CN115057809B - 一种4-(2,4-二氟苯甲酰基)-哌啶的制备方法 - Google Patents
一种4-(2,4-二氟苯甲酰基)-哌啶的制备方法 Download PDFInfo
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- WQJPGQDCLBMXMH-UHFFFAOYSA-N (2,4-difluorophenyl)-piperidin-4-ylmethanone Chemical compound FC1=CC(F)=CC=C1C(=O)C1CCNCC1 WQJPGQDCLBMXMH-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 23
- 239000007800 oxidant agent Substances 0.000 claims abstract description 13
- RLZUIPTYDYCNQI-UHFFFAOYSA-N (2,4-difluorophenyl)hydrazine Chemical compound NNC1=CC=C(F)C=C1F RLZUIPTYDYCNQI-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910052751 metal Inorganic materials 0.000 claims abstract description 12
- 239000002184 metal Substances 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 9
- 230000001590 oxidative effect Effects 0.000 claims abstract description 9
- 238000005859 coupling reaction Methods 0.000 claims abstract description 5
- 150000003254 radicals Chemical class 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 36
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 18
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 7
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 6
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 claims description 6
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 6
- 229960003280 cupric chloride Drugs 0.000 claims description 5
- 239000002798 polar solvent Substances 0.000 claims description 5
- FUFZNHHSSMCXCZ-UHFFFAOYSA-N 5-piperidin-4-yl-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole Chemical compound FC(F)(F)C1=CC=CC(C=2N=C(ON=2)C2CCNCC2)=C1 FUFZNHHSSMCXCZ-UHFFFAOYSA-N 0.000 claims description 4
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 4
- 229940045803 cuprous chloride Drugs 0.000 claims description 4
- 229940032296 ferric chloride Drugs 0.000 claims description 4
- 229960002089 ferrous chloride Drugs 0.000 claims description 4
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- HRVXPXCISZSDCC-UHFFFAOYSA-N piperidine-4-carbaldehyde Chemical compound O=CC1CCNCC1 HRVXPXCISZSDCC-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 238000007429 general method Methods 0.000 abstract 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
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- 150000001875 compounds Chemical class 0.000 description 4
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- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000000164 antipsychotic agent Substances 0.000 description 3
- -1 benzoyl cycloalkane Chemical class 0.000 description 3
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- 208000028017 Psychotic disease Diseases 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
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- 230000005855 radiation Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229960001534 risperidone Drugs 0.000 description 2
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- QPJONRGTWKXJLG-UHFFFAOYSA-N (2,4-difluorophenyl)-piperidin-4-ylmethanone;hydrochloride Chemical compound Cl.FC1=CC(F)=CC=C1C(=O)C1CCNCC1 QPJONRGTWKXJLG-UHFFFAOYSA-N 0.000 description 1
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-UHFFFAOYSA-N 0.000 description 1
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- PMXMIIMHBWHSKN-UHFFFAOYSA-N 3-{2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl}-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCC(O)C4=NC=3C)=NOC2=C1 PMXMIIMHBWHSKN-UHFFFAOYSA-N 0.000 description 1
- TXNLQUKVUJITMX-UHFFFAOYSA-N 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine Chemical compound CC(C)(C)C1=CC=NC(C=2N=CC=C(C=2)C(C)(C)C)=C1 TXNLQUKVUJITMX-UHFFFAOYSA-N 0.000 description 1
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
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- 150000001408 amides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 229960004372 aripiprazole Drugs 0.000 description 1
- 150000003934 aromatic aldehydes Chemical class 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 229940127236 atypical antipsychotics Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000007809 chemical reaction catalyst Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 229960001076 chlorpromazine Drugs 0.000 description 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
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- 239000003792 electrolyte Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 239000000203 mixture 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
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 229960001057 paliperidone Drugs 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 238000013032 photocatalytic reaction Methods 0.000 description 1
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 1
- 229940001470 psychoactive drug Drugs 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- 229960004431 quetiapine Drugs 0.000 description 1
- URKOMYMAXPYINW-UHFFFAOYSA-N quetiapine Chemical compound C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 URKOMYMAXPYINW-UHFFFAOYSA-N 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- XGPOMXSYOKFBHS-UHFFFAOYSA-M sodium;trifluoromethanesulfonate Chemical compound [Na+].[O-]S(=O)(=O)C(F)(F)F XGPOMXSYOKFBHS-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- ZVQXQPNJHRNGID-UHFFFAOYSA-N tetramethylsuccinonitrile Chemical compound N#CC(C)(C)C(C)(C)C#N ZVQXQPNJHRNGID-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 229960000607 ziprasidone Drugs 0.000 description 1
- MVWVFYHBGMAFLY-UHFFFAOYSA-N ziprasidone Chemical compound C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 MVWVFYHBGMAFLY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
- C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
-
- 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
- Y02P20/584—Recycling of catalysts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了有机合成化工领域内的一种4‑(2,4‑二氟苯甲酰基)‑哌啶的制备方法,具体为:以4‑哌啶甲醛和2,4‑二氟苯肼为原料,在金属催化剂和氧化剂下,经自由基偶联反应制备4‑(2,4‑二氟苯甲酰基)‑哌啶。本发明提供的路线步骤简短,条件温和,产品收率高,为4‑(2,4‑二氟苯甲酰基)‑哌啶的制备提供了一种通用的新方法。
Description
技术领域
本发明属于有机合成化工领域,具体涉及一种4-(2,4-二氟苯甲酰基)-哌啶的合成新方法。
背景技术
随着社会的进步、生活与工作节奏的加快,人们的竞争压力和生活压力也与日俱增,然而,人们的心理承受能力却越来越弱,精神病患者人数不断增长。自第一类抗精神病药物氯丙嗪上市至今,抗精神病药物的研究已有70多年,许多新型的抗精神病药物不断出现,给精神病患者带来了希望,抗精神病药物的研究与开发已越来越受到人们的重视。目前,临床上普遍使用的非典型抗精神病药物有利培酮、喹硫平、齐拉西酮、阿立哌唑等,它们在精神病治疗上效果显著。
4-(2,4-二氟苯甲酰基)-哌啶是精神疾病治疗药物利培酮的中间体,同时也是精神分裂症治疗新药帕潘立酮的关键中间体。由于该产品具有良好的市场前景,其合成工艺研究一直受到研究者的重视。
目前,文献报道的合成苯甲酰基环烷烃类似物的方法主要有以下几种:
(1)Soon Hyeok Hong等,报道了金属膦配体催化活化酰胺和烷烃化合物的直接C(sp3)-H酰化反应,用于合成苯甲酰基环烷烃类似物。该反应以氯化镍为金属催化剂,K2CO3为缚酸剂,Ir[dF(CF3)ppy]2(dtbbpy)PF6(1mol%)为氧化剂,以蓝光辐射诱导酰胺C-N键裂解和活化C(sp3)-H键得到苯甲酰基环烷烃类似物。
(2)Hua Fu课题组,开发了一种三氟甲基亚磺酸钠介导的羟基化合物的有氧氧化光催化反应,用于合成羰基类化合物。该反应以乙腈为溶剂,室温下通过400-405nm光辐射12h,将羟基氧化为羰基。
(3)Zenghui Ye等,在甲醇体系中,以苯乙烯为起始原料,TMSN3为添加剂,n-Bu4NBF4(0.05M)为电解质,通过电催化-氧化反应合成苯甲酰基环烷烃类似物。
(4)王贝等,以4-哌啶甲酸为起始原料,首先利用乙酸酐将氨基进行保护、以氯化亚砜进行酰氯化,随后与1,3-二氟苯发生傅克酰基化反应及脱保护生成4-(2,4-二氟苯甲酰基)-哌啶盐酸盐。该合成方法合成繁琐,以氯化亚砜进行酰氯化会对反应设备有一定的腐蚀性。
为了克服上述方法的缺点,例如使用贵金属催化剂、反应条件苛刻、合成步骤繁琐等。
发明内容
本发明提供了一种4-(2,4-二氟苯甲酰基)-哌啶的制备方法,以4-哌啶甲醛和2,4-二氟苯肼为原料,经自由基偶联反应制备4-(2,4-二氟苯甲酰基)-哌啶化合物,该反应步骤简短,反应条件温和,合成成本低廉,收率最高可达82.6%。
目标化合物4-(2,4-二氟苯甲酰基)-哌啶,其结构如下I所示:
本发明采取的技术方案如下:一种4-(2,4-二氟苯甲酰基)-哌啶的制备方法,其以4-哌啶甲醛和2,4-二氟苯肼为原料,在金属催化剂和氧化剂下及极性溶剂中,经自由基偶联反应得到4-(2,4-二氟苯甲酰基)-哌啶,反应式如下:
其中金属催化剂为氯化亚铜(CuCl)、氯化铜(CuCl2)、氯化铁(FeCl3)、氯化亚铁(FeCl2)中的一种,金属催化剂的添加量为2,4-二氟苯肼摩尔量的0.02-0.07倍。优选方案是所述金属催化剂为氯化铜(CuCl2),添加量为2,4-二氟苯肼摩尔量的0.05倍。
其中氧化剂优选为间氯过氧苯甲酸(m-CPBA)、过氧化叔丁醇(TBHP)中的一种。
极性溶剂优选为乙醇、四氢呋喃、二甲基亚砜中的一种。其中二甲基亚砜最优。
反应温度选自35-60℃。优选为40℃。
本发明的有益效果如下:
(1)本发明提供了一条4-(2,4-二氟苯甲酰基)-哌啶合成的新路线,以4-哌啶甲醛和2,4-二氟苯肼为原料,经自由基偶联反应制备4-(2,4-二氟苯甲酰基)-哌啶。
(2)本发明制备路线简洁、催化剂为氯化铜、氧化剂为过氧化叔丁醇,具有催化剂廉价易得的优势。
(3)本发明提供的路线,反应条件温和,操作简单,具有良好的推广应用价值。
附图说明
图1为目标化合物的核磁氢谱。
图2为目标化合物的核磁碳谱。
图3为目标化合物的核磁氟谱。
具体实施方式
实施例中使用的分析仪器与设备:核磁共振仪(AVANCE DMXⅡⅠ500M,Bruker公司);三用紫外线分析仪(ZF-6)。
实施例1
4-(2,4-二氟苯甲酰基)-哌啶的制备
在50ml的圆底烧瓶中依次加入4-哌啶甲醛(1.728g,12mmol)、25mL二甲基亚砜、2,4-二氟苯肼(1.130g,10mmol)、氯化铜(0.067g,0.5mmol)和过氧化叔丁醇(TBHP,1.800g,20mmol),40℃加热反应6h(TLC跟踪反应进程);反应结束后,用旋转蒸发仪浓缩反应体系,浓缩液用纯净水(100ml)和乙酸乙酯(20ml*3)萃取,分层,有机相用无水硫酸钠干燥、浓缩得粗品;经柱层析纯化得纯品1.858g,收率82.6%。
从图1-图3可见:
4-(2,4-Difluorobenzoyl)-piperidine(1.858g,82.6%):Yellow oil.1H NMR(500MHz,DMSO-d6)δ9.25(s,2H),7.86(td,J=8.7,6.6Hz,1H),7.37(ddd,J=11.7,9.3,2.5Hz,1H),7.19(td,J=8.5,2.5Hz,1H),3.40(tt,J=11.1,3.6Hz,1H),3.19(dt,J=12.8,3.7Hz,2H),2.91(td,J=12.5,3.1Hz,2H),1.88(dd,J=14.5,3.6Hz,2H),1.71(qd,J=11.1,10.7,5.8Hz,2H).13C NMR(125MHz,DMSO-d6):δ198.86(d,4J=3.63Hz),165.36(dd,1JCF=252.13Hz,3JCF=12.63Hz),161.72(dd,1JCF=254.63Hz,3JCF=12.88Hz),133.20(dd,3JCF=10.88Hz,4JCF=4.0Hz),121.88(dd,3JCF=12.50Hz,4JCF=3.63Hz),112.96(dd,2JCF=21.50Hz,4JCF=3.50Hz),105.74(t,2J=26.38Hz),44.44(d,4JCF=4.63Hz),44.41,42.66;19F NMR(500MHz,DMSO-d6):δ-102.62(d,4J=3.25Hz),-107.38(d,4J=3.13Hz).
实施例2
催化剂的筛选
本实施例的实验条件、投料量与实施例1相同,选择不同的催化剂进行实验,具体如表1所示:
表1
由表1可见,当选用氯化亚锌为催化剂时反应收率最低;选用氯化亚铜、氯化铁、氯化亚铁为催化剂时,反应收率分别为74.2%、72.5%和61.0%,而选用氯化铜(CuCl2)为催化剂时,反应收率最高,为82.6%;综上,本发明优先选用氯化铜(CuCl2)为反应催化剂。
实施例3
氯化铜(CuCl2)用量的筛选
本实施例的实验条件、投料量与实施例1相同,选择不同剂量的氯化铜进行实验,具体如表2所示:
表2
由表2可见,氯化铜的用量为0.2mmol时,反应收率仅为68.5%;当用量为0.5mmol时,反应收率为82.6%,然而,继续增加氯化铜的用量,反应收率没有明显提高,考虑收率,可选择氯化铜的摩尔用量为0.2-0.7mmol,也就是氯化铜的添加量为2,4-二氟苯肼摩尔量的0.02-0.07倍;选用0.5mmol氯化铜最优。
更换氯化亚铜、氯化铁、氯化亚铁分别进行实验,其收率趋势与表2一致,可确定金属催化剂的添加量为2,4-二氟苯肼摩尔量的0.02-0.07倍。
实施例4:氧化剂的筛选
本实施例的实验条件、投料量与实施例1相同,选择不同的反应氧化剂进行实验,具体如表3所示:
表3
由表3可见,当选用间氯过氧苯甲酸(m-CPBA)、双氧水(H2O2)、过硫酸钾(K2S2O8)、过硫酸钠(Na2S2O8)为氧化剂时,反应收率分别为73.0%、20.5%、45.6%和47.0%;当选用过氧化叔丁醇(TBHP)为氧化剂时,当反应收率最高,为82.6%;综上,本发明选用间氯过氧苯甲酸(m-CPBA)、过氧化叔丁醇(TBHP)作为氧化剂。
实施例5:反应溶剂的筛选
本实施例的实验条件、投料量与实施例1相同,选择不同反应溶剂进行实验,具体如表4所示:
表4
由表4可见,当反应溶剂为纯净水时,反应收率最低,为23.5%;当反应溶剂为乙醇、乙腈、二氯甲烷、四氢呋喃时,反应收率分别为73.0%、36.5%、35.0%和81.0%;当选用二甲基亚砜为溶剂时,反应收率最高,为82.6%;综上,本发明可选用乙醇、四氢呋喃和二甲基亚砜为溶剂,其中二甲基亚砜最优。
实施例6:反应温度的筛选
本实施例的实验条件、投料量与实施例1相同,选择不同的反应温度进行实验,具体如表5所示
表5
催化剂 | 氧化剂 | 溶剂 | 温度(℃) | 收率(%) | |
1 | CuCl2(5mol%) | TBHP | DMSO | 25 | trace |
2 | CuCl2(5mol%) | TBHP | DMSO | 30 | 42.9 |
3 | CuCl2(5mol%) | TBHP | DMSO | 35 | 65.2 |
4 | CuCl2(5mol%) | TBHP | DMSO | 40 | 82.6 |
5 | CuCl2(5mol%) | TBHP | DMSO | 45 | 79.6 |
6 | CuCl2(5mol%) | TBHP | DMSO | 50 | 74.3 |
7 | CuCl2(5mol%) | TBHP | DMSO | 55 | 72.7 |
8 | CuCl2(5mol%) | TBHP | DMSO | 60 | 68.0 |
由表5可见,当温度为25℃时,反应收率最低;当反应收率为40℃时,反应收率最高,为82.6%;然而,继续提升反应温度,反应收率明显下降,这是芳醛被氧化成为羧酸所致。综上,本发明反应温度可选为35-60℃,优选为40℃。
需要声明的是,上述具体实施方式意在证明本发明所提供技术方案的实际应用,不应解释为对本发明保护范围的限定。对于本发明创造所属技术领域的普通技术人员来说,在不脱离本发明创造构思的前提下,还可以做出若干简单推演或替换,都应当视为属于本发明创造的保护范围。
Claims (5)
1.一种4-(2,4-二氟苯甲酰基)-哌啶的制备方法,其特征在于:以4-哌啶甲醛和2,4-二氟苯肼为原料,在金属催化剂和氧化剂下及极性溶剂中,经自由基偶联反应得到4-(2,4-二氟苯甲酰基)-哌啶,反应温度为35-60℃;反应式如下:
;
所述金属催化剂为氯化亚铜、氯化铜、氯化铁、氯化亚铁中的一种,金属催化剂的添加量为2,4-二氟苯肼摩尔量的0.02-0.07倍;所述氧化剂为间氯过氧苯甲酸、过氧化叔丁醇中的一种。
2.根据权利要求1所述的一种4-(2,4-二氟苯甲酰基)-哌啶的制备方法,其特征在于,所述金属催化剂为氯化铜,添加量为2,4-二氟苯肼摩尔量的0.05倍。
3.根据权利要求1所述的一种4-(2,4-二氟苯甲酰基)-哌啶的制备方法,其特征在于,其中极性溶剂为乙醇、四氢呋喃、二甲基亚砜中的一种。
4.根据权利要求3所述的一种4-(2,4-二氟苯甲酰基)-哌啶的制备方法,其特征在于,其中极性溶剂为二甲基亚砜。
5.根据权利要求1所述的一种4-(2,4-二氟苯甲酰基)-哌啶的制备方法,其特征在于,反应温度为40℃。
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EP0428437A1 (fr) * | 1989-11-07 | 1991-05-22 | Adir Et Compagnie | Dérivés du 1,2-benzisoxazole, leurs procédés de préparation et les compositions pharmaceutiques qui les contiennent |
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