CN105646414A - Synthetic method of 6-hydroxyl-2-methylbenzofuran type compound - Google Patents
Synthetic method of 6-hydroxyl-2-methylbenzofuran type compound Download PDFInfo
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Abstract
The invention relates to a synthetic method of a 6-hydroxyl-2-methylbenzofuran type compound. The invention belongs to the field of medical intermediates, and more specifically, the invention relates to a method for synthesizing a 6-hydroxyl-2-methylbenzofuran type compound. The 6-hydroxyl-2-methylbenzofuran type compound is an important medical intermediate, and can be used for preparing a variety of anti-cancer drugs.
Description
Technical field
The invention belongs to medicine intermediate field. More specifically, the present invention relates to a kind of method synthesizing 6-hydroxy-2-methyl benzofuran compounds.
Background technology
6-hydroxy-2-methyl cumarone and derivative thereof are the important medicine intermediates of a class, can be used for preparing multiple cancer therapy drug. Such as, they can generate various VEGF R2 (vascularendothelialgrowthreceptor2, VEGFR-2) inhibitor with 4-chloro-quinazoline derivative or 4-chloroquinoline derivatives reaction.
Traditional organic chemical reactions carries out mostly in organic medium, and the organic liquid waste of generation can discharge a large amount of toxic substances in air, soil and river, pollutes environment, brings harm to human health and social development. Enterprise consumes a huge sum of money because of pollution administration, restricts the development of enterprise self. Therefore, find one of the Critical policies that a kind of eco-friendly chemical reaction medium is also design and synthesis technique.
The synthetic route of compound 6-hydroxy-2-methyl cumarone is reported by many sections of documents. Such as, the synthetic method of the 6-hydroxy-2-methyl cumarone recorded in patent application WO2005/063739 is taking 3-methoxyphenol as starting raw material, and successively by iodo, closed loop, demethylation three-step reaction synthesis target product, its synthetic route is as shown in Figure 1. There is the problems such as the reagent used is expensive, iodide reaction selectivity is not high, receipts rate is low and demethylating reaction is difficult in this operational path, is not therefore suitable for suitability for industrialized production. Again such as; patent application US2007/0265332 reports the synthetic method of the compound 6-hydroxy-2-methyl cumarone of a kind of improvement; take Resorcinol as starting raw material; successively through Friedel-Crafts reaction (Friedel-Craftsreaction), closed loop, protecting five steps such as phenolic hydroxyl group, reduction, Deprotection to be obtained by reacting target product with front three silicon base, its synthetic route is as shown in Figure 2. This operational path need to be obtained by reacting target product through five steps, and relates to the protection to 3-position phenol and the process of deprotection, and reaction product needs silica gel column chromatography purifying, and reaction process is comparatively loaded down with trivial details.
In order to reach scale and the requirement of 6-hydroxy-2-methyl benzofuran compounds suitability for industrialized production, the method for synthesis 6-hydroxy-2-methyl benzofuran compounds that the present invention provides a kind of improvement, that optimize. The method all uses water as solvent in the structure and reduction reaction step of cumarone ring, and reaction conditions is gentleer, environmental protection;Without the need to being protected by 3-position hydroxyl and direct reducing carbonyl in reaction process, decrease reactions steps; The reaction scheme of the present invention is three-step reaction only, it is not necessary to silica gel column chromatography purifying, is applicable to suitability for industrialized production completely.
Summary of the invention
The present invention provides a kind of method (being hereafter called " method of the present invention ") of the 6-of synthesis hydroxy-2-methyl benzofuran compounds, and as shown in Figure 3, described method comprises the following steps its synthetic route:
A () makes compound 1
Friedel-Crafts reaction is carried out for halogen acylting agent 2 with �� halogen,
Obtain compound 3,
In various above, R1It is selected from hydrogen or C1-6Alkyl; R2It is selected from C1-6Alkyl or phenyl; X is selected from chlorine or bromine independently of one another;
B () take water as solvent, make compound 3 carry out ring-closure reaction in the presence of an inorganic base, obtain compound 4,
Wherein R1And R2As in step (a) define;
C () take water as solvent, under strong inorganic base exists, make compound 4 carry out reduction reaction by sodium borohydride or POTASSIUM BOROHYDRIDE; After reaction terminates, adjust ph is 3��5, obtains target compound 5,
Wherein R1And R2As in step (a) define.
In some embodiments of the method for the present invention, R1It is hydrogen or methyl.
In some embodiments of the method for the present invention, R2It is methyl, ethyl, n-propyl, sec.-propyl or phenyl.
In some embodiments of the method for the present invention, �� halogen is the chloro-propionyl chloride of 2-, the bromo-propionyl bromide of 2-, the chloro-butyryl chloride of 2-, 2-chloro-2-phenyl-Acetyl Chloride 98Min. or the chloro-4-methyl-valeryl chloride of 2-for halogen acylting agent 2.
In the method for the invention, the Friedel-Crafts reaction in step (a) can adopt popular response condition well-known to those skilled in the art to carry out, such as, can carry out in halogenated hydrocarbon solvent in the presence of a catalyst. In some embodiments, catalyzer used in Friedel-Crafts reaction can be selected from aluminum trichloride (anhydrous), Zinc Chloride Anhydrous, FERRIC CHLORIDE ANHYDROUS, alchlor, tin tetrachloride, titanium tetrachloride, boron trichloride, boron tribromide and boron trifluoride, it will be preferred that aluminum trichloride (anhydrous). In some embodiments, halogenated hydrocarbon solvent used in Friedel-Crafts reaction is methylene dichloride, ethylene dichloride or its mixture. In some embodiments, in step (a), compound 1 and �� halogen mol ratio=1 for halogen acylting agent 2: (1��1.05). In some embodiments, mol ratio=1 of compound 1 and catalyzer: (1��1.05).
In the method for the invention, " mineral alkali " described in step (b) plays a role as acid binding agent, that is, the hydrohalogen generated for neutralizing in closed reaction. Therefore, any mineral alkali that can neutralize hydrohalogen as known in the art all can be used in step (b). Can be used on the example of the mineral alkali in step (b) and include but not limited to the carbonate of basic metal or alkaline-earth metal, supercarbonate, oxyhydroxide etc., the supercarbonate of preferred as alkali or alkaline-earth metal, more preferably the supercarbonate of basic metal, such as sodium bicarbonate. In some embodiments of the method for the present invention, in step (b), mol ratio=1 of compound 3 and mineral alkali: (1��2.2). In some embodiments, the ring-closure reaction in step (b) carries out at the temperature of 0 DEG C��10 DEG C. In some embodiments, in step (b), after ring-closure reaction terminates, the pH value of reaction solution is adjusted to 6��7, thus it is settled out compound 4.
In the method for the invention, " strong inorganic base " described in step (c) be the carbonate of basic metal or the oxyhydroxide of basic metal preferably, such as sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide etc.In some embodiments of method of the present invention, in step (c), mol ratio=1 of compound 4 and strong inorganic base: (1��1.1). In some embodiments of the method for the present invention, in step (c), compound 4 and mol ratio=1 of sodium borohydride or POTASSIUM BOROHYDRIDE: (2.5��3). In some embodiments of the method for the present invention, the reduction reaction of step (c) carries out as follows: add in reaction vessel by compound 4, sodium hydroxide and water, mixture temperature is reduced to 5 DEG C��15 DEG C, then add sodium borohydride in batches, after reinforced, reaction system be warming up to 15 DEG C��25 DEG C and react.
The method of the present invention all uses water as solvent in the ring-closure reaction of step (b) and the reduction reaction of step (c), has that cost is low, reaction scheme is simple, reaction conditions is gentle, environmental protection, last handling process are easy, be suitable for the advantages such as suitability for industrialized production.
Term used herein " alkyl " refer to there is 1 to 6 carbon atom, the saturated monovalent hydrocarbon of the straight or branched such as with 1,2,3,4,5,6 carbon atom, it is preferable that refer to the saturated monovalent hydrocarbon of the straight or branched with 1 to 4 carbon atom. The alkyl with 1 to 6 carbon atom is simply expressed as " C1-6Alkyl ", the alkyl with 1 to 4 carbon atom is simply expressed as " C1-4Alkyl ", the alkyl of other carbonatoms can also represent in a similar manner. The example of alkyl is including, but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl etc.
Term used herein " halogen " refers to fluorine, chlorine, bromine or iodine, it is preferable that fluorine, chlorine and bromine, it is more preferable to chlorine and bromine.
Term used herein " halohydrocarbon " refers to the hydrocarbon by the saturated, unsaturated of one or more halogen substiuted or aromatics, such as hydrofluoric ether, hydrochloric ether, hydrobromic ether and iodo hydrocarbon, the halohydrocarbon that wherein said halohydrocarbon is preferably saturated, more preferably saturated hydrochloric ether, even more preferably chlorine is for C1-6Alkane. The example of halohydrocarbon is including, but not limited to methylene dichloride, ethylene dichloride or its mixture etc.
Term " C used herein1-6Alkane " refer to the saturated hydrocarbon of the straight or branched with 1 to 6 carbon atom. C1-6The example of alkane is including, but not limited to methane, ethane, n-propane, isopropyl alkane etc.
Term used herein " basic metal " means the element lithium (Li) of IA race in the periodic table of elements, sodium (Na), potassium (K), rubidium (Rb), caesium (Cs), francium (Fr), it is preferable that sodium and potassium.
Term used herein " alkaline-earth metal " means Group IIA element beryllium (Be) in the periodic table of elements, magnesium (Mg), calcium (Ca), strontium (Sr), barium (Ba) and radium (Ra), preferred calcium and magnesium, it is most preferred that calcium.
In any structural formula herein, if there is vacant valency on any atom, in fact this vacant valency is the hydrogen atom specifically do not described in order to simplicity.
Herein, if give title and the structural formula of this compound for a compound simultaneously, when the two is inconsistent, it is as the criterion with the structure of compound, unless context shows that the structure of compound is incorrect and title is correct.
Embodiment
Following embodiment is the illustration to the present invention, it should not when being understood to limit the scope of the invention by any way. Disclosed data (such as, amount, temperature etc.) strive ensureing its accuracy, but also can there is some experimental errors and skew.Unless otherwise indicated, otherwise part number in the present invention is weight part number, and temperature is centigradetemperature, and pressure is normal atmosphere or close to normal atmosphere. All hydrogen modal data are recorded by Varian400-MR. The present invention's all reagent used are commercial channel and obtain.
It is below the abbreviation list used in embodiment:
DCM methylene dichloride
DCE ethylene dichloride
Et3N triethylamine
EtOH ethanol
HOAc acetic acid
MeOH methyl alcohol
NaOMe sodium methylate
Ph phenyl
THF tetrahydrofuran (THF)
TBSCl TERT-BUTYL DIMETHYL CHLORO SILANE
LC-MS liquid chromatography-mass spectrography
G gram
L liter
Ml milliliter
Mol mole
H hour
Ph phenyl
Embodiment 1
A) synthesis of the chloro-1-of 2-(2,4-dihydroxyl-phenyl)-propane-1-ketone
In reaction flask, add Resorcinol (110g, 1mol), ethylene dichloride (1100ml), replace 3 times with nitrogen, internal temperature is reduced to 0��5 DEG C, add aluminum trichloride (anhydrous) (134g, 1mol). Control internal temperature is 0��5 DEG C, slowly drips and adds the chloro-propionyl chloride (127g, 1mol) of 2-. After dropwising, being naturally warming up to room temperature (15��25 DEG C), stirring is spent the night, with LC-MS monitoring reaction. Reaction solution is poured in 2L trash ice after terminating by reaction, and a large amount of yellow solid precipitates out. Take out filter, wash filter cake with water to neutral. 40��50 DEG C of drying under reduced pressure, obtain faint yellow solid title compound 151.3g, purity 99.5%, receipts rate 75.6%.
1HNMR (400MHz, CD3OD) �� 7.78 (d, J=9.0Hz, 1H), 6.39 (dd, J=8.9,2.4Hz, 1H), 6.29 (d, J=2.3Hz, 1H), 5.46 (q, J=6.6Hz, 1H), 1.65 (d, J=6.6Hz, 3H).
B) synthesis of 6-hydroxy-2-methyl cumarone-3-ketone
The chloro-1-(2 of 2-is added in reaction flask, 4-dihydroxyl-benzene is usurped)-propane-1-ketone (60g, 0.3mol), water (600ml), internal temperature is reduced to 0��10 DEG C, add sodium bicarbonate (50.4g, 0.6mol). After reinforced, being naturally warming up to room temperature (15��25 DEG C), stirring is spent the night, with LC-MS monitoring reaction. After reaction terminates, slowly dripping the aqueous hydrochloric acid that adds 5%, regulate pH value to 6��7 of reaction solution, a large amount of white solid precipitates out. Take out filter, wash filter cake with water to neutral. 40��50 DEG C of drying under reduced pressure, obtain pale solid title compound 37g, purity 99.6%, receipts rate 75%.
1HNMR (400MHz, CD3OD) �� 7.46 (d, J=8.6Hz, 1H), 6.55 (dd, J=8.6,0.9Hz, 1H), 6.42 (brs, 1H), 4.64 (q, J=7.1Hz, 1H), 1.43 (d, J=7.1Hz, 3H).
C) synthesis of 6-hydroxy-2-methyl-cumarone
6-hydroxyl 2-methyl cumarone-3-ketone (42g, 0.256mol), water (630ml), sodium hydroxide (10g, 0.256mol) is added in reaction flask. Internal temperature is reduced to 5��15 DEG C, adds sodium borohydride (27g, 0.714mol) in batches. After reinforced, being naturally warming up to room temperature (15��25 DEG C), stirring is spent the night, with LC-MS monitoring reaction. After reaction terminates, filter, use little water washing leaching cake, merging filtrate. Slowly regulate pH value to 3��5 of filtrate with 5% aqueous hydrochloric acid, by ethyl acetate (100ml �� 3) aqueous phase extracted, merge organic phase. In organic phase, add dried over sodium sulfate, take out filter, with a little ethyl acetate washing leaching cake, merging filtrate. Concentrating under reduced pressure filtrate, obtains light tan solid title compound 26g, purity 95.3%, receipts rate 66%.
1HNMR (400MHz, CD3OD) �� 7.19 (d, J=8.3Hz, 1H), 6.79 (d, J=2.0Hz, 1H), 6.65 (dd, J=8.3,2.0Hz, 1H), 6.25 (brs, 1H), 2.35 (d, J=0.8Hz, 3H).
Embodiment 2
The synthesis of the bromo-1-of 2-(2,4-dihydroxyl-phenyl)-propane-1-ketone
Reaction conditions is with embodiment 1a), obtain title compound, it is faint yellow solid, purity 99.5%, receipts rate 42%.
1HNMR (400MHz, CD3OD) �� 7.79 (d, J=9.0Hz, 1H), 6.39 (dd, J=8.9,2.4Hz, 1H), 6.29 (d, J=2.4Hz, 1H), 5.53 (q, J=6.6Hz, 1H), 1.81 (d, J=6.6Hz, 3H).
Embodiment 3
A) synthesis of the chloro-1-of 2-(2,4-dihydroxyl-phenyl)-butane-1-ketone
Reaction conditions is with embodiment 1a), obtain title compound, it is faint yellow solid, purity 99%, receipts rate 40.6%.
1HNMR (400MHz, CD3OD) �� 7.78 (d, J=8.8Hz, 1H), 6.39 (dd, J=8.9,2.4Hz, 1H), 6.28 (d, J=2.4Hz, 1H), 5.28 (dd, J=7.8,6.0Hz, 1H), 2.20-2.04 (m, 1H), 2.03-1.89 (m, 1H), (1.03 t, J=7.4Hz, 3H).
B) synthesis of 2-ethyl-6-hvdroxv-benzofuran-3-ketone
Reaction conditions is with embodiment 1b), obtain title compound, it is white solid, purity 99.3%, receipts rate 84.2%.
1HNMR (400MHz, CD3OD) �� 7.46 (d, J=8.5Hz, 1H), 6.56 (dd, J=8.6,2.0Hz, 1H), 6.44 (d, J=2.0Hz, 1H), 4.56 (dd, J=7.0,4.5Hz, 1H), 2.04-1.94 (m, 1H), 1.81-1.71 (m, 1H), 0.97 (t, J=7.4Hz, 3H).
C) synthesis of 6-hydroxyl-2-Ethyl-benzofuran
Reaction conditions is with embodiment 1c), obtain title compound, it is white solid, purity 99.5%, receipts rate 85%.
1HNMR (400MHz, CD3OD) �� 7.22 (d, J=8.3Hz, 1H), 6.81 (brd, J=2.0Hz, 1H), 6.67 (dd, J=8.3,2.2Hz, 1H), 6.26 (d, J=1.0Hz, 1H), 2.70 (qd, J=7.5,1.0Hz, 2H), (1.27 t, J=7.6Hz, 3H).
Embodiment 4
A) synthesis of the chloro-1-of 2-(2,4-dihydroxyl-phenyl)-2-phenyl-ethane-1-ketone
Reaction conditions is with embodiment 1a), obtain title compound, it is white solid, purity 95%, receipts rate 96.5%.
1HNMR (400MHz, CD3OD) �� 7.77 (d, J=9.0Hz, 1H), 7.50 (brd, J=7.0Hz, 2H), 7.39-7.28 (m, 3H), 6.65 (s, 1H), 6.32 (dd, J=8.9,2.4Hz, 1H), 6.27 (d, J=2.3Hz, 1H).
B) synthesis of 6-hydroxyl-2-phenyl-cumarone-3-ketone
Reaction conditions is with embodiment 1b), obtain title compound, it is white solid, purity 99%, receipts rate 61.6%.
1HNMR (400MHz, CD3OD) �� 7.50 (d, J=8.6Hz, 1H), 7.38-7.30 (m, 5H), 6.62 (dd, J=8.5,2.0Hz, 1H), 6.56 (brd, J=2.0Hz, 1H), 5.58 (s, 1H). C) synthesis of 6-hydroxyl-2-phenyl-cumarone
Reaction conditions is with embodiment 1c), obtain title compound, it is white solid, purity 99.9%, receipts rate 71.4%.
1HNMR (400MHz, CD3OD) �� 7.81-7.80 (m, 1H), 7.79-7.78 (m, 1H), 7.41 (brt, J=7.7Hz, 2H), 7.36 (dd, J=8.4,0.4Hz, 1H), 7.29 (brt, J=7.2Hz, 1H), 7.03 (d, J=0.9Hz, 1H), 6.93-6.91 (m, 1H), 6.74 (dd, J=8.4,2.2Hz, 1H).
Embodiment 5
A) synthesis of the chloro-1-of 2-(2,4-dihydroxyl-phenyl)-4-methyl-pentane-1-ketone
Reaction conditions is with embodiment 1a), obtain title compound, it is yellow oil, purity 94.5%, receipts rate 54%.
1HNMR (400MHz, CD3OD) �� 7.78 (d, J=9.0Hz, 1H), 6.40 (dd, J=8.9,2.4Hz, 1H), 6.29 (d, J=2.4Hz, 1H), 5.36 (dd, J=7.9,6.4Hz, 1H), 1.91-1.86 (m, 2H), 1.84-1.76 (m, 1H), 0.96 (d, J=6.5Hz, 3H), 0.95 (d, J=6.5Hz, 3H).
B) synthesis of 6-hydroxyl-2-isobutyl-cumarone-3-ketone
Reaction conditions is with embodiment 1b), obtain title compound, it is white solid, purity 95%, receipts rate 57.4%.
1HNMR (400MHz, CD3OD) �� 7.45 (brd, J=8.4Hz, 1H), 6.55 (dd, J=8.6,2.0Hz, 1H), 6.42 (brd, J=2Hz, 1H), 4.63 (dd, J=9.8,3.5Hz, 1H), 2.03-1.87 (m, 1H), 1.73 (ddd, J=14.4,8.4,3.5Hz, 1H), 1.52 (ddd, J=14.4,9.8,5.5Hz, 1H), 1.00 (d, J=6.5Hz, 3H), 0.98 (d, J=6.5Hz, 3H).
C) synthesis of 6-hydroxyl-2-isobutyl-cumarone
Reaction conditions is with embodiment 1c), obtain title compound, it is tawny oily matter, purity 89%, receipts rate 57.4%.
1HNMR (400MHz, CD3OD) �� 7.21 (brd, J=8.4Hz, 1H), 6.793 (brd, J=2Hz, 1H), 6.66 (dd, J=8.3,2.2Hz, 1H), 6.26 (dd, J=0.8,1.6Hz, 1H), 2.54 (d, J=6.2Hz, 2H), 2.08-1.96 (m, 1H), 0.94 (d, J=6.7Hz, 6H).
Embodiment 6
A) synthesis of the chloro-1-of 2-(2,4-dihydroxyl-6-methyl-phenyl)-propane-1-ketone
Reaction conditions is with embodiment 1a), obtain title compound, it is yellow solid, purity 99.3%, receipts rate 39.6%.
1HNMR (400MHz, CD3OD) �� 6.19 (brd, J=2.0, Hz, 1H), 6.15 (brd, J=2.4Hz, 1H), 5.35 (q, J=7.2Hz, 1H), 2.18 (s, 3H), 1.59 (d, J=7.2Hz, 3H).
B) synthesis of 6-hydroxyl-2,4-dimethyl-cumarone-3-ketone
Reaction conditions is with embodiment 1b), obtain title compound, it is white solid, purity 99%, receipts rate 61%.
1HNMR (400MHz, CD3OD) �� 6.31-6.30 (m, 1H), 6.23 (brd, J=2.0Hz, 1H), 4.59 (q, J=7.1Hz, 1H), 2.45 (s, 3H), 1.42 (d, J=7.1Hz, 3H).
C) synthesis of 6-hydroxyl-2,4-dimethyl-cumarone
Reaction conditions is with embodiment 1c), obtain title compound, it is white solid, purity 94.7%, receipts rate 81%.
1HNMR (400MHz, CD3OD) �� 6.61 (brs, 1H), 6.49-6.47 (m, 1H), 6.31-6.28 (m, 1H), 2.35 (d, J=1.2Hz, 3H), 2.34 (s, 3H).
Embodiment 7
A) synthesis of the chloro-1-of 2-(2,4-dihydroxyl-3-methyl-phenyl)-propane-1-ketone
Reaction conditions is with embodiment 1a), obtain title compound, it is faint yellow solid, purity 95.8%, receipts rate 36%. MS (m/z)=215.1 [M+H]+��
1HNMR (400MHz, CD3OD) �� 7.65 (d, J=8.9Hz, 1H), 6.42 (d, J=8.9Hz, 1H), 5.49 (q, J=6.6Hz, 1H), 2.04 (s, 3H), 1.66 (d, J=6.6Hz, 3H).
B) synthesis of 6-hydroxyl-2,7-dimethyl-cumarone-3-ketone
Reaction conditions is with embodiment 1b), obtain title compound, it is tawny solid, receipts rate 95.2%, purity 49.0%. MS (m/z)=179.15 [M+H]+��
1HNMR (400MHz, CD3OD) �� 7.31 (d, J=8.0Hz, 1H), 6.57 (d, J=8.0Hz, 1H), 4.71-4.62 (m, 1H), 2.08 (s, 3H), 1.44 (d, J=6.8Hz, 3H).
C) synthesis of 2,7-dimethyl-6-hydroxyl benzofuran
Reaction conditions is with embodiment 1c), obtain title compound, it is yellow solid, purity 93.1%, receipts rate 48.8%. MS (m/z)=163.15 [M+H]+��
1HNMR (400MHz, CD3OD) �� 7.01 (d, J=7.6Hz, 1H), 6.64 (d, J=7.9Hz, 1H), 6.23 (s, 1H), 2.36 (s, 3H), 2.28 (s, 3H).
Accompanying drawing explanation
Fig. 1 is the synthetic method of the 6-hydroxy-2-methyl cumarone recorded in patent application WO2005/063739, and it is taking 3-methoxyphenol as starting raw material, has synthesized target product by iodo, closed loop, demethylation three-step reaction successively.
Fig. 2 is the synthetic method of the compound 6-hydroxy-2-methyl cumarone of the improvement that patent application US2007/0265332 reports; it take Resorcinol as starting raw material, successively through Friedel-Crafts reaction, closed loop, protect five steps such as phenolic hydroxyl group, reduction, Deprotection to be obtained by reacting target product with front three silicon base.
Fig. 3 is the method for the synthesis 6-hydroxy-2-methyl benzofuran compounds of the present invention, wherein R1It is selected from hydrogen or C1-6Alkyl; R2It is selected from C1-6Alkyl or phenyl; X is selected from chlorine or bromine independently of one another.
Claims (17)
1. synthesizing the method for 6-hydroxy-2-methyl benzofuran compounds, described method comprises the following steps:
A () makes compound 1
Friedel-Crafts reaction is carried out for halogen acylting agent 2 with �� halogen,
Obtain compound 3,
In various above, R1It is selected from hydrogen or C1-6Alkyl; R2It is selected from C1-6Alkyl or phenyl; X is selected from chlorine or bromine independently of one another;
B () take water as solvent, make compound 3 carry out ring-closure reaction in the presence of an inorganic base, obtain compound 4,
Wherein R1And R2As in step (a) define;
C () take water as solvent, under strong inorganic base exists, make compound 4 carry out reduction reaction by sodium borohydride or POTASSIUM BOROHYDRIDE; After reaction terminates, adjust ph is 3��5, obtains target compound 5,
Wherein R1And R2As in step (a) define.
2. method according to claim 1, wherein R1It is hydrogen or methyl; And R2It is methyl, ethyl, n-propyl, sec.-propyl or phenyl.
3. method according to claim 1 and 2, wherein said �� halogen is the chloro-propionyl chloride of 2-, the bromo-propionyl bromide of 2-, the chloro-butyryl chloride of 2-, 2-chloro-2-phenyl-Acetyl Chloride 98Min. or the chloro-4-methyl-valeryl chloride of 2-for halogen acylting agent 2.
4. method as claimed in any of claims 1 to 3, wherein the Friedel-Crafts reaction in step (a) carries out in the presence of a catalyst in halogenated hydrocarbon solvent.
5. method according to claim 4, wherein said catalyzer is selected from aluminum trichloride (anhydrous), Zinc Chloride Anhydrous, FERRIC CHLORIDE ANHYDROUS, alchlor, tin tetrachloride, titanium tetrachloride, boron trichloride, boron tribromide and boron trifluoride.
6. method according to claim 5, wherein said catalyzer is aluminum trichloride (anhydrous).
7., according to method described in any one in claim 4 to 6, wherein said halogenated hydrocarbon solvent is selected from methylene dichloride, ethylene dichloride and its mixture.
8. method as claimed in any of claims 1 to 7, wherein in step (a), compound 1 and �� halogen mol ratio=1:(1��1.05 for halogen acylting agent 2).
9. according to method described in any one in claim 4 to 8, wherein in step (a), mol ratio=1:(1��1.05 of compound 1 and catalyzer).
10. according to method described in any one in claim 1-9, wherein in step (b), mol ratio=1:(1��2.2 of compound 3 and mineral alkali).
11. methods according to claim 1-10, wherein the mineral alkali described in step (b) is the carbonate of basic metal or alkaline-earth metal, supercarbonate or oxyhydroxide, the supercarbonate of preferred as alkali or alkaline-earth metal, it is more preferable to the supercarbonate of basic metal, such as sodium bicarbonate.
12. according to method described in any one in claim 1-11, and wherein the ring-closure reaction in step (b) carries out at the temperature of 0 DEG C��10 DEG C.
The pH value of reaction solution, according to method described in any one in claim 1-12, wherein in step (b), after ring-closure reaction terminates, is adjusted to 6��7, thus is settled out compound 4 by 13..
14. according to method described in any one in claim 1-13, wherein in step (c), and mol ratio=1:(1��1.1 of compound 4 and strong inorganic base).
15. according in claim 1-14 described in any one starve method, wherein the strong inorganic base described in step (c) is the carbonate of basic metal or the oxyhydroxide of basic metal, such as sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide.
16. according to method described in any one in claim 1-15, wherein in step (c), and compound 4 and mol ratio=1:(2.5��3 of sodium borohydride or POTASSIUM BOROHYDRIDE).
17. according to method described in any one in claim 1-16, wherein the reduction reaction of step (c) carries out as follows: add in reaction vessel by compound 4, sodium hydroxide and water, mixture temperature is reduced to 5 DEG C��15 DEG C, then add sodium borohydride in batches, after reinforced, reaction system be warming up to 15 DEG C��25 DEG C and react.
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