CN114133412A - 一种手性1,2-双[(2-甲氧基苯基)苯基膦基]乙烷的制备方法 - Google Patents
一种手性1,2-双[(2-甲氧基苯基)苯基膦基]乙烷的制备方法 Download PDFInfo
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- QKZWXPLBVCKXNQ-UHFFFAOYSA-N (2-methoxyphenyl)-[2-[(2-methoxyphenyl)-phenylphosphanyl]ethyl]-phenylphosphane Chemical compound COC1=CC=CC=C1P(C=1C=CC=CC=1)CCP(C=1C(=CC=CC=1)OC)C1=CC=CC=C1 QKZWXPLBVCKXNQ-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 claims abstract description 16
- -1 (2-methoxyphenyl) (phenyl) phosphine oxide chloride Chemical compound 0.000 claims abstract description 15
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 12
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 7
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052751 metal Inorganic materials 0.000 claims abstract description 5
- 239000002184 metal Substances 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 238000000967 suction filtration Methods 0.000 claims description 10
- 239000012065 filter cake Substances 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- 238000010791 quenching Methods 0.000 claims description 8
- 230000000171 quenching effect Effects 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000004537 pulping Methods 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- ZDHXKXAHOVTTAH-UHFFFAOYSA-N trichlorosilane Chemical compound Cl[SiH](Cl)Cl ZDHXKXAHOVTTAH-UHFFFAOYSA-N 0.000 claims description 6
- 239000005052 trichlorosilane Substances 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 4
- YONLFQNRGZXBBF-KBPBESRZSA-N (2s,3s)-2,3-dibenzoyloxybutanedioic acid Chemical group O([C@H](C(=O)O)[C@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-KBPBESRZSA-N 0.000 claims description 3
- ZSTIGUNBSZBXLU-UHFFFAOYSA-N (2-methoxyphenyl)-[2-[(2-methoxyphenyl)-phenylphosphanyl]oxyethoxy]-phenylphosphane Chemical compound COC1=CC=CC=C1P(C=1C=CC=CC=1)OCCOP(C=1C(=CC=CC=1)OC)C1=CC=CC=C1 ZSTIGUNBSZBXLU-UHFFFAOYSA-N 0.000 claims description 2
- ZLGQYDRAWIFUHX-UHFFFAOYSA-N CC.COC1=C(C=CC=C1)PC1=CC=CC=C1 Chemical compound CC.COC1=C(C=CC=C1)PC1=CC=CC=C1 ZLGQYDRAWIFUHX-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- 229960001270 d- tartaric acid Drugs 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000003446 ligand Substances 0.000 abstract description 2
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- HTDQSWDEWGSAMN-UHFFFAOYSA-N 1-bromo-2-methoxybenzene Chemical compound COC1=CC=CC=C1Br HTDQSWDEWGSAMN-UHFFFAOYSA-N 0.000 description 2
- VQWBGASXMXZTEZ-UHFFFAOYSA-N 1-methoxy-2-[2-[(2-methoxyphenyl)-phenylphosphoryl]ethyl-phenylphosphoryl]benzene Chemical compound COC1=CC=CC=C1P(=O)(C=1C=CC=CC=1)CCP(=O)(C=1C(=CC=CC=1)OC)C1=CC=CC=C1 VQWBGASXMXZTEZ-UHFFFAOYSA-N 0.000 description 2
- VQWBGASXMXZTEZ-HEVIKAOCSA-N 1-methoxy-2-[2-[(2-methoxyphenyl)-phenylphosphoryl]ethyl-phenylphosphoryl]benzene Chemical compound COC1=CC=CC=C1[P@](=O)(CC[P@](=O)(C1=CC=CC=C1)C1=CC=CC=C1OC)C1=CC=CC=C1 VQWBGASXMXZTEZ-HEVIKAOCSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 238000004679 31P NMR spectroscopy Methods 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 239000012069 chiral reagent Substances 0.000 description 2
- GYSVADUBDWVPIT-UHFFFAOYSA-N ethyl-(2-methoxyphenyl)-phenylphosphane Chemical compound C=1C=CC=C(OC)C=1P(CC)C1=CC=CC=C1 GYSVADUBDWVPIT-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 description 1
- VQWBGASXMXZTEZ-KKLWWLSJSA-N 1-methoxy-2-[2-[(2-methoxyphenyl)-phenylphosphoryl]ethyl-phenylphosphoryl]benzene Chemical compound COc1ccccc1[P@@](=O)(CC[P@@](=O)(c1ccccc1)c1ccccc1OC)c1ccccc1 VQWBGASXMXZTEZ-KKLWWLSJSA-N 0.000 description 1
- DPMGLJUMNRDNMX-UHFFFAOYSA-N 4-tert-butyl-2-[2-(4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl)propan-2-yl]-4,5-dihydro-1,3-oxazole Chemical compound CC(C)(C)C1COC(C(C)(C)C=2OCC(N=2)C(C)(C)C)=N1 DPMGLJUMNRDNMX-UHFFFAOYSA-N 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 229910021585 Nickel(II) bromide Inorganic materials 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- IMDXZWRLUZPMDH-UHFFFAOYSA-N dichlorophenylphosphine Chemical compound ClP(Cl)C1=CC=CC=C1 IMDXZWRLUZPMDH-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 1
- CCZVEWRRAVASGL-UHFFFAOYSA-N lithium;2-methanidylpropane Chemical compound [Li+].CC(C)[CH2-] CCZVEWRRAVASGL-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- IPLJNQFXJUCRNH-UHFFFAOYSA-L nickel(2+);dibromide Chemical compound [Ni+2].[Br-].[Br-] IPLJNQFXJUCRNH-UHFFFAOYSA-L 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/5022—Aromatic phosphines (P-C aromatic linkage)
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/505—Preparation; Separation; Purification; Stabilisation
- C07F9/5063—Preparation; Separation; Purification; Stabilisation from compounds having the structure P-H or P-Heteroatom, in which one or more of such bonds are converted into P-C bonds
- C07F9/5068—Preparation; Separation; Purification; Stabilisation from compounds having the structure P-H or P-Heteroatom, in which one or more of such bonds are converted into P-C bonds from starting materials having the structure >P-Hal
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
Abstract
本发明公开了一种手性1,2‑双[(2‑甲氧基苯基)苯基膦基]乙烷的制备方法,属于有机合成领域。该方法以(2‑甲氧基苯基)(苯基)氯化氧膦为起始原料,与金属锂制备得2‑甲氧基苯基)(苯基)氧膦锂,再与1,2‑二溴乙烷反应得到外消旋的1,2‑双[(2‑甲氧基苯基)苯基膦氧基]乙烷,经手性拆分后得到手性1,2‑双[(2‑甲氧基苯基)苯基膦氧基]乙烷,最后通过还原得到三价的手性1,2‑双[(2‑甲氧基苯基)苯基膦基]乙烷。本发明与现有的技术相比反应步骤短,操作简单,收率高,更适合工业化生产。制得的手性1,2‑双[(2‑甲氧基苯基)苯基膦基]乙烷用于手性催化的配体,应用于医药领域。
Description
技术领域
本发明属于有机合成领域,涉及一类有机膦化合物的合成方法,尤其涉及手性1,2-双[(2-甲氧基苯基)苯基膦基]乙烷的制备方法。
背景技术
手性1,2-双[(2-甲氧基苯基)苯基膦基]乙烷是一类重要的手性有机膦配体,它与过渡金属铑形成的配合物在催化不对称氢化反应时具有良好的反应活性和选择性,已经广泛应用于医药中间体合成当中。
文献报道的关于手性1,2-双[(2-甲氧基苯基)苯基膦基]乙烷的合成方法主要是通过邻溴苯甲醚形成格式试剂后与苯基二氯化膦以及手性薄荷醇反应,然后经硼烷保护后与甲基锂反应,再通过异丁基锂锂化,无水氯化铜偶联,二乙胺脱保护得到手性1,2-双[(2-甲氧基苯基)苯基膦基]乙烷( J. Am. Chem. Soc.,1985, 107, 5301)。该方法反应步骤多,操作麻烦,收率低。另外,有专利报道方法在无水无氧氛围中,以1,2-双(二苯基膦基)乙烷为原料,四氢呋喃为溶剂,首先与氢化钠反应,然后在溴化镍和手性2,2'-异亚丙基双(4-叔丁基-2-恶唑啉)的作用下与邻溴苯甲醚反应生成手性1,2-双[(2-甲氧基苯基)苯基膦基]乙烷。该方法需要使用价格昂贵的手性试剂,从而限制了其应用。因此,十分有必要探索出一种更简便,更经济,更适合工业化的合成手性1,2-双[(2-甲氧基苯基)苯基膦基]乙烷的方法。
发明内容
本发明的目的在于提供一种收率高、生产成本低、后处理简单,适合工业化生产的手性1,2-双[(2-甲氧基苯基)苯基膦基]乙烷的制备方法。
为实现上述目的,本发明采用以下技术方案:
一种手性1,2-双[(2-甲氧基苯基)苯基膦基]乙烷的制备方法,包括以下步骤:
(1)在惰气保护下,向干燥反应器中加入(2-甲氧基苯基)(苯基)氯化氧膦,四氢呋喃以及金属锂片,然后在50-60℃下反应10-12h,然后降温至0-10℃下滴加1,2-二溴乙烷,反应结束后停止反应,加水淬灭后浓缩,然后加入甲醇打浆析出固体,抽滤,滤饼即为外消旋的1,2-双[(2-甲氧基苯基)苯基膦氧基]乙烷;
(2)在反应瓶中加入外消旋的1,2-双[(2-甲氧基苯基)苯基膦氧基]乙烷,二氯甲烷溶解,然后滴加手性拆分试剂的甲醇溶液,然后40℃反应10-12h,逐渐析出固体,抽滤,在另一反应瓶中加入滤饼,二氯甲烷,滴加氢氧化钠水溶液,逐渐溶解,分液,干燥后旋干即为手性1,2-双[(2-甲氧基苯基)苯基膦氧基]乙烷;所述的手性拆分试剂为D-二苯甲酰酒石酸或D-酒石酸;
(3)在反应瓶中加入手性1,2-双[(2-甲氧基苯基)苯基膦氧基]乙烷,甲苯,三乙胺,三氯硅烷,100℃反应10h,然后加碱水淬灭,分液,浓缩,甲醇打浆抽滤即得手性1,2-双[(2-甲氧基苯基)苯基膦基]乙烷;
反应路线如下:
进一步,所述步骤(1)中的(2-甲氧基苯基)(苯基)氯化氧膦与金属锂的摩尔比为1:(1.1-1.3)。
进一步,所述步骤(1)中的(2-甲氧基苯基)(苯基)氯化氧膦与1,2-二溴乙烷的摩尔比为1:(0.4-0.5)。
进一步,所述步骤(2)中的外消旋1,2-双[(2-甲氧基苯基)苯基膦氧基]乙烷与手性拆分试剂的摩尔比为1:(1.1-1.4)。
进一步,所述步骤(3)中的手性1,2-双[(2-甲氧基苯基)苯基膦氧基]乙烷、三乙胺和三氯硅烷的的摩尔比为1:3:3-1:4:4。
本发明的有益效果在于:本发明与现有的技术相比,避免了复杂的反应过程,简化了拆分过程,同时又避免了昂贵手性试剂的使用,该发明收率高且终产品的ee值高,ee值在98%以上,能够满足市场需求。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚,下面对本发明的技术方案进行详细描述,但下述实施例仅仅是本发明的一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域技术人员在没有做出创造性劳动的前提下所得到的所有其它实施方式,都属于本发明所保护的范围。
实施例1
本实施例(S,S)-1,2-双[(2-甲氧基苯基)苯基膦基]乙烷的合成方法如下:
(1)惰气保护下,向干燥反应器中加入5g(2-甲氧基苯基)(苯基)氯化氧膦,无水四氢呋喃50ml以及144mg金属锂,然后在50℃下反应10h,然后降温至0。C滴加1.75g 1,2-二溴乙烃,反应结束后停止反应,加水淬灭后浓缩,然后加入甲醇打浆析出固体,抽滤,滤饼即为1,2-双[(2-甲氧基苯基)苯基膦氧基]乙烷,干重3.2g,收率70%;
(2)在反应瓶中加入3.2g 1,2-双[(2-甲氧基苯基)苯基氧膦基]乙烷,30ml二氯甲烷溶解,然后滴加2.8g D-二苯甲酰酒石酸与20ml甲醇配成的溶液,然后40℃反应12h,逐渐析出固体,抽滤,在另一反应瓶中加入滤饼,50ml二氯甲烷,滴加10ml 3N氢氧化钠水溶液,逐渐溶解,分液,干燥后旋干即为(S,S)-1,2-双[(2-甲氧基苯基)苯基氧膦基]乙烷,质量2.7g,收率85%,ee值99.1%;
(3)在反应瓶中加入2.7g(S,S)-1,2-双[(2-甲氧基苯基)苯基氧膦基]乙烷,30ml甲苯,1.67g三乙胺,2.23g三氯硅烷,100℃反应10h,然后加碱水淬灭,分液,浓缩,甲醇打浆抽滤即得(S,S)-1,2-双[(2-甲氧基苯基)苯基氧膦基]乙烷,质量2.26g,收率90%。31P NMR( 121 MHz, CDCl3) δ 18.17 (s) ppm.1H NMR (300 MHz, CDCl3) δ 2.54 – 2.63 (m,4H, 2CH2), 3.61 (s, 2OCH3), 6.80 – 6.82 (m, 2H, ArH), 7.02 – 7.04 (m, 2H,ArH), 7.35 – 7.42 (m, 6H, ArH), 7.44 – 7.47 (m, 2H, ArH), 7.48 – 7.68 (m, 4H,ArH), 7.83 – 7.89 (m, 2H, ArH) ppm.
实施例2
本实施例(R,R)-1,2-双[(2-甲氧基苯基)苯基膦基]乙烷的合成方法如下:
(1)惰气保护下,向干燥反应器中加入5g(2-甲氧基苯基)(苯基)氯化氧膦,无水四氢呋喃50ml以及144mg金属锂,然后在40℃下反应12h,然后降温至0℃滴加1.75g 1,2-二溴乙烃,反应结束后停止反应,加水淬灭后浓缩,然后加入甲醇打浆析出固体,抽滤,滤饼即为1,2-双[(2-甲氧基苯基)苯基膦氧基]乙烷,干重3.2g,收率70%;
(2)在反应瓶中加入3.2g 1,2-双[(2-甲氧基苯基)苯基氧膦基]乙烷,30ml二氯甲烷溶解,然后滴加1.2g L-酒石酸与20ml甲醇配成的溶液,然后40℃反应12h,逐渐析出固体,抽滤,在另一反应瓶中加入滤饼,50ml二氯甲烷,滴加10ml 3N氢氧化钠水溶液,逐渐溶解,分液,干燥后旋干即为(R,R)-1,2-双[(2-甲氧基苯基)苯基膦氧基]乙烷,质量2.5g,收率78%,ee值98.5%;
(3)在反应瓶中加入2.5g(R,R)-1,2-双[(2-甲氧基苯基)苯基膦氧基]乙烷,30ml甲苯,1.67g三乙胺,2.23g三氯硅烷,100℃反应10h,然后加碱水淬灭,分液,浓缩,甲醇打浆抽滤即得(R,R)-1,2-双[(2-甲氧基苯基)苯基氧膦基]乙烷,质量2.0g,收率88%。31P NMR (121 MHz, CDCl3) δ 18.16 (s) ppm.1H NMR (300 MHz, CDCl3) δ 2.53 – 2.61 (m, 4H,2CH2), 3.60 (s, 2OCH3), 6.78 – 6.80 (m, 2H, ArH), 7.01– 7.03 (m, 2H, ArH),7.34 – 7.40 (m, 6H, ArH), 7.42 – 7.45 (m, 2H, ArH), 7.46 – 7.65 (m, 4H, ArH),7.80– 7.86 (m, 2H, ArH) ppm.
以上显示和描述了本发明的基本原理和主要特征以及本发明的优点。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 (5)
1.一种手性1,2-双[(2-甲氧基苯基)苯基膦基]乙烷的制备方法,其特征在于,包括以下步骤:
(1)在惰气保护下,向干燥反应器中加入(2-甲氧基苯基)(苯基)氯化氧膦,四氢呋喃以及金属锂片,然后在50-60℃下反应10-12h,然后降温至0-10℃下滴加1,2-二溴乙烷,反应结束后停止反应,加水淬灭后浓缩,然后加入甲醇打浆析出固体,抽滤,滤饼即为外消旋的1,2-双[(2-甲氧基苯基)苯基膦氧基]乙烷;
(2)在反应瓶中加入外消旋的1,2-双[(2-甲氧基苯基)苯基膦氧基]乙烷,二氯甲烷溶解,然后滴加手性拆分试剂的甲醇溶液,然后40℃反应10-12h,逐渐析出固体,抽滤,在另一反应瓶中加入滤饼,二氯甲烷,滴加氢氧化钠水溶液,逐渐溶解,分液,干燥后旋干即为手性1,2-双[(2-甲氧基苯基)苯基膦氧基]乙烷;所述的手性拆分试剂为D-二苯甲酰酒石酸或D-酒石酸;
(3)在反应瓶中加入手性1,2-双[(2-甲氧基苯基)苯基膦氧基]乙烷,甲苯,三乙胺,三氯硅烷,100℃反应10h,然后加碱水淬灭,分液,浓缩,甲醇打浆抽滤即得手性1,2-双[(2-甲氧基苯基)苯基膦基]乙烷;
反应路线如下:
2.根据权利要求1所述的手性1,2-双[(2-甲氧基苯基)苯基膦基]乙烷的制备方法,其特征在于:所述步骤(1)中的(2-甲氧基苯基)(苯基)氯化氧膦与金属锂的摩尔比为1:(1.1-1.3)。
3.根据权利要求1所述的手性1,2-双[(2-甲氧基苯基)苯基膦基]乙烷的制备方法,其特征在于:所述步骤(1)中的(2-甲氧基苯基)(苯基)氯化氧膦与1,2-二溴乙烷的摩尔比为1:(0.4-0.5)。
4.根据权利要求1所述的手性1,2-双[(2-甲氧基苯基)苯基膦基]乙烷的制备方法,其特征在于:所述步骤(2)中的外消旋1,2-双[(2-甲氧基苯基)苯基膦氧基]乙烷与手性拆分试剂的摩尔比为1:(1.1-1.4)。
5.根据权利要求1所述的手性1,2-双[(2-甲氧基苯基)苯基膦基]乙烷的制备方法,其特征在于:所述步骤(3)中的手性1,2-双[(2-甲氧基苯基)苯基膦氧基]乙烷、三乙胺和三氯硅烷的的摩尔比为1:3:3-1:4:4。
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