CN104086342B - A kind of synthetic method of medicine intermediate aryl substituted carbinol compound - Google Patents
A kind of synthetic method of medicine intermediate aryl substituted carbinol compound Download PDFInfo
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- -1 carbinol compound Chemical class 0.000 title claims abstract description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000010189 synthetic method Methods 0.000 title claims abstract description 19
- 125000003118 aryl group Chemical group 0.000 title claims abstract description 18
- 239000003814 drug Substances 0.000 title abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 15
- 239000001257 hydrogen Substances 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- 239000003446 ligand Substances 0.000 claims description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- 229910052763 palladium Inorganic materials 0.000 claims description 10
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- OIXUJRCCNNHWFI-UHFFFAOYSA-N 1,2-dioxane Chemical compound C1CCOOC1 OIXUJRCCNNHWFI-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000011160 research Methods 0.000 abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 63
- 239000002904 solvent Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 239000012141 concentrate Substances 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
- 230000008020 evaporation Effects 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 239000011259 mixed solution Substances 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229960001866 silicon dioxide Drugs 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 101150003085 Pdcl gene Proteins 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 150000002431 hydrogen Chemical class 0.000 description 6
- 238000005984 hydrogenation reaction Methods 0.000 description 6
- 238000009413 insulation Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 125000001475 halogen functional group Chemical group 0.000 description 4
- 239000000935 antidepressant agent Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 238000007259 addition reaction Methods 0.000 description 2
- 150000003934 aromatic aldehydes Chemical class 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003149 muscarinic antagonist Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000001519 thymoleptic effect Effects 0.000 description 2
- OJFSXZCBGQGRNV-INIZCTEOSA-N (S)-carbinoxamine Chemical compound C1([C@H](OCCN(C)C)C=2N=CC=CC=2)=CC=C(Cl)C=C1 OJFSXZCBGQGRNV-INIZCTEOSA-N 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-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
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical group CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- ABUKMOCUMIPDHV-UHFFFAOYSA-N 2-phenoxy-2-phenylacetic acid Chemical class C=1C=CC=CC=1C(C(=O)O)OC1=CC=CC=C1 ABUKMOCUMIPDHV-UHFFFAOYSA-N 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 102000003834 Histamine H1 Receptors Human genes 0.000 description 1
- 108090000110 Histamine H1 Receptors Proteins 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000001022 anti-muscarinic effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229960002881 clemastine Drugs 0.000 description 1
- YNNUSGIPVFPVBX-NHCUHLMSSA-N clemastine Chemical compound CN1CCC[C@@H]1CCO[C@@](C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 YNNUSGIPVFPVBX-NHCUHLMSSA-N 0.000 description 1
- 239000002308 endothelin receptor antagonist Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000002788 histamine agent Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- BNFDLGUZDIWYJK-UHFFFAOYSA-N n,n-dimethyl-2-[(4-methylphenyl)-phenylmethoxy]ethanamine;hydrochloride Chemical compound [Cl-].C=1C=C(C)C=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 BNFDLGUZDIWYJK-UHFFFAOYSA-N 0.000 description 1
- QVYRGXJJSLMXQH-UHFFFAOYSA-N orphenadrine Chemical compound C=1C=CC=C(C)C=1C(OCCN(C)C)C1=CC=CC=C1 QVYRGXJJSLMXQH-UHFFFAOYSA-N 0.000 description 1
- 229960003941 orphenadrine Drugs 0.000 description 1
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- JKDRQYIYVJVOPF-FDGPNNRMSA-L palladium(ii) acetylacetonate Chemical compound [Pd+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O JKDRQYIYVJVOPF-FDGPNNRMSA-L 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000006250 specific catalysis Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- 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
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Abstract
The present invention relates to a kind of synthetic method of medicine intermediate aryl substituted carbinol compound, described method comprises in organic solvent, under catalyzer and part exist, in hydrogen atmosphere, make aryl aldehyde cpd and succimide compounds react, and one-step synthesis obtains object product, described method of the present invention has good ease-to-operate and aftertreatment is simplified, and product yield is high, purity is high, thus has good scientific research value and prospects for commercial application.
Description
Technical field
The present invention relates to a kind of synthetic method of alcohol compound, particularly a kind of synthetic method of medicine intermediate aryl substituted carbinol compound, belongs to organic chemical synthesis field.
Background technology
Aryl substituted carbinol compound and derivative thereof are the important oxygenatedchemicalss of a class, it is not only used as important intermediate and building block (Schmidt in organic synthesis, F. people is waited, " Catalytic asymmetric approaches towards enantiomerically enricheddiarylmethanols and diarylmethylamines ", Chem.Soc.Rev.2006,35:454-470), and at medicinal chemistry art also play an important role.
Aryl substituted carbinol compound is present in natural widely as a kind of common molecule fragment or (such as sees a) Welch W.M. containing in the drug molecule of physiology or pharmacologically active of synthetic, Deng people, " Nontricyclic antidepressant agents derived from cis-andtrans-1-amino-4-aryltetralins ", J.Med.Chem.1984,27,1508-1515; B) people such as Astles P.C., " Selective ETA antagonists.5.Discovery andstructure-activity relationships of phenoxyphenylacetic acid derivatives ", J.Med.Chem.2000,43,900-910; C) Nilvebrant L., " Andersson K.-E., Gillberg P.-G.et al.Tolterodine-a new bladder-selective antimuscarinicagent ", Eur.J.Pharmacol.1997,327,195-207).Such as it is all present in thymoleptic orphenadrine and neobenodine, anti-H1 histamine agent medicine clemastine and has in very strong optionally medicine (S)-carbinoxamine H1-receptor.
In addition, aryl replaces methyl alcohol and derivative or synthetic drugs molecule thereof as the precursor of the compound of 1,1-alkyl diaryl skeleton.Compound containing 1,1-alkyl diaryl skeleton has antimuscarinics medicine, thymoleptic and endothelin antagonist isoreactivity.
As mentioned above; although the addition reaction of metal arylide reagent to aromatic aldehyde receives the extensive concern of researcher; but because usual used reagent is as very active in aryl Grignard reagent and aryl lithium; have that severe reaction conditions, functional group compatibility are poor and to shortcomings such as environment are friendly not, the application that these are reacted is greatly limited.Therefore, people have been developed organotin and (have such as been seen Li, C.J., Meng Y, " Grignard-type carbonylphenylation in water and under air atmosphere ", J.Am.Chem.Soc.2000,122,9538-9539), organic zinc (is such as shown in (a) P.I.Dosa, the people such as J.C.Ruble, J.Org.Chem., 1997,62,444, the people such as (b) Y.Kondo, J.Org.Chem., 1994,59,4717, the people such as (c) C.Bolm, J.Am.Chem.Soc., 2002,124,14850, the people such as (d) A.L.Braga, Chem.Commun., 2005,2512, the people such as (e) M.Fontes, J.Org.Chem., 2004,69,2532, the people such as (f) R.Infante, Org.Biomol.Chem., 2011, 9, 6691), organosilicon (Tomita, the people such as D, " Enantioselective Alkenylation andPhenylation Catalyzed by a Chiral CuF Complex ", J.Am.Chem.Soc.2005, 127, 4138-4139), organic titanium (Weber, the people such as B, Tetrahedron1994, 50, 7473), Organogallium (X.Jia, the people such as L.Fang, " Highly Efficient and Facile ArylTransfer to Aldehydes Using the ArB (OH)
2-GaMe
3", Synlett, 2009,495) and the metal arylide reagent such as organoaluminum people such as (, J.Am.Chem.Soc., 2006,128,14808) K.-H.Wu to the addition reaction strategy of aromatic aldehyde, realize the synthesis that aryl replaces methyl alcohol compounds.
But up to now, these all methods still exist some defects, such as metal reagent synthesis is complicated, expensive, aftertreatment is loaded down with trivial details, products collection efficiency is too low.
Therefore, for the new synthetic method of research and development aryl substituted carbinol compound, be not only of great immediate significance, and industrially especially pharmaceutical field there are good scientific research value and prospects for commercial application and potentiality.
Summary of the invention
In view of this, in order to solve many defects such as too low in yield, the expensive catalyst that exists in above-mentioned prior art, the reaction of the present inventor to synthesizing aryl substituted carbinol compound conducts in-depth research, and after paying a large amount of creative work, thus completes the present invention.
The present invention relates to a kind of preparation method of medicine intermediate aryl substituted carbinol compound, described method comprises in organic solvent, under catalyzer and part exist, aryl aldehyde cpd and succimide compounds are reacted, and one-step synthesis obtain aryl substituted carbinol compound.
Specifically, the invention provides the synthetic method of aryl substituted carbinol compound shown in a kind of formula (I), described method comprises: under palladium catalyst and containing n-donor ligand exist, in hydrogen atmosphere, make formula (II) compound and formula (III) compound react in organic solvent, production (I) compound
Wherein, Ar
1group for following formula (A) or (B):
Wherein, R
1be selected from H, C
1-C
6alkyl, C
1-C
6alkoxyl group, halogen, halo C
1-C
6alkyl or halo C
1-C
6alkoxyl group;
R
2be selected from H, C
1-C
6alkyl, C
1-C
6alkoxyl group, halogen, halo C
1-C
6alkyl, halo C
1-C
6alkoxyl group or nitro;
X, Y are selected from C, O, S or N independently of one another.
Wherein, the wavy line representative in formula (A) or (B) is connected with the hydroxyl C in formula (I) or is connected with the aldehyde radical in formula (II).
In described synthetic method of the present invention, described palladium catalyst is acid chloride (Pd (OAc)
2), Palladous chloride, palladium trifluoroacetate (Pd (O
2cCF
3)
2), PdCl
2(PPh
3)
2, PdCl
2(dppf)
2, PdCl
2(dppe), PdCl
2(cod), PdCl
2(py)
2, PdCl
2(MeCN)
2, Pd (acac)
2, Pd (PPh
3)
4, Pd
2(dba)
3, Pd
2(dba)
2in any one or multiple mixture, most preferably be Pd (PPh
3)
4.
In described synthetic method of the present invention, described containing n-donor ligand is following formula: compound:
Wherein, R
3-R
6be selected from H, carbonyl, phenyl or C independently of one another
1-6alkyl.
Wherein, R
4, R
5"---" connected between two carbon atoms be singly-bound or double bond.
Described containing n-donor ligand is preferably L1, L2 or L3 of following formula:
Described containing n-donor ligand most preferably is L1.
In described synthetic method of the present invention, described formula (II) compound is 1:2-4 with the mol ratio of (III) compound, exemplarily such as can be 1:2,1:2.5,1:3,1:3.5 or 1:4.
In described synthetic method of the present invention, the mol ratio of described formula (II) compound and described palladium catalyst is 1:0.02-0.1, such as, can be 1:0.02,1:0.04,1:0.06,1:0.08 or 1:0.1.
In described synthetic method of the present invention, the mol ratio of described palladium catalyst and described containing n-donor ligand is 1:0.5-2, such as, can be 1:0.5,1:1,1:1.5 or 1:2.
In described synthetic method of the present invention, organic solvent when formula (II) and (III) react is 1,4-dioxane, tetrahydrofuran (THF) (THF), toluene, dimethylbenzene, normal hexane, hexanaphthene, ethyl acetate, Virahol, N, any one or mixture multiple arbitrarily in dinethylformamide (DMF), dimethyl sulfoxide (DMSO) (DMSO), tetracol phenixin, acetone, benzene, chlorobenzene, 1,6-dioxane, 2-methyltetrahydrofuran, methylene dichloride, trichloromethane, ethylene dichloride, ether, methyl alcohol, ethanol, n-propyl alcohol etc.
Described organic solvent is preferably Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF) (THF), toluene, dimethylbenzene, normal hexane, hexanaphthene, ethyl acetate, most preferably is Isosorbide-5-Nitrae-dioxane.
In described synthetic method of the present invention, temperature of reaction is 50-90 DEG C, such as can be 50 DEG C, 60 DEG C, 70 DEG C, 80 DEG C or 90 DEG C in non-limiting manner.
In described synthetic method of the present invention, the reaction times is generally 10-20 hour, is such as 10 hours, 12 hours, 15 hours, 17 hours, 19 hours or 20 hours in non-limiting manner.
In described synthetic method of the present invention, described hydrogen atmosphere realizes by conventional means, such as continue to pass into hydrogen or in closed container, keep the hydrogen atmosphere of certain pressure to react in reaction system, these are all routine techniques means, and this is no longer going to repeat them.
In described synthetic method of the present invention, there is no particular limitation in aftertreatment, such as, can be: after reaction terminates, water is added in reaction mixture, with extracted with diethyl ether 2-4 time, combined ether layer, and with anhydrous sodium sulfate drying, after filtering, evaporation removing ether concentrates, enriched material is crossed 300-400 order silicagel column, using the mixed solution of ethyl acetate/petroleum ether as eluent, the wherein volume ratio 1:10-15 of ethyl acetate and sherwood oil, thus obtain target product formula (I) compound
In sum, the present invention uses suitable catalyzer and part, thus makes that formula (II) compound and formula (III) compound can react and a step obtains aryl substituted carbinol compound.Described method is owing to employing specific catalysis/ligand system and suitable organic solvent, and have that reaction is simple, product yield and the more high plurality of advantages of purity, it is the brand-new synthetic method of aryl substituted carbinol compound, preparation for this compounds provides new synthetic route, has good researching value and prospects for commercial application.
Embodiment
Below by specific embodiment, the present invention is described in detail; but the purposes of these exemplary embodiments and object are only used for exemplifying the present invention; not any type of any restriction is formed to real protection scope of the present invention, more non-protection scope of the present invention is confined to this.
Embodiment 1
Under room temperature, in reaction vessel, add 20mmol formula (II) compound, 40mmol formula (III) compound, 0.4mmol Pd (PPh
3)
4with 0.2mmol ligand L 1, and then add 100ml solvent Isosorbide-5-Nitrae-dioxane, be warming up to 50 DEG C continuing to pass into stirring under hydrogen, and insulation reaction 20 hours at such a temperature.
After reaction terminates, 100ml water is added in reaction mixture, by extracted with diethyl ether 2-4 time, combined ether layer, and with anhydrous sodium sulfate drying, after filtering, evaporation removing ether concentrates, and enriched material is crossed 300-400 order silicagel column, using the mixed solution of ethyl acetate/petroleum ether as eluent, the wherein volume ratio 1:5 of ethyl acetate and sherwood oil, thus target product formula (I) compound obtained as white solid, its productive rate is 97.4%, and purity is 98.1% (HPLC).
Fusing point: 67-68 DEG C.
Nucleus magnetic resonance:
1h NMR (CDCl
3, 300MHz): δ 2.27 (s, 1H), 5.86 (s, 1H), 7.23-7.31 (m, 2H), 7.33-7.43 (m, 8H);
13C NMR(CDCl
3,125MHz):δ78.2,126.0(2C),128.4(2C),129.1(4C),143.2(2C)。
Embodiment 2
Under room temperature, in reaction vessel, add 20mmol formula (II) compound, 60mmol formula (III) compound, 1mmol Pd (PPh
3)
4with 1mmol ligand L 1, and then add 100ml solvent Isosorbide-5-Nitrae-dioxane, be warming up to 60 DEG C continuing to pass into stirring under hydrogen, and insulation reaction 15 hours at such a temperature.
After reaction terminates, 90ml water is added in reaction mixture, by extracted with diethyl ether 2-4 time, combined ether layer, and with anhydrous sodium sulfate drying, after filtering, evaporation removing ether concentrates, and enriched material is crossed 300-400 order silicagel column, using the mixed solution of ethyl acetate/petroleum ether as eluent, the wherein volume ratio 1:10 of ethyl acetate and sherwood oil, thus target product formula (I) compound obtained as oily matter, its productive rate is 98.8%, and purity is 97.2% (HPLC).
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz): δ 2.90 (s, 3H), 2.39 (s, 1H), 5.77 (s, 1H), 7.08 (d, J=5.0Hz, 1H), 7.11-7.28 (m, 4H), 7.31-7.39 (m, 4H);
13C NMR(CDCl
3,125MHz):δ21.2,76.7,125.5,126.0,126.7,128.3(2C),128.8,129.2,129.4(2C),138.3,142.9,143.0。
Embodiment 3
Under room temperature, in reaction vessel, add 20mmol formula (II) compound, 80mmol formula (III) compound, 2mmol Pd (PPh
3)
4with 4mmol ligand L 1, and then add 100ml solvent Isosorbide-5-Nitrae-dioxane, be warming up to 70 DEG C continuing to pass into stirring under hydrogen, and insulation reaction 20 hours at such a temperature.
After reaction terminates, 80ml water is added in reaction mixture, by extracted with diethyl ether 2-4 time, combined ether layer, and with anhydrous sodium sulfate drying, after filtering, evaporation removing ether concentrates, and enriched material is crossed 300-400 order silicagel column, using the mixed solution of ethyl acetate/petroleum ether as eluent, the wherein volume ratio 1:15 of ethyl acetate and sherwood oil, thus target product formula (I) compound obtained as oily matter, its productive rate is 97.6%, and purity is 98.4% (HPLC).
Nucleus magnetic resonance:
1h NMR (CDCl
3, 300MHz): δ 2.31 (s, 1H), 3.83 (s, 3H), 5.86 (s, 1H), 6.87 (d, J=11Hz, 1H), 6.98 (d, J=11Hz, 2H), 7.27-7.45 (m, 6H);
13C NMR(CDCl
3,125MHz):δ56.0,76.3,111.7,113.8,120.5,126.4,128.4(2C),129.2(2C),130.2,143.1,144.2,160.6。
Embodiment 4
Under room temperature, in reaction vessel, add 20mmol formula (II) compound, 45mmol formula (III) compound, 1.5mmol Pd (PPh
3)
4with 2.5mmol ligand L 1, and then add 100ml solvent Isosorbide-5-Nitrae-dioxane, be warming up to 80 DEG C continuing to pass into stirring under hydrogen, and insulation reaction 15 hours at such a temperature.
After reaction terminates, 110ml water is added in reaction mixture, by extracted with diethyl ether 2-4 time, combined ether layer, and with anhydrous sodium sulfate drying, after filtering, evaporation removing ether concentrates, and enriched material is crossed 300-400 order silicagel column, using the mixed solution of ethyl acetate/petroleum ether as eluent, the wherein volume ratio 1:7 of ethyl acetate and sherwood oil, thus target product formula (I) compound obtained as oily matter, its productive rate is 96.9%, and purity is 98.1% (HPLC).
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz): δ 2.45 (s, 1H), 5.79 (s, 1H), 7.20-7.26 (m, 3H), 7.29-7.38 (m, 5H), 7.40 (s, 1H);
13C NMR(CDCl
3,125MHz):δ75.8,126.0,126.5,126.6,126.7,128.3(2C),128.8,129.2(2C),134.4,143.1,144.8。
Embodiment 5
Under room temperature, in reaction vessel, add 20mmol formula (II) compound, 55mmol formula (III) compound, 0.8mmol Pd (PPh
3)
4with 1mmol ligand L 1, and then add 100ml solvent Isosorbide-5-Nitrae-dioxane, be warming up to 90 DEG C continuing to pass into stirring under hydrogen, and insulation reaction 13 hours at such a temperature.
After reaction terminates, 120ml water is added in reaction mixture, by extracted with diethyl ether 2-4 time, combined ether layer, and with anhydrous sodium sulfate drying, after filtering, evaporation removing ether concentrates, and enriched material is crossed 300-400 order silicagel column, using the mixed solution of ethyl acetate/petroleum ether as eluent, the wherein volume ratio 1:9 of ethyl acetate and sherwood oil, thus target product formula (I) compound obtained as oily matter, its productive rate is 98.7%, and purity is 98.6% (HPLC).
Nucleus magnetic resonance:
1h NMR (CDCl
3, 300MHz): δ 2.24 (s, 1H), 5.76 (s, 1H), 7.55-7.77 (m, 2H), 7.25-7.47 (m, 7H);
13C NMR(CDCl
3,125MHz):δ78.2,124.1(2C),126.1,128.4(2C),129.1(2C),129.3(2C),143.0,145.8,149.2。
Embodiment 6
Under room temperature, in reaction vessel, add 20mmol formula (II) compound, 65mmol formula (III) compound, 2mmol Pd (PPh
3)
4with 1.5mmol ligand L 1, and then add 100ml solvent Isosorbide-5-Nitrae-dioxane, be warming up to 75 DEG C continuing to pass into stirring under hydrogen, and insulation reaction 15 hours at such a temperature.
After reaction terminates, 100ml water is added in reaction mixture, by extracted with diethyl ether 2-4 time, combined ether layer, and with anhydrous sodium sulfate drying, after filtering, evaporation removing ether concentrates, and enriched material is crossed 300-400 order silicagel column, using the mixed solution of ethyl acetate/petroleum ether as eluent, the wherein volume ratio 1:10 of ethyl acetate and sherwood oil, thus target product formula (I) compound obtained as oily matter, its productive rate is 96.5%, and purity is 98.6% (HPLC).
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz): δ 2.28 (s, 1H), 5.74 (s, 1H), 5.91 (dd, J=1.5,3.0Hz, 2H), 6.70-6.74 (m, 1H), 6.81-6.84 (m, 2H), 7.22-7.25 (m, 1H), 7.31-7.43 (m, 4H);
13C NMR(CDCl
3,125MHz):δ76.6,93.4,115.0,115.6,126.0,128.3(2C),128.7(2C),136.4,138.0,143.5,145.2,148.2。
Can be found out by above-described embodiment 1-6, described method of the present invention can make the succimide compounds single step reaction of the aryl aldehyde cpd of formula (II) and formula (III) and obtain aryl substituted carbinol compound, has good productive rate and purity.
Embodiment 7-18
Replace with except following part except by ligand L 1 wherein, implement embodiment 7-18 respectively in the mode identical with embodiment 1-6, as shown in the table.
As seen from the above table, when using other part, even if all have identical phenanthroline precursor structure, but still productive rate is caused to have significant reduction, wherein catalysed promoted effect is L1>L2>L3, and wherein ligand L 1 has best catalysed promoted effect.
Embodiment 19-30
Remove Pd (PPh wherein
3)
4replace with outside following palladium catalyst, implement embodiment 19-30 respectively in the mode identical with embodiment 1-6, as shown in the table.
As can be seen here, when using other palladium catalysts, causing product significantly to reduce, even can not react, this demonstrate that Pd (PPh
3)
4for described reaction of the present invention, there is unique specific specificity.
Embodiment 31-42
Replace with except following solvent except by solvent Isosorbide-5-Nitrae-dioxane, implement embodiment 31-42 respectively in the mode identical with embodiment 1-13, use the yield of solvent, embodiment corresponding relation and corresponding product as shown in the table.
As seen from the above table, when using other solvent outside Isosorbide-5-Nitrae-dioxane, also described reaction can be carried out, wherein tetrahydrofuran (THF) (THF), toluene, dimethylbenzene, normal hexane, hexanaphthene, ethyl acetate still obtain good productive rate, and it is larger that other solvent then reduces amplitude.When this demonstrate that Isosorbide-5-Nitrae-dioxane as solvent, there is effect the most excellent.
In sum, clearly can be found out by above-mentioned all embodiments, when applying the method according to the invention, especially use Pd (PPh
3)
4during with ligand L 1, can obtain aryl substituted carbinol compound with high yield and high purity, the selection of solvent simultaneously also has a certain impact to reaction, in all solvents, finds that Isosorbide-5-Nitrae-dioxane has best effect.
Should be appreciated that the purposes of these embodiments is only not intended to for illustration of the present invention limit the scope of the invention.In addition; also should understand; after having read technology contents of the present invention, those skilled in the art can make various change, amendment and/or modification to the present invention, and these all equivalent form of values fall within the protection domain that the application's appended claims limits equally.
Claims (9)
1. a synthetic method for aryl substituted carbinol compound shown in formula (I), described method comprises:
Under palladium catalyst and containing n-donor ligand exist, in hydrogen atmosphere, formula (II) compound and formula (III) compound is made to react in organic solvent, production (I) compound,
Wherein, Ar
1group for following formula (A) or (B):
Wherein, R
1be selected from H, C
1-C
6alkyl, C
1-C
6alkoxy or halogen;
R
2be selected from H or nitro;
X, Y are selected from C, O, S or N independently of one another;
Described palladium catalyst is Pd (PPh
3)
4;
Described containing n-donor ligand is the L1-L3 of following formula:
2. the method for claim 1, is characterized in that: described containing n-donor ligand is L1.
3. the method for claim 1, is characterized in that: described formula (II) compound is 1:2-4 with the mol ratio of (III) compound.
4. the method for claim 1, is characterized in that: the mol ratio of described formula (II) compound and described palladium catalyst is 1:0.02-0.1.
5. the method for claim 1, is characterized in that: the mol ratio of described palladium catalyst and described containing n-donor ligand is 1:0.5-2.
6. the method for claim 1, it is characterized in that: described organic solvent is 1,4-dioxane, tetrahydrofuran (THF), toluene, dimethylbenzene, normal hexane, hexanaphthene, ethyl acetate, Virahol, N, any one or mixture multiple arbitrarily in dinethylformamide, dimethyl sulfoxide (DMSO), tetracol phenixin, acetone, benzene, chlorobenzene, 1,6-dioxane, 2-methyltetrahydrofuran, methylene dichloride, trichloromethane, ethylene dichloride, ether, methyl alcohol, ethanol, n-propyl alcohol.
7. method as claimed in claim 6, is characterized in that: described organic solvent is Isosorbide-5-Nitrae-dioxane.
8. the method for claim 1, is characterized in that: temperature of reaction is 50-90 DEG C
9. the method for claim 1, is characterized in that: the reaction times is 10-20 hour.
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