CN105198841B - Synthetic method for drug intermediate polysubstituted furan compound - Google Patents
Synthetic method for drug intermediate polysubstituted furan compound Download PDFInfo
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- CN105198841B CN105198841B CN201510680594.XA CN201510680594A CN105198841B CN 105198841 B CN105198841 B CN 105198841B CN 201510680594 A CN201510680594 A CN 201510680594A CN 105198841 B CN105198841 B CN 105198841B
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 31
- -1 polysubstituted furan compound Chemical class 0.000 title claims abstract description 26
- 239000003814 drug Substances 0.000 title abstract description 6
- 229940079593 drug Drugs 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- 239000003054 catalyst Substances 0.000 claims abstract description 22
- 239000000654 additive Substances 0.000 claims abstract description 19
- 230000000996 additive effect Effects 0.000 claims abstract description 19
- 239000000203 mixture Substances 0.000 claims abstract description 18
- 239000007800 oxidant agent Substances 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 16
- 239000003960 organic solvent Substances 0.000 claims abstract description 16
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 239000012298 atmosphere Substances 0.000 claims abstract description 7
- 150000002367 halogens Chemical class 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims abstract description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 31
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 26
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 18
- 239000003513 alkali Substances 0.000 claims description 16
- 230000001590 oxidative effect Effects 0.000 claims description 16
- GFHNAMRJFCEERV-UHFFFAOYSA-L cobalt chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Co+2] GFHNAMRJFCEERV-UHFFFAOYSA-L 0.000 claims description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 14
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 14
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 12
- 229910052707 ruthenium Inorganic materials 0.000 claims description 12
- XPDWGBQVDMORPB-UHFFFAOYSA-N trifluoromethane acid Natural products FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 claims description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical class ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 239000000758 substrate Substances 0.000 abstract description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 1
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 235000002639 sodium chloride Nutrition 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 6
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical group CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 239000012450 pharmaceutical intermediate Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 208000035126 Facies Diseases 0.000 description 4
- 150000002240 furans Chemical class 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- XTEGARKTQYYJKE-UHFFFAOYSA-M Chlorate Chemical compound [O-]Cl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 150000003842 bromide salts Chemical class 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 description 2
- 229940113115 polyethylene glycol 200 Drugs 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 238000006941 Feist-Bénary synthesis reaction Methods 0.000 description 1
- 238000006086 Paal-Knorr synthesis reaction Methods 0.000 description 1
- 229910002666 PdCl2 Inorganic materials 0.000 description 1
- 229920000604 Polyethylene Glycol 200 Polymers 0.000 description 1
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229940097267 cobaltous chloride Drugs 0.000 description 1
- 238000007366 cycloisomerization reaction Methods 0.000 description 1
- SWSFSSDDGJUTGP-UHFFFAOYSA-N di(cyclopropen-1-yl)methanone Chemical class C=1CC=1C(=O)C1=CC1 SWSFSSDDGJUTGP-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 125000003186 propargylic group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/40—Radicals substituted by oxygen atoms
- C07D307/42—Singly bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/36—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a synthetic method for a polysubstituted furan compound as shown in the following formula (III). The synthetic method comprises the following steps: under the air atmosphere, in the presence of a catalyst, an oxidizing agent, an additive and soda, stirring a compound as shown in a formula (I) of the description and a compound as shown in a formula (II) of the description in an organic solvent at the temperature of 60-80 DEG C to enable the mixture to react for 7-10 hours, after the reaction, performing after-treatment to obtain the compound as shown in the formula (III) of the description, wherein each of R1and R2 is independently selected from H or C1-C6 alkyl; R3 is selected from H, C1-C6 alkyl, C1-C6 alkoxy or halogen; X is a halogen. According to the method, through the use of a suitable substrate as well as selection and synergism of the catalyst, the oxidizing agent, the additive, soda and the organic solvent, a high-yield target product can be obtained; the synthetic method has an excellent application prospect and a wide industrial production potentiality in the technical field of drug intermediate synthesis.
Description
Technical field
The present invention relates to a kind of synthetic method of heterocyclic compound, relate more particularly to a kind of pharmaceutical intermediate that can be used as
The synthetic method of polysubstituted furfuran compound, belongs to medicine intermediate synthesis field.
Background technology
In organic chemistry filed, polysubstituted furfuran compound is a kind of important five member ring heterocyclic compound, and which is universal
Among being present in the natural molecule of multiple biological activities, and can be used to build many drug molecules or make as synthetic intermediate
With.Therefore, that researches and develops polysubstituted furfuran compound efficiently synthesizes the extensive concern that technique has caused scientific research personnel.
The traditional method of synthesis furfuran compound generally adopts Paal-Knorr methods and Feist-Benary methods, and these are
Classical furan synthetic method in organic synthesiss；Additionally, other conjunctions of many furfuran compounds have also been expanded in prior art
Into technique, for example：
(" the 2,3,4-or 2,3,5-Trisubstituted Furans such as Ma Shengming:Catalyst-
Controlled Highly Regioselective Ring-Opening Cycloisomerization Reaction of
Cyclopropenyl Ketones ", J.Am.Chem, Soc., 2003,125,12386-12387) one kind is reported using ring third
Alkenyl ketone is raw material, CuI or PdCl2(CH3CN)2For catalyst, Jing cyclisation isomerization prepares the side of polysubstituted furfuran compound
Method, its reaction equation are as follows：
(" Cu (the I)-Catalyzed Regioselective Synthesis of such as Jose Barluenga
Polysubstituted Furans from Propargylic Esters via Postulated(2-Furyl)carbene
Complexes ", J.Am.Chem, Soc., 2008,130,13528-13529) report it is that a kind of Cu (I) is catalyzed, by propargyl
The method that ester prepares polysubstituted furfuran compound, its reaction equation are as follows：
However, these methods still suffer from certain defect, such as yield is excessively low.
In order to expand substrate spectrum and exploitation Novel synthesis technology, the present inventor passes through to read substantial amounts of academic documents, and
The species of required reagent is screened and compounded by experiment, so as to propose a kind of pharmaceutical intermediate polysubstituted furan
The synthetic method of compound, the method have the advantages that reaction yield height, reaction condition are gentle, and the new substrate class for adopting
Type, with extensive prospects for commercial application.
The content of the invention
In order to overcome many defects as indicated above, present inventor has performed in-depth study and exploration, are paying
After enough creative works, so as to complete the present invention.
Specifically, technical scheme and content are related to polysubstituted furan chemical combination shown in a kind of lower formula (III)
The synthetic method of thing, methods described include：Under air atmosphere and in organic solvent, in catalyst, oxidant, additive and alkali
In the presence of, the following formula: compound and lower formula (II) compound stirring reaction 7-10 hour at 60-80 DEG C is located after after completion of the reaction
Manage and obtain the formula (III) compound,
Wherein, R1、R2It is each independently selected from H or C1-C6Alkyl；
R3Selected from H, C1-C6Alkyl, C1-C6Alkoxy or halogen；
X is halogen.
In the synthetic method of the present invention, the C1-C6The implication of alkyl refers to the straight chain with 1-6 carbon atom
Or branched alkyl, can for example be methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, uncle in non-limiting manner
Butyl, n-pentyl, isopentyl or n-hexyl etc..
In the synthetic method of the present invention, the C1-C6The implication of alkoxyl refers to the C with above-mentioned implication1-C6
The group that alkyl is obtained after being connected with oxygen atom.
In the synthetic method of the present invention, the halogen is halogen, for example, can be F, Cl, Br or I.
In the synthetic method of the present invention, the catalyst is four carbonyl dichlorides, two ruthenium or triphenylphosphine ruthenic chloride
In any one mixture with cobalt chloride hexahydrate, wherein appointing in four carbonyl dichlorides, two ruthenium or triphenylphosphine ruthenic chloride
A kind of mol ratio with cobalt chloride hexahydrate of meaning is 1:0.5.Most preferably mol ratio is 1:0.5 four carbonyl dichlorides, two ruthenium and
The mixture of cobalt chloride hexahydrate.
In the synthetic method of the present invention, the oxidant is tert-butyl hydroperoxide (TBHP), diphenyl peroxide
Formyl, iodobenzene diacetate (PhI (OAc)2) or [double (trifluoroacetic acid) iodine] benzene (PhI (TFA)2) in any one, most preferably
PhI(TFA)2。
The present invention the synthetic method in, the additive be N- normal-butyl-N- crassitude Bromides, N- just
It is any in butyl-N- crassitudes chlorate or double (fluoroform sulphonyl) inferior amine salts of N- normal-butyl-N- crassitudes
Double (fluoroform sulphonyl) inferior amine salts of one kind, most preferably N- normal-butyls-N- crassitudes.
The present invention the synthetic method in, the alkali be NaOH, sodium carbonate, potassium acetate, Sodium ethylate, potassium tert-butoxide,
Any one in N, N'- dimethyl-ethylenediamine (DMEDA) or DIPEA (DIPEA), most preferably DIPEA.
The present invention the synthetic method in, the organic solvent be volume ratio be DMF (DMF),
DMSO (dimethyl sulfoxide), benzene, ethanol, acetonitrile, 1,4- dioxane, isopropanol, polyethylene glycol 200 (PEG-200) or second two
Any one in alcohol or arbitrarily various mixture, the mixture of most preferably DMSO and acetonitrile, wherein DMSO and acetonitrile
Volume ratio is 2:1.
Wherein, the consumption of the organic solvent does not have strict restriction, and those skilled in the art can be according to practical situation
Carry out suitable selection and determine, to facilitate reaction to carry out and post processing, here is no longer carried out in detail such as its consumption size
It is thin to describe.
In the synthetic method of the present invention, formula (I) compound is 1 with the mol ratio of formula (II) compound:
1.4-2, for example, can be 1:1.4、1:1.6、1:1.8 or 1:2.
In the synthetic method of the present invention, formula (I) compound is 1 with the mol ratio of catalyst:0.12-
0.18, i.e., four carbonyl dichlorides, two ruthenium or triphenylphosphine of the mole dosage and the composition catalyst of described formula (I) compound
Any one in ruthenic chloride is 1 with the ratio of the total moles consumption of cobalt chloride hexahydrate:0.12-0.18, for example, can be 1:0.12、
1:0.14、1:0.16 or 1:0.18.
In the synthetic method of the present invention, formula (I) compound is 1 with the mol ratio of oxidant:1-1.6, example
Can such as be 1:1、1:1.3 or 1:1.6.
In the synthetic method of the present invention, formula (I) compound is 1 with the mol ratio of additive:0.2-0.3,
Can for example be 1:0.2、1:0.25 or 1:0.3.
In the synthetic method of the present invention, formula (I) compound is 1 with the mol ratio of alkali:1-1.5, for example may be used
For 1:1、1:1.2、1:1.4 or 1:1.5.
In the synthetic method of the present invention, the rear post processing for terminating is reacted specific as follows：After reaction terminates, will reaction
System naturally cools to room temperature, filters, and filtrate is fully washed with saturated aqueous common salt；Chloroform extraction 2-3 time is subsequently adding, is associated with
Machine phase, concentrating under reduced pressure, residue cross flash chromatography on silica gel, and the mixed solvent using the acetone of equal-volume ratio and petroleum ether is used as pouring
Washing liquid, so as to obtain the formula (III) compound.
In sum, the invention provides a kind of synthesis side of the polysubstituted furfuran compound that can be used as pharmaceutical intermediate
Method, use of the methods described by suitable substrates, and the selection by catalyst, oxidant, additive, alkali and organic solvent with
Collaboration, obtains purpose product such that it is able to high yield, have a good application prospect in medicine intermediate synthesis technical field and
Extensive industrial production potential.
Specific embodiment
Below by specific embodiment, the present invention is described in detail, but the purposes of these exemplary embodiments and
Purpose is only used for enumerating the present invention, not constitutes any type of any restriction to the real protection scope of the present invention, more non-to incite somebody to action
Protection scope of the present invention is confined to this.
Embodiment 1
Under air atmosphere, (it is 2 for volume ratio to appropriate organic solvent:1 DMSO and the mixture of acetonitrile) in, add
The upper formula (I) compounds of 100mmol, the upper formula (II) compounds of 140mmol, 12mmol catalyst (are tetra- carbonyl dichlorides two of 8mmol
The mixture of ruthenium and 4mmol cobalt chloride hexahydrates), 100mmol oxidant PhI (TFA)2, 20mmol additive N- normal-butyl-N-
Double (fluoroform sulphonyl) inferior amine salts of crassitude and 100mmol alkali DIPEA, then heat to 60 DEG C, and at such a temperature
Stirring reaction 10 hours；
After reaction terminates, reaction system is naturally cooled to into room temperature, filtered, filtrate is fully washed with saturated aqueous common salt；So
Addition chloroform extraction 2-3 time, merges organic faciess afterwards, and concentrating under reduced pressure, residue cross flash chromatography on silica gel, with the third of equal-volume ratio
Used as leacheate, so as to obtain upper formula (III) compound, yield is 95.7% to the mixed solvent of ketone and petroleum ether.
1H NMR(CDCl3,400MHz):δ 7.75 (d, J=8.4Hz, 2H), 7.66 (d, J=8.8Hz, 2H), 7.43 (t, J
=8.4Hz, 2H), 7.32-7.28 (m, 1H), 6.97 (d, J=8.8Hz, 2H), 6.54 (s, 1H), 3.88 (s, 3H), 2.35 (s,
3H)。
Embodiment 2
Under air atmosphere, (it is 2 for volume ratio to appropriate organic solvent:1 DMSO and the mixture of acetonitrile) in, add
The upper formula (I) compounds of 100mmol, the upper formula (II) compounds of 170mmol, 15mmol catalyst (are tetra- carbonyl dichlorides of 10mmol
The mixture of two rutheniums and 5mmol cobalt chloride hexahydrates), 130mmol oxidant PhI (TFA)2, 25mmol additive N- normal-butyls-
Double (fluoroform sulphonyl) inferior amine salts of N- crassitudes and 125mmol alkali DIPEA, then heat to 70 DEG C, and in the temperature
Lower stirring reaction 8 hours；
After reaction terminates, reaction system is naturally cooled to into room temperature, filtered, filtrate is fully washed with saturated aqueous common salt；So
Addition chloroform extraction 2-3 time, merges organic faciess afterwards, and concentrating under reduced pressure, residue cross flash chromatography on silica gel, with the third of equal-volume ratio
Used as leacheate, so as to obtain upper formula (III) compound, yield is 95.5% to the mixed solvent of ketone and petroleum ether.
1H NMR(CDCl3,400MHz):δ 7.63 (d, J=8.8Hz, 2H), 7.55 (d, J=8.4Hz, 2H), 7.32 (t, J
=8.0Hz, 2H), 7.25 (d, J=8.4Hz, 2H), 7.21-7.16 (m, 1H), 6.53 (s, 1H), 2.27 (s, 3H).
Embodiment 3
Under air atmosphere, (it is 2 for volume ratio to appropriate organic solvent:1 DMSO and the mixture of acetonitrile) in, add
The upper formula (I) compounds of 100mmol, the upper formula (II) compounds of 200mmol, 18mmol catalyst (are tetra- carbonyl dichlorides of 12mmol
The mixture of two rutheniums and 6mmol cobalt chloride hexahydrates), 160mmol oxidant PhI (TFA)2, 30mmol additive N- normal-butyls-
Double (fluoroform sulphonyl) inferior amine salts of N- crassitudes and 150mmol alkali DIPEA, then heat to 80 DEG C, and in the temperature
Lower stirring reaction 7 hours；
After reaction terminates, reaction system is naturally cooled to into room temperature, filtered, filtrate is fully washed with saturated aqueous common salt；So
Addition chloroform extraction 2-3 time, merges organic faciess afterwards, and concentrating under reduced pressure, residue cross flash chromatography on silica gel, with the third of equal-volume ratio
Used as leacheate, so as to obtain upper formula (III) compound, yield is 95.8% to the mixed solvent of ketone and petroleum ether.
1H NMR(CDCl3,400MHz):δ 7.53 (d, J=8.0Hz, 4H), 7.16-7.08 (m, 4H), 6.47 (s, 1H),
2.33(s,3H),2.25(s,3H),2.21(s,3H)。
Embodiment 4
Under air atmosphere, (it is 2 for volume ratio to appropriate organic solvent:1 DMSO and the mixture of acetonitrile) in, add
The upper formula (I) compounds of 100mmol, the upper formula (II) compounds of 190mmol, 13.5mmol catalyst (are tetra- carbonyl dichlorides of 9mmol
The mixture of two rutheniums and 4.5mmol cobalt chloride hexahydrates), 120mmol oxidant PhI (TFA)2, the positive fourths of 27mmol additive N-
Double (fluoroform sulphonyl) inferior amine salts of base-N- crassitudes and 140mmol alkali DIPEA, then heat to 65 DEG C, and in the temperature
The lower stirring reaction of degree 9 hours；
After reaction terminates, reaction system is naturally cooled to into room temperature, filtered, filtrate is fully washed with saturated aqueous common salt；So
Addition chloroform extraction 2-3 time, merges organic faciess afterwards, and concentrating under reduced pressure, residue cross flash chromatography on silica gel, with the third of equal-volume ratio
Used as leacheate, so as to obtain upper formula (III) compound, yield is 95.3% to the mixed solvent of ketone and petroleum ether.
1H NMR(CDCl3,400MHz):δ7.71-7.64(m,4H),7.42-7.33(m,4H),7.28-7.21(m,2H),
6.67 (s, 1H), 2.73 (q, J=7.6Hz, 2H), 1.26 (t, J=7.6Hz, 3H).
Embodiment 5-16
Embodiment 5-8：Except four carbonyl dichlorides, two ruthenium in catalyst is replaced with addition to triphenylphosphine ruthenic chloride, other are grasped
Make constant, so as to repetition implements embodiment 1-4, sequentially obtain embodiment 5-8.
Embodiment 9-12：Except catalyst is replaced with four carbonyl of one-component that consumption is the total consumption sum of original two kinds of components
Outside two ruthenium of base dichloride, other operations are constant, so as to repetition implements embodiment 1-4, sequentially obtain embodiment 9-12.
Embodiment 13-16：Except catalyst is replaced with the one-component six that consumption is the total consumption sum of original two kinds of components
Outside hydrated cobalt chloride, other operations are constant, so as to repetition implements embodiment 1-4, sequentially obtain embodiment 13-16.
As a result see the table below 1.
Table 1
As can be seen here, when four carbonyl dichlorides, two ruthenium or cobalt chloride hexahydrate is used alone, six water are especially single use
When closing cobaltous chloride as catalyst, yield is significantly reduced.And the catalytic effect of triphenylphosphine ruthenic chloride is significantly lower than four
Two ruthenium of carbonyl dichloride.It can also be seen that when four carbonyl two rutheniums of dichloride is used alone, its yield will be less than triphenyl on the contrary
The yield of the mixed catalyst of phosphine ruthenic chloride and cobalt chloride hexahydrate, with reference to only using 38.5- during cobalt chloride hexahydrate
39.2% yield, this proves that cobalt chloride hexahydrate serves synergy really, and this is non-obvious.
Embodiment 17-28
Embodiment 17-20：Except by oxidant by PhI (TFA)2Replace with outside TBHP, other operations are constant, so as to repeat
Embodiment 1-4 is implemented, embodiment 17-20 is sequentially obtained.
Embodiment 21-24：Except by oxidant by PhI (TFA)2Replace with outside dibenzoyl peroxide, other operations are not
Become, so as to repetition implements embodiment 1-4, sequentially obtain embodiment 21-24.
Embodiment 25-28：Except by oxidant by PhI (TFA)2Replace with PhI (OAc)2Outward, other operations are constant, other
Operation is constant, so as to repetition implements embodiment 1-4, sequentially obtains embodiment 25-28.
As a result 2 be see the table below.
Table 2
As can be seen here, in oxidant, PhI (TFA)2With best effect, even very similar with which PhI
(OAc)2, its yield also has substantially to be reduced.
Embodiment 29-40
Embodiment 29-32：Except additive is replaced by double (fluoroform sulphonyl) inferior amine salt of N- normal-butyl-N- crassitudes
It is changed to outside N- normal-butyl-N- crassitude Bromides, other operations are constant, so as to repetition implements embodiment 1-4, sequentially
Obtain embodiment 29-32.
Embodiment 33-36：Except additive is replaced by double (fluoroform sulphonyl) inferior amine salt of N- normal-butyl-N- crassitudes
It is changed to outside N- normal-butyl-N- crassitude chlorates, other operations are constant, so as to repetition implements embodiment 1-4, sequentially
Obtain embodiment 33-36.
Embodiment 37-40：Except additive N- normal-butyl-N- crassitudes double (fluoroform sulphonyl) inferior amine salts are given
Omit outer, other operations are constant, and other operations are constant, so as to repetition implements embodiment 1-4, sequentially obtain embodiment
37-40。
As a result 3 be see the table below.
Table 3
As can be seen here, the use of additive, significantly improves products collection efficiency and (is increased substantially to reality by 77.8-79.5%
Apply a 1-4 higher than 95%), but in additive, double (fluoroform sulphonyl) inferior amine salt tools of N- normal-butyl-N- crassitudes
There is best improvement performance.
Embodiment 41-46
In addition to using different alkali, other operation all sames, so as to be implemented with the same way with embodiment 1-4 respectively
Embodiment 41-46, the alkali for being used, embodiment corresponding relation and products collection efficiency see the table below 4.
Table 4
As can be seen here, in all of alkali, DIPEA has best effect, under other alkali cause yield to have significantly
Drop.
Embodiment 47-55
In addition to following single organic solvent is adopted, other operation all sames, so as to the same way with embodiment 1-4
And embodiment 47-55 is implemented respectively, single organic solvent, embodiment corresponding relation and the products collection efficiency for being used see the table below 5.
Table 5
As can be seen here, when using single organic solvent, its yield is significantly reduced, and when using DMSO and acetonitrile
During mixture, products collection efficiency has significant improvement.
Summary, present inventors have proposed a kind of synthesis of the polysubstituted furfuran compound that can be used as pharmaceutical intermediate
Method, use of the methods described by suitable substrates, and by the selection of catalyst, oxidant, additive, alkali and organic solvent
With collaboration, purpose product is obtained such that it is able to high yield, have a good application prospect in medicine intermediate synthesis technical field
With extensive industrial production potential.
It should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to limit the protection model of the present invention
Enclose.Additionally, it will also be appreciated that after the technology contents for having read the present invention, those skilled in the art can make each to the present invention
Plant and change, change and/or modification, all these equivalent form of value equally falls within the guarantor limited by the application appended claims
Within the scope of shield.
Claims (7)
1. the synthetic method of polysubstituted furfuran compound shown in a kind of lower formula (III), methods described include：Under air atmosphere
In organic solvent, in the presence of catalyst, oxidant, additive and alkali, lower formula (I) compound and lower formula (II) compound exist
Stirring reaction 7-10 hour at 60-80 DEG C, it is post-treated after completion of the reaction and obtain the formula (III) compound,
Wherein, R1、R2It is each independently selected from H or C1-C6Alkyl；
R3Selected from H, C1-C6Alkyl, C1-C6Alkoxy or halogen；
X is halogen；
The catalyst is any one in four carbonyl dichlorides, two ruthenium or triphenylphosphine ruthenic chloride and cobalt chloride hexahydrate
Mixture, wherein four carbonyl dichlorides, two ruthenium or any one mol ratio with cobalt chloride hexahydrate in triphenylphosphine ruthenic chloride
For 1:0.5；
The oxidant is [double (trifluoroacetic acid) iodine] benzene；
The additive is double (fluoroform sulphonyl) inferior amine salts of N- normal-butyl-N- crassitudes；
The alkali be N, N- diisopropylethylamine；
The organic solvent is the mixture of dimethyl sulfoxide and acetonitrile, and wherein dimethyl sulfoxide and the volume ratio of acetonitrile are 2:1.
2. synthetic method as claimed in claim 1, it is characterised in that：It is 1 that the catalyst is mol ratio:0.5 four carbonyls
The mixture of two ruthenium of dichloride and cobalt chloride hexahydrate.
3. synthetic method as claimed in claim 1, it is characterised in that：Formula (I) compound is rubbed with formula (II) compound
You are than being 1:1.4-2.
4. synthetic method as claimed in claim 1, it is characterised in that：Formula (I) compound with the mol ratio of catalyst is
1:0.12-0.18。
5. synthetic method as claimed in claim 1, it is characterised in that：Formula (I) compound with the mol ratio of oxidant is
1:1-1.6。
6. synthetic method as claimed in claim 1, it is characterised in that：Formula (I) compound with the mol ratio of additive is
1:0.2-0.3。
7. the synthetic method as described in any one of claim 1-6, it is characterised in that：Formula (I) compound and alkali mole
Than for 1:1-1.5.
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| CN106243072B (en) * | 2016-07-18 | 2018-09-28 | 重庆医科大学 | The method that alkali-free, condition of no solvent prepare furane derivative by Feist-Benary reactions |
| CN106432050A (en) * | 2016-09-27 | 2017-02-22 | 李纪焕 | Improved synthesis method for imine compound |
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