CN110590583A - 一种地诺帕明及其中间体的制备方法 - Google Patents
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 28
- 239000003054 catalyst Substances 0.000 claims abstract description 21
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims abstract description 15
- 230000003197 catalytic effect Effects 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 239000003446 ligand Substances 0.000 claims description 20
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 18
- 229910052751 metal Inorganic materials 0.000 claims description 14
- 239000002184 metal Substances 0.000 claims description 13
- ANOUKFYBOAKOIR-UHFFFAOYSA-N 3,4-dimethoxyphenylethylamine Chemical compound COC1=CC=C(CCN)C=C1OC ANOUKFYBOAKOIR-UHFFFAOYSA-N 0.000 claims description 12
- 150000002503 iridium Chemical class 0.000 claims description 11
- -1 3, 5-dimethylphenyl Chemical group 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- LJYOFQHKEWTQRH-UHFFFAOYSA-N 2-bromo-1-(4-hydroxyphenyl)ethanone Chemical compound OC1=CC=C(C(=O)CBr)C=C1 LJYOFQHKEWTQRH-UHFFFAOYSA-N 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- 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
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 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
- 230000000536 complexating effect Effects 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 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
- 229910052741 iridium Inorganic materials 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
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 claims description 2
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims 2
- 238000010668 complexation reaction Methods 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 238000007039 two-step reaction Methods 0.000 claims 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 20
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000007787 solid Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- VHSBBVZJABQOSG-INIZCTEOSA-N denopamine Chemical compound C1=C(OC)C(OC)=CC=C1CCNC[C@H](O)C1=CC=C(O)C=C1 VHSBBVZJABQOSG-INIZCTEOSA-N 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- HKJSUKPBCYPOJO-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)ethanamine;hydrobromide Chemical compound Br.COC1=CC=C(CCN)C=C1OC HKJSUKPBCYPOJO-UHFFFAOYSA-N 0.000 description 2
- TXFPEBPIARQUIG-UHFFFAOYSA-N 4'-hydroxyacetophenone Chemical compound CC(=O)C1=CC=C(O)C=C1 TXFPEBPIARQUIG-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 229950007304 denopamine Drugs 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000003760 magnetic stirring Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010037423 Pulmonary oedema Diseases 0.000 description 1
- GQENPXQJRUSMDY-UHFFFAOYSA-N [Ir+].ClC1=CCCC=CCC1 Chemical group [Ir+].ClC1=CCCC=CCC1 GQENPXQJRUSMDY-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 102000016967 beta-1 Adrenergic Receptors Human genes 0.000 description 1
- 108010014494 beta-1 Adrenergic Receptors Proteins 0.000 description 1
- 230000003177 cardiotonic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- ORBBTCHHNMWMCP-UHFFFAOYSA-K cycloocta-1,5-diene trichloroiridium Chemical group [Ir](Cl)(Cl)Cl.C1=CCCC=CCC1 ORBBTCHHNMWMCP-UHFFFAOYSA-K 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 208000005333 pulmonary edema Diseases 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
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- 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
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- 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
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
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- 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
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/60—Reduction reactions, e.g. hydrogenation
- B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
- B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
- B01J2231/643—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of R2C=O or R2C=NR (R= C, H)
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/827—Iridium
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
本发明公开了一种地诺帕明及其中间体的制备方法,具体为通过Ir/f‑amphox催化不对称氢化制备地诺帕明的方法。该方法步骤简单,操作简便,条件温和,可以高效不对称氢化合成地诺帕明,催化剂用量可以仅为0.002mol%(S/C=50,000),具有巨大的工业应用价值。
Description
技术领域
本发明属于医药化学合成领域,具体涉及一种地诺帕明及其中间体的制备方法。
背景技术
地诺帕明(Denopamine),化学名为:(R-[[[2-(3,4-二甲氧基苯基)乙基]氨基]甲基]-4-羟基苯甲醇,CAS:71771-90-9,分子式:C18H23ClNO4,分子量:317.383,结构式为:
地诺帕明[商品名:Kalgut(カルグート)]由日本田边三菱制药株式会社有限公司(Tanabe Seiyaku,Co.,Ltd.)研发,1988年4月首次在日本上市。该化合物是一种口服强心药(5mg或10mg的片剂或5%的细粒),可选择性地刺激肾上腺素能β1-受体,使心肌收缩力持续加强,但对β2-和α-受体几无刺激作用,故不影响心搏数,用于治疗心绞痛,也可能具有治疗充血性心力衰竭和清除肺水肿的潜在用途。
现有技术中关于地诺帕明的合成方法的专利文献主要有CN107021884A,CN1237574A;Yakugaku zasshi,1986,106(1),80-89;Chem.Pharm.Bull.,1993,41(4),639-642;Chem.Eur.J.2007,13,7780–7784等。在实现本发明过程中,发明人发现现有技术中至少存在如下问题:
中国科学院成都有机化学研究所专利文件CN1237574A中公开了地诺帕明消旋体的制备方法,具体如下:
在该方法中,第一步使用三乙胺为碱,反应可控性差,不利于放大;最后一步,2g底物需要使用5%钯-活性炭0.1g催化氢化,催化效率低,生产成本高,并且最终得到的化合物为消旋体,需要经过拆分才可以获得所需构型化合物。
田边制药株式会社有机化学研究所在文献Yakugaku zasshi,1986,106(1),80-89中公开了合成地诺帕明的方法,具体如下:
该方法反应路线长,得到的中间体需要经过手性拆分,至少需要浪费掉一半的物料,最后还需要使用大量重金属催化脱去酚羟基上的保护,进一步增加了成本。
田边三棱制药株式会社有限公司在文献Chem.Pharm.Bull.,1993,41(4),639-642中公开了一种对应选择性合成地诺帕明的方法,具体如下:
使用方法B在四氢呋喃中,在2-3℃条件下,还原2f结果最好(88%ee,95%yield),所得氢化产物还需要经过进一步重结晶,以获得符合手性需求的中间体,然后经过脱去保护基团,获得最终地诺帕明化合物。该方法路线长,生产成本高,三废多。
张绪穆等人在文献Chem.Eur.J.2007,13,7780–7784中公开了一种不对称氢化法制备地诺帕明的方法,具体如下:
该方法以对羟基苯乙酮为起始物料,最终获得的地诺帕明ee值仅88%,达不到制药要求,仍需要经过重结晶提高ee值,并且底物对催化剂的转化数仅达到100,放大生产成本高。
发明内容
一方面提供了一种地诺帕明关键中间体α-氨基酮及其通过Ir/f-amphox催化不对称氢化合成地诺帕明的方法,至少解决上述背景技术中提到的的某些问题。
本发明是通过以下技术方案实行的。
诺帕明关键中间体α-氨基酮IV的制备:
第一步反应:3,4-二甲氧基苯乙胺III与2-溴-4'-羟基苯乙酮II在乙腈中反应完成后,过滤除去固体,浓缩滤液;固体经过碱游离后可直接继续下一次和2-溴-4'-羟基苯乙酮II发生第一步反应。第二步反应:滤液再溶解于丙酮,通入过量氯化氢气体,过滤,使用丙酮洗涤滤饼,得到纯白色固体,真空干燥即得到地诺帕明关键中间体α-氨基酮IV。
所述3,4-二甲氧基苯乙胺III与2-溴-4'-羟基苯乙酮II的摩尔比例为1.90-2.2∶1。
通过Ir/f-amphox催化不对称氢化合成地诺帕明的方法:
在氢气氛围下,在质子性有机溶剂中,由手性配体f-amphox(L)与金属铱盐络合得到的催化剂的存在下,加入关键中间体α-氨基酮IV和碱,发生不对称氢化反应,得到地诺帕明I;
所述手性配体f-amphox为下述通式L所表示的化合物:
通式L中R表示甲基、异丙基、叔丁基、苯基、苄基或其它任意的C1-C6的直链、支链或环状取代基;Ar表示苯基、4-甲基苯基、4-甲氧基苯基、3,5-二甲基苯基、3,5-二甲基-4-甲氧基苯基、3,4,5-三甲基苯基、3,5-二叔丁基苯基、3,5-二叔丁基-4-甲氧基、3,5-二叔丁基-4-甲基。
地诺帕明中间体α-氨基酮IV进行不对称氢化反应时,反应温度为30~70℃,氢气压力为20~60大气压,反应时间为6~120小时
所述催化剂是由手性配体f-amphox(L)与金属铱盐在iPrOH中络合得到。金属铱盐与手性配体的摩尔比为0.5:1.0-1.2,反应温度为室温,反应时间为1~3小时。本发明优选的金属铱盐为[Ir(COD)Cl]2。
络合得到的催化剂不进行分离,直接在碱存在下用于催化不对称氢化反应。
所述碱与地诺帕明中间体α-氨基酮IV的摩尔比例为2.0~2.4∶1。
所述催化剂与地诺帕明中间体α-氨基酮IV的摩尔比例为1:1000-50000,优选1:30000-50000。
上述技术方案中的一个技术方案具有如下优点或有益效果:
总之,本发明采用三齿配体催化剂体系Ir/f-amphox,由于其高度的稳定性和反应活性,克服了由于产物对催化剂金属中心配位导致的失活。与现有技术相比,工艺更为先进。尤其是在手性生成步骤,本发明技术可以得到大于99%的对映选择性和高达50,000的催化剂转化数(TON),远远高于目前所有的已知公开报道。同时,与现有技术相比,本发明工艺操作简捷,中间产物及三废明显减少,适宜工业化放大生产。
另外,本发明方法操作简单、成本低廉同时转化率和选择性都极高,具有原子经济性高,环境友好的特点,具有极高的工业化价值。
具体实施方式
为了使本领域的技术人员更好地理解本发明的技术方案,下面进一步披露一些非限制实施例对本发明作进一步的详细说明。
本发明方法在制备地诺帕明关键中间体α-氨基酮IV时,第一步反应所用溶剂优选为乙腈,丙酮,四氢呋喃,乙酸乙酯,甲基叔丁基醚等,进一步优选为乙腈;第二步反应所用溶剂优选为乙醇,乙腈,丙酮,四氢呋喃,甲基叔丁基醚等,进一步优选为丙酮。
本发明方法为在手性催化剂的存在下进行的地诺帕明中间体α-氨基酮IV的不对称氢化反应,该催化剂是由金属铱盐与手性配体f-amphox配合而成的,配体结构如通式如L所示。
在本发明中优选的金属铱盐为[Ir(COD)Cl]2,其中文全称为:1,5-环辛二烯氯化铱二聚体,英文全称为:Chloro(1,5-cyclooctadiene)iridium(I)dimer。
在本发明中手性配体与所述金属铱盐在iPrOH中反应得到目标催化剂时,金属铱盐与手性配体的摩尔比为0.5:1.0~1.2,优选后为0.5:1.0~1.1,进一步优选为0.5:1.05。
在本发明中,手性配体与所述金属铱盐在溶剂中反应得到目标催化剂时,反应温度可以根据需要设置,优选后为30~70℃,进一步优选为55-60℃。
在本发明中,反应氢气压力为30~60大气压,优选后为30-50大气压,进一步优选为40-45大气压。
在本发明中,所述碱包括:叔丁醇锂,叔丁醇钠,叔丁醇钾,甲醇锂,甲醇钠,甲醇钾,氢氧化锂,氢氧化钠,氢氧化钾,碳酸钠,碳酸钾,碳酸铯中的一种或几种。优选后为叔丁醇钠或叔丁醇钾,进一步优选为叔丁醇钠。
在本发明中,使α-氨基酮IV与碱的摩尔比例为1:2.0~2.4,优选后为1:2.15~2.25,进一步优选为1:2.2。
在本发明中,使α-氨基酮IV于iPrOH中的摩尔浓度为0.2~2.5,优选后为1.5~2.25,进一步优选为2.0~2.1。
另外,在本发明中,使α-氨基酮IV发生不对称氢化反应时,α-氨基酮IV与催化剂的摩尔比例为1000~50000∶1,优选1:20000-50000,进一步优选为1:30000。此时,实际上对于α-氨基酮与原位催化剂的摩尔比例没有任何限制,因为原位催化剂的催化效率之高使得在使用很少量的原位催化剂的情况下,也能够使酮的不对称氢化顺利地进行,并且能够获得很高的转化率和诱导效果。
实施例1:诺帕明关键中间体α-氨基酮IV的制备
在带磁力搅拌的100mL圆底烧瓶中,依次加入3.62g(20.0mmol)3,4-二甲氧基苯乙胺III和20mL乙腈,冰水浴10分钟,然后再滴加2.15g(10.0mmol)2-溴-4'-羟基苯乙酮II的乙腈溶液20mL,搅拌0.5~1.0小时,过滤,分别收集3,4-二甲氧基苯乙胺氢溴酸盐固体和浅黄色滤液,滤液浓缩,重新溶解于丙酮,通入氯化氢气体,至不再有固体产生,低温(-10℃)搅拌0.5小时。过滤,以丙酮洗涤三次,抽干,真空干燥,即可得到诺帕明关键中间体α-氨基酮IV白色固体3.3g(yield 94%)。1H NMR(400MHz,DMSO-d6)δ:10.86(s,1H),9.26(s,2H),7.96-7.82(m,2H),7.00-6.85(m,4H),6.81-6.74(m,1H),4.68(s,2H),3.76(s,3H),3.73(s,3H),3.24-3.12(m,2H),3.03-2.92(m,2H).
实施例2:诺帕明关键中间体α-氨基酮IV的制备
在带磁力搅拌的2000mL圆底烧瓶中,依次加入181.3g(1.0mol)3,4-二甲氧基苯乙胺III和1500mL乙腈,冰水浴10分钟,然后分批加入107.6g(0.5mol)2-溴-4'-羟基苯乙酮II,搅拌1小时,过滤,分别收集3,4-二甲氧基苯乙胺氢溴酸盐固体和橘红色滤液,滤液浓缩,重新溶解于丙酮,通入氯化氢气体,至不再有固体产生,低温(-10℃)搅拌0.5小时。过滤,以丙酮洗涤三次,抽干,真空干燥,即可得到诺帕明关键中间体α-氨基酮IV白色固体142.9.0g(yield 81%)。1H NMR(400MHz,DMSO-d6)δ:10.86(s,1H),9.26(s,2H),7.96-7.82(m,2H),7.00-6.85(m,4H),6.81-6.74(m,1H),4.68(s,2H),3.76(s,3H),3.73(s,3H),3.24-3.12(m,2H),3.03-2.92(m,2H).
实施例3:从α-氨基酮I制备地诺帕明(S/C=2 000)
在高纯氩气氛围下,将[Ir(COD)Cl]2(3.4mg,5μmol)和手性配体(11.6mg,R=tBu,10μmol)溶于异丙醇(1mL)中,在室温条件下搅拌3小时,得到橙色澄清溶液。以微量注射器取该橙色溶液10μL(0.01mmol%),加入到α-氨基酮IV(70.4mg,0.2mmol)、异丙醇(1mL)和叔丁醇钠(0.44mmol)的混合体系中。将反应体系置于高压釜中,在室温和H2(40atm)条件下搅拌16小时。使用稀盐酸(2M)调节pH=7-8,加入二氯甲烷,水洗,饱和食盐水洗,无水硫酸钠干燥,浓缩溶剂后得到白色固体。产物产率>99%,经HPLC分析,测得ee值(ee>99%)。1H NMR(400MHz,CDCl3)δ7.14-7.05(m,2H),6.85-6.76(m,2H),6.72-6.64(m,3H),3.78(s,3H),3.76(s,3H),2.85-2.75(m,2H),2.73-2.63(m,4H).13C NMR(101MHz,CDCl3).
实施例4:从α-氨基酮I制备地诺帕明(S/C=5 000)
在高纯氩气氛围下,将[Ir(COD)Cl]2(3.4mg,5μmol)和手性配体(11.6mg,R=tBu,10μmol)溶于异丙醇(1mL)中,在室温条件下搅拌3小时,得到橙色澄清溶液。以微量注射器取该橙色溶液100μL(0.1mmol%),加入到α-氨基酮IV(1.76g,5.0mmol)、异丙醇(5.0mL)和叔丁醇钠(1.06g,11.0mmol)的混合体系中。将反应体系置于高压釜中,在55℃和H2(40atm)条件下搅拌96小时。使用稀盐酸(2M)调节pH=7-8,加入二氯甲烷,水洗,饱和食盐水洗,无水硫酸钠干燥,浓缩溶剂后得到白色固体。产物产率>99%,经HPLC分析,测得ee值(ee>99%)。
实施例5:从α-氨基酮I制备地诺帕明(S/C=10 000)
在高纯氩气氛围下,将[Ir(COD)Cl]2(3.4mg,5μmol)和手性配体(11.6mg,R=tBu,10μmol)溶于异丙醇(1mL)中,在室温条件下搅拌3小时,得到橙色澄清溶液。以微量注射器取该橙色溶液100μL(0.1mol%),加入到α-氨基酮IV(3.52g,10.0mmol)、异丙醇(5.0mL)和叔丁醇钠(2.11g,22.0mmol)的混合体系中。将反应体系置于高压釜中,在55℃和H2(40atm)条件下搅拌96小时。使用稀盐酸(2M)调节pH=7-8,加入二氯甲烷,水洗,饱和食盐水洗,无水硫酸钠干燥,浓缩溶剂后得到白色固体。产物产率>99%,经HPLC分析,测得ee值(ee>99%)。
实施例6:从α-氨基酮I制备地诺帕明(S/C=20 000)
在高纯氩气氛围下,将[Ir(COD)Cl]2(3.4mg,5μmol)和手性配体(11.6mg,R=tBu,10μmol)溶于异丙醇(1mL)中,在室温条件下搅拌3小时,得到橙色澄清溶液。以微量注射器取该橙色溶液100μL(0.1mol%),加入到α-氨基酮IV(7.04g,20.0mmol)、异丙醇(10.0mL)和叔丁醇钠(4.22g,44.0mmol)的混合体系中。将反应体系置于高压釜中,在55℃和H2(40atm)条件下搅拌96小时。使用稀盐酸(2M)调节pH=7-8,加入二氯甲烷,水洗,饱和食盐水洗,无水硫酸钠干燥,浓缩溶剂后得到白色固体。产物产率>99%,经HPLC分析,测得ee值(ee>99%)。
实施例7:从α-氨基酮I制备地诺帕明(S/C=50 000)
在高纯氩气氛围下,将[Ir(COD)Cl]2(3.4mg,5μmol)和手性配体(11.6mg,R=tBu,12μmol)溶于异丙醇(1mL)中,在室温条件下搅拌3小时,得到橙色澄清溶液。以微量注射器取该橙色溶液120μL(0.12mol%),加入到α-氨基酮IV(21.1g,60.0mmol)、异丙醇(30.0mL)和叔丁醇钠(12.7g,132.0mmol)的混合体系中。将反应体系置于高压釜中,在55℃和H2(40atm)条件下搅拌120小时。使用稀盐酸(2M)调节pH=7-8,加入二氯甲烷,水洗,饱和食盐水洗,无水硫酸钠干燥,浓缩溶剂后得到白色固体。产物产率>99%,经HPLC分析,测得ee值(ee>99%)。
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.地诺帕明中间体IV制备方法,其特征在于:
2-溴-4'-羟基苯乙酮II与3,4-二甲氧基苯乙胺III在溶剂中经过两步反应制备得到地诺帕明中间体α-氨基酮IV。
。
2.催化不对称氢化制备地诺帕明I的方法,其特征在于:
在氢气氛围下,在质子性有机溶剂中,由手性配体f-amphox与金属铱盐络合得到的催化剂的存在下,加入地诺帕明中间体α-氨基酮IV和碱,发生不对称氢化反应,得到地诺帕明I:
所述手性配体f-amphox为下述通式L所表示的化合物:
通式L中R表示甲基、异丙基、叔丁基、苯基、苄基或其它任意的C1-C6的直链或支链或环状取代基;Ar表示苯基、4-甲基苯基、4-甲氧基苯基、3,5-二甲基苯基、3,5-二甲基-4-甲氧基苯基、3,4,5-三甲基苯基、3,5-二叔丁基苯基、3,5-二叔丁基-4-甲氧基、3,5-二叔丁基-4-甲基。
3.根据权利要求1所述的制备方法,其特征在于,所述2-溴-4'-羟基苯乙酮II与3,4-二甲氧基苯乙胺III的摩尔比为1:1.9-2.2。
4.根据权利要求1所述的制备方法,其特征在于,所述溶剂为乙腈。
5.根据权利要求2所述的制备方法,其特征在于,所述不对称氢化反应的反应温度为30~70℃,氢气压力为20~60大气压,反应时间为6~120小时。
6.根据权利要求2所述的制备方法,其特征在于,所述催化剂由手性配体f-amphox与金属铱盐在iPrOH中络合得到;所述金属铱盐与手性配体f-amphox的摩尔比为0.5:1.0-1.2,络合反应温度为室温,络合反应时间为1~3小时。
7.根据权利要求6所述的方法,其特征在于,络合得到的催化剂不进行分离,直接用于催化不对称氢化反应。
8.根据权利要求2至6任一所述的方法,其特征在于,所述金属铱盐为[Ir(COD)Cl]2。
9.根据权利要求2所述的方法,其特征在于,所述碱与地诺帕明中间体α-氨基酮IV的摩尔比例为2.0~2.4∶1。
10.根据权利要求2或9所述的方法,其特征在于,所述碱包括:叔丁醇锂,叔丁醇钠,叔丁醇钾,甲醇锂,甲醇钠,甲醇钾,氢氧化锂,氢氧化钠,氢氧化钾,碳酸钠,碳酸钾,碳酸铯,三乙胺,N,N-二异丙基乙胺中的一种或几种。
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