pH＝9，分层，水相用二氯甲烷萃取，合并有机相，有机相用水和饱和氯化钠洗涤，无水硫酸钠干燥，随后有机相浓缩，HPLC 88％，柱层析乙酸乙酯/正庚烷＝1/10洗脱得到1-溴-2-氟-4-异丙氧基苯7.6g，收率81.3％，HPLC98.1％。1HNMR(400MHz,CDCl3):7.44-7.32(m,1H),6.87-6.84(m,1H),6.58-6.55(m,1H),4.46-4.42(m,1H),1.33-1.29(m,6H).
羟基上保护试验比较结果：
溴化反应试验比较结果：
通过上表可以确定异丙基保护整体收率最高，价格最低，条件温和。
实施例4
氮气保护下，将15.4g(0.1mol,1eq)1-氟-3-异丙氧基苯与100mL1,2-二氯乙烷混合，控制温度0至10℃，分批加入35.2g(0.099mol,1eq)90％吡啶鎓三溴化物，加入完毕，反应2小时，HPLC检测原料剩余2％。加入冰水，加入碳酸钠饱和水溶液调节pH＝9，分层，水相用1,2-二氯乙烷萃取，合并有机相，有机相用水和饱和氯化钠各洗涤一次，无水硫酸钠干燥，有机相浓缩得到22.4g1-溴-2-氟-4-异丙氧基苯，HPLC91％，不用纯化直接下一步。
氮气保护下，将15.4g(0.1mol,1eq)1-氟-3-异丙氧基苯与100mL1,2-二氯乙烷混合，控制温度0至10℃，滴加含49.2g(0.1mol,1eq)98％四丁基三溴化铵/50mL二氯甲烷，加入完毕，反应2小时，HPLC检测原料剩余1％。加入冰水，加入碳酸钠饱和水溶液调节pH＝9，分层，水相用1,2-二氯乙烷萃取，合并有机相，有机相用水和饱和氯化钠各洗涤一次，无水硫酸钠干燥，有机相浓缩得到23.1g 1-溴-2-氟-4-异丙氧基苯，HPLC 95.2％，不用纯化直接下一步。
实施例5
氮气保护下，将实施例4产物22.4g 1-溴-2-氟-4-异丙氧基苯和200mL四氢呋喃混合，降温至-5℃，控制温度-5℃至0℃缓慢滴加2.0mol/L异丙基氯化镁四氢呋喃溶液60mL，随后升温至5-10℃反应1小时。降温至-15℃，滴加含9.5g DMF的四氢呋喃溶液20mL，随后缓慢升温至室温反应2小时，2N盐酸淬灭，MTBE萃取，合并有机相，饱和氯化钠洗，无水硫酸钠干燥，有机相浓缩后减压蒸馏得到2-氟-4-异丙氧基苯甲醛17.2g，HPLC纯度91.2％，无需纯化直接用于下一步。
实施例6
氮气保护下，将实施例5产物17.2g 2-氟-4-异丙氧基苯甲醛和200mL二氯甲烷混合，控制-15℃至0℃下通入49.2g三氯化硼，控温-15℃至-10℃反应2小时。倒入冰水，加入碳酸钠固体调节pH＝6-7，随后加入浓盐酸调节pH＝1-2，分层明显，水相用二氯甲烷萃取，有机相饱和食盐水洗，无水硫酸钠干燥，浓缩后减压蒸馏得到2-氟-4-羟基苯甲醛粗品13.3g，加入80g异丙醚，升温至60-65℃重结晶得到10.7g2-氟-4-羟基苯甲醛，HPLC纯度99.6％，收率76.4％。ESI-MS:m/z＝139[M-H]。1H NMR(400MHz,CDCl3):10.34(s,1H),9.45(s,1H),7.54-7.41(m,2H),6.88-6.85(m,1H).
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 (8)
1.一种2-氟-4-羟基苯甲醛的制备方法，其特征在于，包括如下步骤：
第一步：将3-氟苯酚、碳酸钾和2-溴丙烷在有机溶剂中混合，升温反应得到1-氟-3-异丙氧基苯；
第二步：将1-氟-3-异丙氧基苯溶于有机溶剂中，与溴代试剂反应得到1-溴-2-氟-4-异丙氧基苯；
第三步：将1-溴-2-氟-4-异丙氧基苯溶于四氢呋喃中，-10℃至0℃滴加异丙基氯化镁/四氢呋喃溶液，格氏交换后加入DMF反应得到2-氟-4-异丙氧基苯甲醛；
第四步：将2-氟-4-异丙氧基苯甲醛与三氯化硼反应，脱保护得到2-氟-4-羟基苯甲醛。
2.根据权利要求1所述2-氟-4-羟基苯甲醛的制备方法，其特征在于：第一步中，所述有机溶剂选自乙腈、丙酮、四氢呋喃或DMF。
3.根据权利要求1所述2-氟-4-羟基苯甲醛的制备方法，其特征在于：第一步中，所述3-氟苯酚、碳酸钾与2-溴丙烷摩尔比为1：1.80-2.30：1.20-1.40。
4.根据权利要求1所述2-氟-4-羟基苯甲醛的制备方法，其特征在于：第二步中，溴代试剂选自四丁基三溴化铵或吡啶鎓三溴化物。
5.根据权利要求1所述2-氟-4-羟基苯甲醛的制备方法，其特征在于：第二步中，有机溶剂选自1,2-二氯乙烷或二氯甲烷。
6.根据权利要求1所述2-氟-4-羟基苯甲醛的制备方法，其特征在于：第二步中，所述1-氟-3-异丙氧基苯与溴代试剂摩尔比例为1：0.98-1.05。
7.根据权利要求1所述2-氟-4-羟基苯甲醛的制备方法，其特征在于：第三步中，所述1-溴-2-氟-4-异丙氧基苯、异丙基氯化镁与DMF摩尔比为1：1.15-1.20：1.25-1.35。
8.根据权利要求1所述2-氟-4-羟基苯甲醛的制备方法，其特征在于：第四步中，所述2-氟-4-异丙氧基苯甲醛与三氯化硼摩尔比为1：2--5.5。
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