CN107652274B - 一种季戊四醇固载的（s）或（r）-二苯基脯氨醇及其制备方法及应用 - Google Patents
一种季戊四醇固载的（s）或（r）-二苯基脯氨醇及其制备方法及应用 Download PDFInfo
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- CN107652274B CN107652274B CN201710815956.0A CN201710815956A CN107652274B CN 107652274 B CN107652274 B CN 107652274B CN 201710815956 A CN201710815956 A CN 201710815956A CN 107652274 B CN107652274 B CN 107652274B
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- Prior art keywords
- pentaerythritol
- cbz
- immobilized
- diphenylprolinol
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- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title abstract description 20
- OGCGXUGBDJGFFY-UHFFFAOYSA-N diphenylprolinol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O)C1CCCN1 OGCGXUGBDJGFFY-UHFFFAOYSA-N 0.000 claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 14
- -1 pentaerythritol tetraazide compound Chemical class 0.000 claims abstract description 12
- 150000002576 ketones Chemical class 0.000 claims abstract description 10
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims abstract description 8
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims abstract description 7
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims abstract description 6
- 150000004702 methyl esters Chemical class 0.000 claims abstract description 4
- JJPDLJMISDLYON-UHFFFAOYSA-N [N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-].OCC(CO)(CO)CO Chemical compound [N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-].OCC(CO)(CO)CO JJPDLJMISDLYON-UHFFFAOYSA-N 0.000 claims abstract description 3
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 claims abstract 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 38
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical group [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 150000004820 halides Chemical class 0.000 claims description 4
- 239000003495 polar organic solvent Substances 0.000 claims description 4
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 2
- 239000007818 Grignard reagent Substances 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 150000003512 tertiary amines Chemical group 0.000 claims description 2
- JQIVECLQPHOSDY-KRWDZBQOSA-N [(2r)-1,2-diphenylpyrrolidin-2-yl]methanol Chemical compound C([C@]1(CO)C=2C=CC=CC=2)CCN1C1=CC=CC=C1 JQIVECLQPHOSDY-KRWDZBQOSA-N 0.000 claims 3
- VVKAGQHUUDRPOI-PIJUOVFKSA-N 1-O-benzyl 2-O-methyl (2R)-4-hydroxypyrrolidine-1,2-dicarboxylate Chemical compound COC(=O)[C@H]1CC(O)CN1C(=O)OCc1ccccc1 VVKAGQHUUDRPOI-PIJUOVFKSA-N 0.000 claims 1
- 239000002585 base Substances 0.000 claims 1
- 239000003054 catalyst Substances 0.000 abstract description 16
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 abstract 1
- GQONLASZRVFGHI-UHFFFAOYSA-M phenylmagnesium chloride Chemical compound Cl[Mg]C1=CC=CC=C1 GQONLASZRVFGHI-UHFFFAOYSA-M 0.000 abstract 1
- 229940059574 pentaerithrityl Drugs 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- 238000001914 filtration Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 238000006722 reduction reaction Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-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
- 238000004440 column chromatography Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 150000003333 secondary alcohols Chemical class 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- SWPMXMVTNUTKEX-YNMFNDETSA-N benzyl (2R)-2-(hydroxymethyl)-2,3-diphenylpyrrolidine-1-carboxylate Chemical compound C(=O)(OCC1=CC=CC=C1)N1[C@@](C(CC1)C1=CC=CC=C1)(CO)C1=CC=CC=C1 SWPMXMVTNUTKEX-YNMFNDETSA-N 0.000 description 3
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical class [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- KTMKRRPZPWUYKK-UHFFFAOYSA-N methylboronic acid Chemical compound CB(O)O KTMKRRPZPWUYKK-UHFFFAOYSA-N 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- XXFUZSHTIOFGNV-UHFFFAOYSA-N 1-bromoprop-1-yne Chemical compound CC#CBr XXFUZSHTIOFGNV-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- HQGAJOFIQLBIIM-AWEZNQCLSA-N (1r)-2-bromo-1-(3-nitro-4-phenylmethoxyphenyl)ethanol Chemical compound [O-][N+](=O)C1=CC([C@H](CBr)O)=CC=C1OCC1=CC=CC=C1 HQGAJOFIQLBIIM-AWEZNQCLSA-N 0.000 description 1
- GMVPRGQOIOIIMI-UHFFFAOYSA-N (8R,11R,12R,13E,15S)-11,15-Dihydroxy-9-oxo-13-prostenoic acid Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(O)=O GMVPRGQOIOIIMI-UHFFFAOYSA-N 0.000 description 1
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 1
- 229930182836 (R)-noradrenaline Natural products 0.000 description 1
- WAPNOHKVXSQRPX-UHFFFAOYSA-N 1-phenylethanol Chemical compound CC(O)C1=CC=CC=C1 WAPNOHKVXSQRPX-UHFFFAOYSA-N 0.000 description 1
- PBAAKBQGBSUCTG-UHFFFAOYSA-N 2-bromo-1-(3-nitro-4-phenylmethoxyphenyl)ethanone Chemical compound [O-][N+](=O)C1=CC(C(=O)CBr)=CC=C1OCC1=CC=CC=C1 PBAAKBQGBSUCTG-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- BPZSYCZIITTYBL-YJYMSZOUSA-N R-Formoterol Chemical compound C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-YJYMSZOUSA-N 0.000 description 1
- KONLIBVIAJDWIR-UHFFFAOYSA-N [methyl(sulfo)boranyl]methane Chemical compound CB(C)S(O)(=O)=O KONLIBVIAJDWIR-UHFFFAOYSA-N 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229940061720 alpha hydroxy acid Drugs 0.000 description 1
- 150000001280 alpha hydroxy acids Chemical class 0.000 description 1
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 1
- 235000008206 alpha-amino acids Nutrition 0.000 description 1
- XPNGNIFUDRPBFJ-UHFFFAOYSA-N alpha-methylbenzylalcohol Natural products CC1=CC=CC=C1CO XPNGNIFUDRPBFJ-UHFFFAOYSA-N 0.000 description 1
- 229960000711 alprostadil Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- ZTTCLPRVUXKXAX-UHFFFAOYSA-N cyclopenta-1,3-diene cyclopenta-2,4-diene-1,2-diol iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.Oc1ccc[c-]1O ZTTCLPRVUXKXAX-UHFFFAOYSA-N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 229960002464 fluoxetine Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- IWCVDCOJSPWGRW-UHFFFAOYSA-M magnesium;benzene;chloride Chemical compound [Mg+2].[Cl-].C1=CC=[C-]C=C1 IWCVDCOJSPWGRW-UHFFFAOYSA-M 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- PLFLRQISROSEIJ-UHFFFAOYSA-N methylborane Chemical compound CB PLFLRQISROSEIJ-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- QNDVLZJODHBUFM-WFXQOWMNSA-N okadaic acid Chemical compound C([C@H](O1)[C@H](C)/C=C/[C@H]2CC[C@@]3(CC[C@H]4O[C@@H](C([C@@H](O)[C@@H]4O3)=C)[C@@H](O)C[C@H](C)[C@@H]3[C@@H](CC[C@@]4(OCCCC4)O3)C)O2)C(C)=C[C@]21O[C@H](C[C@@](C)(O)C(O)=O)CC[C@H]2O QNDVLZJODHBUFM-WFXQOWMNSA-N 0.000 description 1
- VEFJHAYOIAAXEU-UHFFFAOYSA-N okadaic acid Natural products CC(CC(O)C1OC2CCC3(CCC(O3)C=CC(C)C4CC(=CC5(OC(CC(C)(O)C(=O)O)CCC5O)O4)C)OC2C(O)C1C)C6OC7(CCCCO7)CCC6C VEFJHAYOIAAXEU-UHFFFAOYSA-N 0.000 description 1
- JTHLRRZARWSHBE-UHFFFAOYSA-N pent-4-yn-2-ol Chemical compound CC(O)CC#C JTHLRRZARWSHBE-UHFFFAOYSA-N 0.000 description 1
- PJGSXYOJTGTZAV-UHFFFAOYSA-N pinacolone Chemical compound CC(=O)C(C)(C)C PJGSXYOJTGTZAV-UHFFFAOYSA-N 0.000 description 1
- DFOXKPDFWGNLJU-UHFFFAOYSA-N pinacolyl alcohol Chemical compound CC(O)C(C)(C)C DFOXKPDFWGNLJU-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 1
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- 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
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0272—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255
- B01J31/0275—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255 also containing elements or functional groups covered by B01J31/0201 - B01J31/0269
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B41/00—Formation or introduction of functional groups containing oxygen
- C07B41/02—Formation or introduction of functional groups containing oxygen of hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
-
- 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
-
- 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
-
- 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
-
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明公开了一种季戊四醇固载的（S/R）‑二苯基脯氨醇及其制备方法与应用。如式（I）所示。所述催化剂的制备含以下步骤：季戊四醇与对甲苯磺酰氯反应制得季戊四醇磺酸酯，再与叠氮化钠反应制得季戊四叠氮化合物；（S/R）‑N‑Cbz‑4‑羟基脯氨酸甲酯与溴丙炔反应制得（S/R）‑N‑Cbz‑4‑炔甲氧基脯氨酸甲酯，接着与苯基氯化镁反应制备（S/R）‑N‑Cbz‑4‑炔甲氧基二苯基脯氨醇。其与季戊四叠氮化合物反应、再经脱Cbz基制得季戊四醇固载的（S/R）‑二苯基脯氨醇。所述季戊四醇固载的（S/R）‑二苯基脯氨醇可在潜手性酮的不对称转化生成（R/S）‑仲醇的反应中应用。催化剂可循环利用。
Description
技术领域
本发明涉及催化有机合成领域，具体地说，涉及一种季戊四醇固载的（S）或（R）-二苯基脯氨醇及其制备方法及应用。
背景技术
CBS-噁唑硼烷催化剂是不对称还原反应中重要的手性催化剂，广泛应用于不对称合成领域中极重要的手性配体与手性中间体以及生物活性物质和天然物质的合成，具有巨大的市场潜力。1981年，S.Istuno 课题组首先报道了化学计量的手性胺醇和硼烷四氢呋喃复合物的混合物能将前手性酮以高对映选择性、高收率转化为手性仲醇，产物构型明确：(S)-胺醇和硼烷四氢呋喃复合物还原酮得到（R）-仲醇，(R)-胺醇和硼烷四氢呋喃复合物还原酮得到（S）-仲醇。几年后，E.J.Corey课题组报道了（S）或（R）-2-甲基-CBS-噁唑硼烷催化剂及其制备方法。该催化剂的优点是（1）容易制备；（2）对空气和水相对较稳定；（3）反应时间短；（4）立体选择性高；（5）收率高；（6）易于回收；（7）易于预测产物绝对构型。目前，该类催化剂广泛应用于前手性酮的不对称还原反应，制备手性α-羟基酸、α-氨基酸、C2对称二茂铁二醇、炔丙基乙醇、前列腺素E1、dysidiolide、冈田酸、氟西汀等。尽管如此，手性催化剂的稳定性还是相对较差，不易回收。研究一种方便的回收该催化剂的方法，是降低前手性酮还原成手性醇制备成本的关键。
季戊四醇分子内有多个羟基、分子量很小，催化剂载量与季戊四醇分子结构中的羟基数量近乎相同，有更准确的分子结构，拥有和传统树状化合物载体相同的功能作用，而且在反应体系中，能通过加入乙醚沉淀、过滤的方式从反应体系中简单回收，是一种较理想的催化剂载体。（S）或（R）-2-甲基-CBS-噁唑硼烷催化剂的前体是（S）或（R）-二苯基脯氨醇，它在（S）或（R）-2-甲基-CBS-噁唑硼烷催化剂制备成本中占主要比重，本发明涉及将（S）或（R）-二苯基脯氨醇固载到季戊四醇分子上，使其与甲基硼酸原位产生（S）或（R）-2-甲基-CBS-噁唑硼烷起催化作用，并可回收循环利用。
发明内容
本发明的目的在于提供一种季戊四醇固载的（S）或（R）-二苯基脯氨醇及其制备方法及应用。
本发明提供的季戊四醇固载的（S）或（R）-二苯基脯氨醇，其结构如式（I）所示：
本发明还提供所述季戊四醇固载的（S）或（R）-二苯基脯氨醇的制备方法，所述方法包括以下步骤：
a. 季戊四醇在吡啶存在下，先与对甲苯磺酰氯反应制备季戊四醇磺酸酯，然后在极性有机溶剂中，季戊四醇与叠氮化钠在100℃反应制备季戊四叠氮化合物；
b.（S）或（R）-N-Cbz-4-羟基脯氨酸甲酯在碱存在下，与溴丙炔反应制得（S）或（R）-N-Cbz-4-炔甲氧基脯氨酸甲酯；
c.（S）或（R）-N-Cbz-4-炔甲氧基脯氨酸甲酯在无水四氢呋喃中，与格氏试剂苯基氯化镁反应制备（S）或（R）-N-Cbz-4-炔甲氧基二苯基脯氨醇；
d. 在卤化亚铜和有机胺作用下，（S）或（R）-N-Cbz-4-炔甲氧基二苯基脯氨醇与季戊四叠氮化合物反应制得季戊四醇固载的N-Cbz-二苯基脯氨醇；
e.再经pd-C/H2脱Cbz保护基制得季戊四醇固载的（S）或（R）-二苯基脯氨醇。
其合成路线如下所示：
在上述季戊四醇固载的（S）或（R）-二苯基脯氨醇的制备方法中，所述的步骤a中的极性有机溶剂为DMF，DMSO，NMP，二氧六环中的一种或几种。所述的步骤b中的碱为Cs2CO3,K2CO3, Na2CO3和各种叔胺。所述的步骤d中的卤化亚铜为CuBr, CuCl，CuI。所述的步骤d中的有机胺为N,N,N’,N",N"'-五甲基二亚乙基三胺。
本发明还提供了所述季戊四醇固载的（S）或（R）-二苯基脯氨醇的应用。季戊四醇固载的（S）或（R）-二苯基脯氨醇在一定条件下与甲基硼酸作用原位产生手性B-甲基硼杂噁唑烷催化剂，再与二甲硫醚硼烷反应，可在潜手性酮的不对称转化成（R）或（S）-仲醇的反应中应用。
在上述应用中，N2下，将一定量的季戊四醇固载的（S）或（R）-二苯基脯氨醇与一定量的甲基硼酸在甲苯中回流至无水产生，过滤，加一定量的无水四氢呋喃溶解，得到季戊四醇固载的B-甲基硼杂噁唑烷四氢呋喃溶液。反应式如下所示：
N2下，反应器中加入一定量的无水四氢呋喃，再加入一定量的季戊四醇固载的B-甲基硼杂噁唑烷催化剂、BH3·SMe2和酮，室温反应，加入一定量甲醇，搅拌，减压浓缩至原体积的三分之一，加入乙醚，析出季戊四醇固载的（S）或（R）-二苯基脯氨醇，过滤，固体依次用水、甲醇、二氯甲烷和无水四氢呋喃洗涤，干燥，回收利用。滤液依次用5%H2O2、稀硫酸和水洗涤，干燥，浓缩，柱层析纯化，制得相应的（R）或（S）-仲醇。反应式如下所示：
式中，R1,R2各自独立为烷基，烃基，苯基，取代苯基，芳基，取代芳基。
本发明的有益效果主要体现在：涉及的季戊四醇固载的（S）或（R）-二苯基脯氨醇结构新颖，合成简单，收率高，可以高效用于多种底物酮的不对称还原反应。季戊四醇固载的（S）或（R）-二苯基脯氨醇易与产物分离、回收，循环利用5次，催化活性不变。
具体实施方式
下面结合具体实施例对本发明进行进一步描述，但本发明的保护范围并不仅限于此：
实施例1-2说明的是所述季戊四醇固载的（S）或（R）-二苯基脯氨醇的合成。
实施例3-7说明的是所述季戊四醇固载的（S）或（R）-二苯基脯氨醇在将酮转化成（R）或（S）-仲醇的反应中的应用。
实施例1
季戊四醇固载的（S）-二苯基脯氨醇的制备：
将2.04g(10.7mmol)对甲苯磺酰氯加入250mL反应瓶内,再加12mL干燥的吡啶，室温搅拌至固体全部溶解，冰浴将体系温度降至5℃左右，分批次加入0.34g(2.5mmol)单季戊四醇，室温搅拌8h。向体系中加入50mL水，反应2h，抽滤，固体用水洗涤，二氯甲烷溶解，甲醇沉淀，得到白色粉末状季戊四醇磺酸酯1.45g，收率78%。Mp:148.5-150℃。
将3.0g(4.0mmol)季戊四醇磺酸酯，3.0g(46mmol)叠氮化钠和20mL干燥的N,N-二甲基甲酰胺加入反应器中，100℃反应48h，冷却至室温，抽滤，滤液用50mL饱和食盐水洗涤，乙醚萃取（3x30mL），无水硫酸镁干燥，过滤，浓缩至10mL，密封避光放置备用。取其中少量处理，得到无色透明油状物，经检测确定为季戊四叠氮化合物。1HNMR (400MHz, CDCl3):δ3.27(S,8H)。
将279mg (1mmol)（S）-N-Cbz-4-羟基脯氨酸甲酯，165mg (1.2mmol) K2CO3和6mL丙酮加入反应器中，再加入142mg (1.2mmol)溴丙炔，回流反应5h，过滤，浓缩，柱层析纯化，制得（S）-N-Cbz-4-炔甲氧基脯氨酸甲酯，收率82%。
在10mL（299mg，2.2mmol)苯基氯化镁的无水四氢呋喃溶液中，滴加317mg (1mmol)（S）-N-Cbz-4-炔甲氧基脯氨酸甲酯与5mL无水四氢呋喃的溶液，滴毕，搅拌反应8h，加入6mL饱和氯化铵溶液，搅拌20min，过滤，减压蒸除THF，乙酸乙酯萃取，干燥，浓缩，柱层析纯化，制备（S）-N-Cbz-4-炔甲氧基二苯基脯氨醇，收率77%。
N2保护下，将含20mg (0.85mmol)的季戊四叠氮化合物的乙醚溶液和10mL四氢呋喃加入反应器中，再加入24mg (0.17mmol)溴化亚铜和1.94g (4.4mmol)（S）-N-Cbz-4-炔甲氧基二苯基脯氨醇，35℃反应30min后, 将35uL (0.17mmol) N,N,N’,N",N"'-五甲基二亚乙基三胺(PMEDTA)迅速注入到反应体系中，维续反应24h。减压蒸除溶剂，残渣用二氯甲烷溶解，饱和食盐水洗涤，干燥，浓缩至适量体积，缓慢滴入乙醚，析出沉淀，过滤，真空干燥，白色固体即为季戊四醇固载的N-Cbz-二苯基脯氨醇，收率87%。
将200mg季戊四醇固载的N-Cbz-二苯基脯氨醇加入5mL甲醇中，加入70mg 5%的Pd-C，搅拌下，通入H2 6h，过滤回收Pd-C，滤液浓缩至干，在加入少量二氯甲烷溶解，滴加乙醚，过滤，依次用二氯甲烷、四氢呋喃洗涤，干燥，制得季戊四醇固载的（S）-二苯基脯氨醇，收率90%; 光学纯度 99.7%；MS（ESI)1522.8[M+1]+；[α]D 25-59˚(c0.9,THF)。
实施例2
季戊四醇固载的（R）-二苯基脯氨醇的制备：
用（R）-N-Cbz-4-羟基脯氨酸甲酯代替（S）-N-Cbz-4-羟基脯氨酸甲酯，其它操作同实施例1，制得季戊四醇固载的（R）-二苯基脯氨醇，收率91%；光学纯度 99.7%；MS（ESI)1522.8[M+1]+；[α]D 25 59.1˚ (c 0.95, THF)。
实施例3
（R）-1-苯基乙醇的制备：
N2下，将1mmol季戊四醇固载的（S）-二苯基脯氨醇与4.4mmol甲基硼烷在15mL甲苯中回流至无水产生，过滤，加入1mL的无水四氢呋喃溶解，得到1mol·L-1的季戊四醇固载的B-甲基硼杂噁唑烷的四氢呋喃溶液。
N2下，反应器中加入无水四氢呋喃5mL，再加入1mol·L-1的季戊四醇固载的B-甲基硼杂噁唑烷(0.3mmol)的四氢呋喃溶液、2mol·L-1的BH3·SMe2（25mmol）的THF溶液和苯乙酮25mmol，室温反应5min，滴加1mL甲醇，搅拌10min，减压浓缩至原体积的三分之一，加入乙醚，析出季戊四醇固载的（S）-二苯基脯氨醇，过滤，固体依次用水、甲醇、二氯甲烷和无水四氢呋喃洗涤，干燥，回收循环利用。滤液依次用5%H2O2、稀硫酸和水洗涤，干燥，浓缩，柱层析纯化，制得（R）-1-苯基乙醇。收率94%，ee: 98%；bp : 88-89℃/10 mm Hg，[α]D 25 +42.3˚(neat)。
实施例4
（R）-3-（2-溴-1-羟乙基）乙酸苯酯的制备：
用α-溴代-3-乙酰氧基苯乙酮代替苯乙酮，其它操作同实施例3,制得L-去甲肾上腺素中间体（R）-3-（2-溴-1-羟乙基）乙酸苯酯。收率92%，ee:92%；[α]D 25+46.1˚ (c 0.03,C6H12)。
实施例5
(R)-1-(4- 苄氧基-3- 硝基苯基)-2- 溴乙醇的制备：
用4-苄氧基-3-硝基-α- 溴代苯乙酮代替苯乙酮，其它操作同实施例3,制得(R,R)-福莫特罗中间体(R)-1-(4- 苄氧基-3- 硝基苯基)-2- 溴乙醇。收率95％，ee：95.4%；[α] D 20 -17.9°(c 1, C2H5OH)；mp66～68 ℃；1H NMR (500 MHz, CDCl3)δ: 2.16 (s, 1H,OH), 3.50 (dd, J 1 =10.4 Hz, J 2 =8.7 Hz, 1H, CHBr), 3.64 (dd, J 1 =10.4 Hz, J 2 =3.4Hz, 1H, CHBr), 4.93 (dd, J 1 =8.7 Hz, J 2 =3.4 Hz, 1H, CH), 5.26 (s, 2H, CH2),7.13 (d, J=8.7 Hz, 1H, ArH), 7.34～7.45(m, 5H, ArH), 7.53 (dd, J 1 =8.7 Hz, J 2 =1.9 Hz, 1H, ArH), 7.92 (d, J=1.9 Hz, 1H, ArH)。
实施例6
（S）-1-叔丁基乙醇的制备：
用叔丁基乙酮代替苯乙酮，用季戊四醇固载的（R）-二苯基脯氨醇代替季戊四醇固载的（S）-二苯基脯氨醇，其它操作同实施例3,制得（S）-1-叔丁基乙醇。收率84%，ee：91.9%；[α] D 20-47.9°(c 0.05, CH2Cl2)。
实施例7
季戊四醇固载的（S）-二苯基脯氨醇的循环使用性能测试：
以苯乙酮还原制备（R）-1-苯基乙醇为例，操作与实施例2的方法相同，考察季戊四醇固载的（S）-二苯基脯氨醇回收循环利用次数，结果见表1。结果显示，催化剂循环利用5次，活性不减。
Claims (7)
1.一种季戊四醇固载的(S)或(R)-二苯基脯氨醇，其特征在于，结构式如式(I)所示：
2.根据权利要求1所述的季戊四醇固载的(S)或(R)-二苯基脯氨醇的制备方法，其特征在于包括以下步骤：
a.季戊四醇在吡啶存在下，先与对甲苯磺酰氯反应制备季戊四醇磺酸酯，然后在极性有机溶剂中，季戊四醇磺酸酯与叠氮化钠在100℃反应制备季戊四叠氮化合物；
b.(S)或(R)-N-Cbz-4-羟基脯氨酸甲酯在碱存在下，与溴丙炔反应制得(S)或(R)-N-Cbz-4-炔甲氧基脯氨酸甲酯；
c.(S)或(R)-N-Cbz-4-炔甲氧基脯氨酸甲酯在无水四氢呋喃中，与格氏试剂苯基氯化镁反应制备(S)或(R)-N-Cbz-4-炔甲氧基二苯基脯氨醇；
d.在卤化亚铜和有机胺作用下，(S)或(R)-N-Cbz-4-炔甲氧基二苯基脯氨醇与季戊四叠氮化合物反应制得季戊四醇固载的N-Cbz-二苯基脯氨醇；
e.再经pd-C/H2脱Cbz保护基制得季戊四醇固载的(S)或(R)-二苯基脯氨醇；
其合成路线如下所示：
3.根据权利要求2所述的制备方法，其特征在于，所述的步骤a所述的极性有机溶剂为DMF，DMSO，NMP，二氧六环中的一种或几种。
4.根据权利要求2所述的制备方法，其特征在于，所述的步骤b中的碱为Cs2CO3,K2CO3,Na2CO3和各种叔胺。
5.根据权利要求2所述的制备方法，其特征在于，所述的步骤d中的卤化亚铜为CuBr,CuCl，CuI。
6.根据权利要求2所述的制备方法，其特征在于，所述的步骤d中的有机胺为N,N,N’,N",N"'-五甲基二亚乙基三胺。
7.根据权利要求1所述的季戊四醇固载的(S)或(R)-二苯基脯氨醇在前手性酮的不对称转化成(R)或(S)-仲醇的反应中应用。
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