CN108409802B - 一种(s)-1-二茂铁乙基二甲胺的制备工艺 - Google Patents
一种(s)-1-二茂铁乙基二甲胺的制备工艺 Download PDFInfo
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- DAZXVJBJRMWXJP-UHFFFAOYSA-N n,n-dimethylethylamine Chemical compound CCN(C)C DAZXVJBJRMWXJP-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- 239000003054 catalyst Substances 0.000 claims abstract description 22
- 239000003446 ligand Substances 0.000 claims abstract description 21
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims abstract description 16
- YDZCBKCOBVVHFT-ILKKLZGPSA-N cyclopenta-1,3-diene;(1s)-1-cyclopenta-2,4-dien-1-ylethanol;iron(2+) Chemical compound [Fe+2].C=1C=C[CH-]C=1.C[C@H](O)[C-]1C=CC=C1 YDZCBKCOBVVHFT-ILKKLZGPSA-N 0.000 claims abstract description 15
- UNMQCGHIBZALKM-JZGIKJSDSA-N cyclopenta-1,3-diene;(1s)-1-cyclopenta-2,4-dien-1-yl-n,n-dimethylethanamine;iron(2+) Chemical compound [Fe+2].C=1C=C[CH-]C=1.CN(C)[C@@H](C)C1=CC=C[CH-]1 UNMQCGHIBZALKM-JZGIKJSDSA-N 0.000 claims abstract description 13
- 229910052751 metal Inorganic materials 0.000 claims abstract description 12
- 239000002184 metal Substances 0.000 claims abstract description 12
- -1 acetyl ferrocene Chemical compound 0.000 claims abstract description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims description 10
- 239000012300 argon atmosphere Substances 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 150000001450 anions Chemical group 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- JVJQPDTXIALXOG-UHFFFAOYSA-N nitryl fluoride Chemical compound [O-][N+](F)=O JVJQPDTXIALXOG-UHFFFAOYSA-N 0.000 claims description 2
- 239000012044 organic layer Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims 1
- SPKJCVZOZISLEI-UHFFFAOYSA-N cyclopenta-1,3-diene;1-cyclopenta-1,3-dien-1-ylethanone;iron(2+) Chemical compound [Fe+2].C=1C=C[CH-]C=1.CC(=O)C1=CC=C[CH-]1 SPKJCVZOZISLEI-UHFFFAOYSA-N 0.000 claims 1
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 abstract description 2
- 238000006467 substitution reaction Methods 0.000 abstract description 2
- 230000021736 acetylation Effects 0.000 abstract 1
- 238000006640 acetylation reaction Methods 0.000 abstract 1
- 230000009286 beneficial effect Effects 0.000 abstract 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 abstract 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 2
- MROCJMGDEKINLD-UHFFFAOYSA-N dichlorosilane Chemical compound Cl[SiH2]Cl MROCJMGDEKINLD-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000005712 Baylis-Hillman reaction Methods 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 229910001914 chlorine tetroxide Inorganic materials 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- YLQBEKUKMJWXMC-UHFFFAOYSA-N cyclopenta-1,3-diene cyclopenta-2,4-dien-1-ylphosphane iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.P[c-]1cccc1 YLQBEKUKMJWXMC-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
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
- C07F17/00—Metallocenes
- C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic Table
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2282—Unsaturated compounds used as ligands
- B01J31/2295—Cyclic compounds, e.g. cyclopentadienyls
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/84—Metals of the iron group
- B01J2531/842—Iron
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种(S)‑1‑二茂铁乙基二甲胺的制备工艺。该制备工艺中,以乙酰基二茂铁作为原料,利用金属Ir络合物与手性二茂铁三齿配体L*反应得到的配合物作为催化剂,经不对称催化氢化制得(S)‑1‑二茂铁基乙醇,然后进行乙酰化、二甲胺取代反应,得到(S)‑1‑二茂铁乙基二甲胺。与传统的手性拆分法制备(S)‑1‑二茂铁乙基二甲胺的工艺相比,本发明有益效果主要体现在:反应条件温和、操作简便、立体选择性好、收率高、生产周期短、“三废”量少、易于工业化,具有较大的实施价值和社会经济效益。
Description
技术领域
本发明属于有机合成技术领域,具体涉及一种(S)-1-二茂铁乙基二甲胺的制备工艺。
背景技术
(S)-1-二茂铁乙基二甲胺是一类重要的医药化工中间体,常被用做手性催化剂以及手性配体的关键骨架。例如,(S)-1-二茂铁乙基二甲胺衍生的二茂铁膦催化剂可以催化不对称Morita-Baylis-Hillman反应(Org.Biomol.Chem.,2017,15,7523-7526;Org.Biomol.Chem.,2016,14,752-760),以较高的收率和ee值得到手性化合物。而(S)-1-二茂铁乙基二甲胺衍生的二茂铁配体也能与金属配位,实现高效不对称催化反应(Angew.Chem.Int.Ed.2014,53,8467-8470;Org.Lett.2017,19,690-693;Org.Lett.2016,18,2938-2941;CN105732725.)。因此,化学家们一直在积极探索(S)-1-二茂铁乙基二甲胺的制备工艺,常用的是利用手性酒石酸对1-二茂铁乙基二甲胺消旋体进行手性拆分(Catalysis Science&Technology,2016,6(1),118-124;精细化工中间体,2015,45(6),48-51.),但是该方法效率较低,通常需要多次拆分才能得到较高ee值的目标化合物。较佳的方法就是通过金属催化的不对称氢化反应将乙酰基二茂铁转化为手性二茂铁基乙醇,再经过简单的酯化,二甲胺取代,制得目标化合物。虽然该方法在(R)-1-二茂铁乙基二甲胺合成上取得了重大突破(Org.Lett.2017,19,690-693;CN103755748),但是对于(S)-1-二茂铁乙基二甲胺的合成,还是存在不足,例如催化剂用量较大以及对映选择性控制不高等(Adv.Synth.Catal.2006,348,370-374;Tetrahedron:Asymmetry 2009,20,584-587)。因此如何简便、大规模制备高对映选择性的(S)-1-二茂铁乙基二甲胺,仍然是一个具有挑战性的任务。
发明内容
针对现有技术中存在的上述问题,本发明的目的在于提供一种(S)-1-二茂铁乙基二甲胺的制备工艺,适于工业化生产应用,可以较方便地制备公斤级的且具有高纯度高对映选择性的(S)-1-二茂铁乙基二甲胺。
本发明的具体技术方案如下:
本发明提供一种高纯度高对映选择性的(S)-1-二茂铁乙基二甲胺的制备工艺,其制备步骤包括:
(1)在0℃~50℃及氩气氛围下,将金属Ir络合物与手性配体L*依次加入到溶剂A中,反应0.5~5小时,制得催化剂[Ir]/L*;
(2)在氩气氛围下,向反应釜中依次加入乙酰基二茂铁1和上述催化剂[Ir]/L*,再加入溶剂B,最后加入碱,置换氢气后,于0℃~100℃以及0.1~10.0MPa下进行不对称加氢反应,2~24小时后制得(S)-1-二茂铁基乙醇2;
(3)0℃~40℃,将上述制备的(S)-1-二茂铁基乙醇与醋酐反应1~5小时后,随后加入质量分数为30%~50%二甲胺水溶液,继续反应1~12小时后,减压浓缩有机层,所得粗品经减压蒸馏,得(S)-1-二茂铁乙基二甲胺3;
所述的制备工艺路线用如下反应式表示:
所述的手性配体L*结构如通式(I)所示:
通式(I)中:R选自甲基、乙基、异丙基、叔丁基、硝基、氟、氯、溴中的一种;R可以位于苯环的邻位、间位或者对位,且R可以为一取代、二取代或者三取代。
所述的3种优选配体L*结构如下:
所述的优选金属络合物包括:[Ir(NBD)2Cl]2、Ir(NBD)2)X、[Ir(COD)Cl]2或[Ir(COD)2]X中的任意一种。其中X为阴离子,X优选为BF4 -、ClO4 -、SbF6 -、PF6 -、CF3SO3 -、B(Ar)4 -。
所述的制备催化剂所用溶剂A和不对称氢化反应所用溶剂B分别选自二氯甲烷、四氢呋喃、甲苯、甲醇、乙醇、正丙醇、异丙醇、叔丁醇中的一种或几种,溶剂A和B可相同。
所述的催化剂与乙酰基二茂铁1的摩尔比为1:100~1:100000。
所述的不对称氢化反应温度优选为20℃~60℃。
所述的不对称氢化反应氢气压力优选为2.0~5.0Mpa。
所述的不对称氢化反应所用的碱选自叔丁基醇钾,叔丁基醇钠,叔丁基醇锂,碳酸铯,碳酸钾,碳酸钠,甲醇钠,氢氧化钠,氢氧化钾中的一种。
通过采用上述技术,与现有技术相比,本发明具有以下优点:
1)本发明反应条件温和、原料易得、实验操作简单;
2)本发明的不对称加氢反应具有高度的对映选择性,选择性的生成(S)-1-二茂铁乙醇,且具有较高的反应活性,催化剂用量可以降至万分之一以下,且能公斤级地制备(S)-1-二茂铁乙基二甲胺;
3)本发明发展了一种新型手性二茂铁配体与金属络合物作为催化剂,通过对乙酰基二茂铁的不对称氢化,再经酯化以及胺化,高对映选择性地生成(S)-1-二茂铁乙基二甲胺的制备工艺,该工艺具有较低的催化剂用量,以及较优的收率和ee值。
具体实施方式
下面通过实施例对本发明加以说明,但本发明不仅限与实施例。
实施例1:配体L1的合成
将化合物4(4.41g,10mmol)溶于8.0mL醋酐中,55℃下反应4小时。反应完毕,减压回收过量的醋酐,然后高真空条件下除去低沸点的杂质,得粗产物5,无需纯化,直接用于下一步。
反应瓶中加入粗产物5(0.46g,0.1mmol)和6(0.54g,0.2mmol),置换氮气后,加入5mL甲醇,50℃下反应12小时。浓缩、柱层析得黄色配体L1(0.41g,61%)。
1H NMR(600MHz,CDCl3)δ7.70(d,J=8.2Hz,2H),7.50–7.44(m,2H),7.39–7.34(m,3H),7.24(d,J=8.1Hz,2H),7.18–7.12(m,1H),7.09–7.01(m,4H),5.89(s,1H),4.49(s,1H),4.34(t,J=2.4Hz,1H),4.05(s,5H),4.03–3.96(m,1H),3.68(s,1H),2.42(s,3H),2.10(s,2H),1.97–1.87(m,1H),1.82(t,J=8.1Hz,1H),1.42–1.47(m,2H),1.33(d,J=6.1Hz,3H),1.11–0.92(m,2H),0.77–0.84(m,,1H),0.24–0.01(m,1H),-0.33(d,J=10.5Hz,1H).13CNMR(151MHz,CDCl3)δ142.8,137.2,135.0,134.9,132.8,132.7,129.4,129.2,128.3,128.3,128.2,128.2,127.5,74.3,74.3,71.2,71.1,69.7,69.6,69.5,69.3,57.8,56.9,32.1,29.8,24.8,24.0,21.6,20.1.
实施例2:配体L2的合成
粗产物5的制备方法同实施例1。
反应瓶中加入粗产物5(0.46g,0.1mmol)和7(0.60g,0.2mmol),置换氮气后,加入5mL甲醇,50℃下反应12小时。浓缩、柱层析得黄色配体L2(0.37g,53%)。
1H NMR(600MHz,CDCl3)δ7.52–7.46(m,2H),7.39–7.34(m,3H),7.14(m,1H),7.01(s,4H),6.91(s,2H),5.92(s,1H),4.48(s,1H),4.35–4.31(s,1H),4.05(m,5H),4.03(s,1H),3.69(s,1H),2.59(s,6H),2.31(s,3H),2.17–2.01(m,2H),1.92–1.84(m,1H),1.75(s,1H),1.43(m,5H),1.27(m,1H),0.96(m,2H),0.81–0.72(m,1H),-0.44(d,J=8.1Hz,1H).13CNMR(151MHz,CDCl3)δ141.45,140.03,139.95,138.98,136.43,136.36,135.03,134.86,134.19,132.59,132.44,131.68,129.14,128.31,128.26,128.12,128.06,74.05,74.00,71.03,71.00,69.62,69.31,69.28,69.14,57.66,56.89,46.18,31.93,29.70,24.78,23.87,23.03,20.86,19.80.
实施例2:配体L3的合成
粗产物5的制备方法同实施例1。
反应瓶中加入粗产物5(0.46g,0.1mmol)和8(0.53g,0.2mmol),置换氮气后,加入5mL甲醇,50℃下反应15小时。浓缩、柱层析得黄色配体L3(0.40g,51%)。
1H NMR(600MHz,CDCl3)δ7.48(m,2H),7.35(m,3H),7.15(s,2H),7.08(t,J=7.1Hz,3H),6.96(t,J=6.8Hz,2H),5.96(s,1H),4.50(s,1H),4.27(s,1H),4.08(m,1H),4.05(d,J=7.0Hz,1H),4.04(s,5H),4.03(d,J=6.8Hz,1H 1H),3.64(s,1H),3.02–2.92(m,1H),2.22–1.92(m,4H),1.49(t,J=10.2Hz,2H),1.39(d,J=5.4Hz,3H),1.28(dd,J=6.8,5.3Hz,6H),1.23(d,J=6.8Hz,6H),1.17(d,J=6.8Hz,6H),1.09–0.96(m,2H),0.14(s,1H),-0.20(d,J=11.5Hz,1H).13C NMR(151MHz,CDCl3)δ152.07,150.28,139.96,139.88,136.45,136.38,135.13,134.96,133.54,132.71,132.56,129.16,128.31,128.26,128.13,128.07,123.62,97.49,74.36,74.31,71.20,71.17,70.01,69.65,69.12,57.40,57.26,46.55,34.09,31.95,29.84,29.70,25.16,25.05,23.89,23.73,23.53,19.75.
实施例4:(S)-1-二茂铁乙基二甲胺的制备
(1)将配体L1(0.32g,0.48mmol),金属[Ir(COD)Cl]2(0.16g,0.22mmol),加入反应瓶中,氩气氛围下加入甲醇(20mL),25℃下搅拌反应0.5h,制得催化剂。
(2)在高压釜中加入乙酰化二茂铁1(1.03kg,4.52mol),加入步骤(1)所制备的催化剂,甲醇钠(1.19g,22mmol),甲醇(1.50L),充入H2(3.0MPa),40℃下反应12h,减压浓缩回收有机溶剂,得(S)-1-二茂铁基乙醇2(1.03kg,4.47mol),收率:99%,纯度为98%,ee值为91%。
(3)将上述制备的(S)-1-二茂铁基乙醇2(1.03kg,4.47mol)、二氯甲烷(3.0L)、三乙胺(902.9g,8.94mol)依次投入到反应釜中,室温下滴加醋酐(683.4g,6.70mol),继续搅拌反应3h;再缓慢滴加33%二甲胺水溶液4.31kg,继续搅拌反应5h后;静止分层,减压浓缩回收二氯加烷,残留物减压蒸馏收集110℃(0.07kPa)的馏分,制得(S)-1-二茂铁乙基二甲胺3(1.00kg),暗红色油状液体,收率:87%;HPLC纯度:98%;ee值:94%。
实施例5:(S)-1-二茂铁乙基二甲胺的制备
(1)将配体L2(0.32g,0.48mmol),金属[Ir(COD)Cl]2(0.16g,0.22mmol),加入反应瓶中,氩气氛围下加入甲醇(20mL),25℃下搅拌反应0.5h,制得催化剂。
(2)在高压釜中加入乙酰化二茂铁1(1.03kg,4.52mol),加入步骤(1)所制备的催化剂,甲醇钠(1.19g,22mmol),甲醇(1.50L),充入H2(3.0MPa),40℃下反应12h,减压浓缩回收有机溶剂,得(S)-1-二茂铁基乙醇2(1.03kg,4.47mol),收率:99%,纯度为98%,ee值为94%。
(3)将上述制备的(S)-1-二茂铁基乙醇2(1.03kg,4.47mol)、二氯甲烷(3.0L)、三乙胺(902.9g,8.94mol)依次投入到反应釜中,室温下滴加醋酐(683.4g,6.70mol),继续搅拌反应3h;再缓慢滴加33%二甲胺水溶液4.31kg,继续搅拌反应5h后;静止分层,减压浓缩回收二氯加烷,残留物减压蒸馏收集110℃(0.07kPa)的馏分,制得(S)-1-二茂铁乙基二甲胺3(1.02kg),暗红色油状液体,收率:89%;HPLC纯度:98%;ee值:96%。
实施例6:(S)-1-二茂铁乙基二甲胺的制备
(1)将配体L3(0.37g,0.48mmol),金属[Ir(COD)Cl]2(0.16g,0.22mmol),加入反应瓶中,氩气氛围下加入甲醇(20mL),25℃下搅拌反应0.5h,制得催化剂。
(2)在高压釜中加入乙酰化二茂铁1(1.03kg,4.52mol),加入步骤(1)所制备的催化剂,甲醇钠(1.19g,22mmol),甲醇(1.50L),充入H2(3.0MPa),40℃下反应12h,减压浓缩回收有机溶剂,得(S)-1-二茂铁基乙醇2(1.03kg,4.47mol),收率:99%,纯度为98%,ee值为92%。
(3)将上述制备的(S)-1-二茂铁基乙醇(1.03kg,4.47mol)、甲基叔丁基醚(3.0L)、三乙胺(677.2g,6.71mol)投入到反应釜中,0℃下滴加醋酐(547.1g,5.36mol),继续搅拌反应3h;然后体系升至室温,缓慢滴加33%二甲胺水溶液1.22kg,加完后升至40℃反应5h。反应完毕后,静止分层,减压浓缩回收甲基叔丁基醚,残留物减压蒸馏收集110℃(0.07kPa)的馏分,制得(S)-1-二茂铁乙基二甲胺(1.00kg),暗红色油状液体,收率:87%;HPLC纯度:98%;ee值为93%。
实施例7:(S)-1-二茂铁乙基二甲胺的制备
(1)将配体L2(0.32g,0.48mmol),金属[Ir(COD)Cl]2(0.16g,0.22mmol),加入反应瓶中,氩气氛围下加入溶剂甲醇(20mL),25℃下搅拌反应5h,制得催化剂。
(2)在高压釜中加入乙酰化二茂铁(1.03kg,4.52mol),加入步骤(1)所制备的催化剂,叔丁醇钠(2.11g,22mmol),甲醇(1.50L),充入H2(3.0MPa),40℃下反应12h,减压浓缩回收有机溶剂,制得(S)-1-二茂铁基乙醇(1.01kg),收率:97%,纯度为98%,ee值为95%。
(3)将上述制备的(S)-1-二茂铁基乙醇(1.01kg,4.38mol)、二氯甲烷(3.0L)、三乙胺(884.8g,8.76mol)投入到反应釜中,室温下缓慢滴加醋酐(670.1g,6.57mol),加完原料后,继续搅拌反应3h;然后滴加33%二甲胺水溶液1.79kg,加完后升至40℃反应8h。反应完毕后,静止分层,减压浓缩回收甲苯,残留物减压蒸馏收集110℃(0.07kPa)的馏分,制得(S)-1-二茂铁乙基二甲胺(0.979kg),暗红色油状液体,收率:87%;HPLC纯度:98%;ee值为97%。
实施例8:(S)-1-二茂铁乙基二甲胺的制备
(1)将配体L2(0.32g,0.48mmol),金属[Ir(COD)Cl]2(0.16g,0.22mmol),加入反应瓶中,氩气氛围下加入溶剂叔丁醇(20mL),25℃下搅拌反应0.5h,制得催化剂。
(2)在高压釜中加入乙酰化二茂铁(1.03kg,4.52mol),加入步骤(1)所制备的催化剂,叔丁醇钠(2.21g,22mmol),叔丁醇(1.50L),充入H2(6.0MPa),40℃下反应6h,减压浓缩回收有机溶剂,制得(S)-1-二茂铁基乙醇(1.02kg),收率:98%,纯度为98%,ee值为96%。
(3)将上述制备的(S)-1-二茂铁基乙醇(1.02kg,4.43mol)、二氯甲烷(3.0L)、三乙胺(902g,8.92mol)投入到反应釜中,0℃下滴加醋酐(682g,6.70mol),加完原料后,升至室温反应3h;再缓慢滴加33%二甲胺水溶液4.31kg,加完后升至室温反应5h。反应完毕后,静止分层,减压浓缩回收甲苯,残留物减压蒸馏收集110℃(0.07kPa)的馏分,制得(S)-1-二茂铁乙基二甲胺(0.99kg),暗红色油状液体,收率:87%;HPLC纯度:99%;ee值为98%。
以上所述仅为本发明的具体实施例,但本发明的技术特征并不局限于此,任何本领域的技术人员在本发明的领域内,所做的变化和修饰皆涵盖在本发明的专利范围之内。
Claims (8)
1.一种(S)-1-二茂铁乙基二甲胺的制备工艺,其特征在于包括如下步骤:
1)在0℃ ~ 50℃及氩气氛围下,将金属Ir络合物与手性配体L*依次加入到溶剂A中,反应0.5~5小时,制得催化剂[Ir]/L*,所述的金属Ir络合物为[Ir(NBD)2Cl]2、Ir(NBD)2)X、[Ir(COD)Cl]2或[Ir(COD)2]X中的任意一种,其中X为阴离子;
2)在氩气氛围下,向反应釜中依次加入式(1)所示的乙酰基二茂铁和步骤1)得到的催化剂[Ir]/L*,再加入溶剂B,最后加入碱,置换氢气后,于0℃ ~ 100℃以及0.1~10.0 MPa下进行不对称加氢反应,2~24小时后制得式(2)所示的(S)-1-二茂铁基乙醇;
3)0℃ ~ 40℃下,将步骤2)制备的(S)-1-二茂铁基乙醇与醋酐反应1~5小时后,随后加入质量分数为30% ~ 50%二甲胺水溶液,继续反应1~12小时后,减压浓缩有机层,所得粗品经减压蒸馏,得式(3)所示的(S)-1-二茂铁乙基二甲胺;
4.如权利要求1所述的(S)-1-二茂铁乙基二甲胺的制备工艺,其特征在于X为BF4⁻、ClO4⁻、SbF6⁻、PF6⁻、CF3SO3⁻、B(Ar)4⁻,其中Ar为芳基。
5.如权利要求1所述的(S)-1-二茂铁乙基二甲胺的制备工艺,其特征在于溶剂A和溶剂B分别选自二氯甲烷、四氢呋喃、甲苯、甲醇、乙醇、正丙醇、异丙醇、叔丁醇中的一种或几种。
6.如权利要求1所述的(S)-1-二茂铁乙基二甲胺的制备工艺,其特征在于催化剂与乙酰基二茂铁的摩尔比为1:100 ~ 1:100000。
7.如权利要求1所述的(S)-1-二茂铁乙基二甲胺的制备工艺,其特征在于步骤2)中的不对称氢化反应温度为20 ℃~60 ℃;氢气压力为2.0~5.0 Mpa。
8.如权利要求1所述的一种 (S)-1-二茂铁乙基二甲胺的制备工艺,其特征在于步骤2)中的碱选自叔丁基醇钾,叔丁基醇钠,叔丁基醇锂,碳酸铯,碳酸钾,碳酸钠,甲醇钠,氢氧化钠,氢氧化钾中的一种。
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