CN106397295A - 2-branch acylation method of solid acid continuous loaded catalyzed aromatic heterocyclic compound - Google Patents
2-branch acylation method of solid acid continuous loaded catalyzed aromatic heterocyclic compound Download PDFInfo
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- CN106397295A CN106397295A CN201610804593.6A CN201610804593A CN106397295A CN 106397295 A CN106397295 A CN 106397295A CN 201610804593 A CN201610804593 A CN 201610804593A CN 106397295 A CN106397295 A CN 106397295A
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- GVGVUNDFQUSHDM-UHFFFAOYSA-N C(c1ccccc1)N1C=CC=CC1 Chemical compound C(c1ccccc1)N1C=CC=CC1 GVGVUNDFQUSHDM-UHFFFAOYSA-N 0.000 description 1
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J29/00—Catalysts comprising molecular sieves
- B01J29/04—Catalysts comprising molecular sieves having base-exchange properties, e.g. crystalline zeolites
- B01J29/06—Crystalline aluminosilicate zeolites; Isomorphous compounds thereof
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/06—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing polymers
- B01J31/08—Ion-exchange resins
- B01J31/10—Ion-exchange resins sulfonated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
- C07D207/48—Sulfur atoms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
- B01J2231/4211—Suzuki-type, i.e. RY + R'B(OR)2, in which R, R' are optionally substituted alkyl, alkenyl, aryl, acyl and Y is the leaving group
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to the technical field of chemical compounds, in particular to a 2-site acylation method of solid acid continuous loaded catalyzed aromatic heterocyclic compound. The method comprises the following steps: filling a continuous reaction device with solid acid catalyst, and continuously adding aromatic heterocyclic compounds and acylating agents to trigger the Friedel-Crafts acylation. The method is a highly efficient green synthesis process which applies heterogeneous catalysis to make the products easily separable, thereby avoiding the use of Lewis acid such as AlCl3 and eliminating the environmental destruction; the method uses continuous operation with mild reaction conditions and short reaction time. The catalyst does not have to be separated and can be recycled. The reaction recovery rate can reach 95% or above. The reaction selectivity is superior. The purity of the product can reach 92% or above. The method is simple in operation, and has obvious advantages especially in enlarged production.
Description
Technical field
The present invention relates to chemosynthesis technical field is and in particular to a kind of solid acid continuous load is catalyzed heteroaromatic compounds
The method that 2- position is acylated.
Background technology
Fu Ke (Friedel Crafts) acylation reaction is found in 1887, is the method for formation C-C key the most ancient
One of.Up to the present, it remains the important means introducing carbonyl on aromatic ring that academia and industrial quarters are used.
The heteroaromatics such as substituted pyrroles, furan, thiophene, indole are contained in a lot of natural products and bioactive compound
Structure, typically, pyrroles and other heterocyclic aromatic compounds of indole are carried out with friedel-crafts acylation needs stoichiometric Louis
This acid, such as：AlCl3、TiCl4、BF3、BeCl2、SnCl4Or SbCl5Deng strong Bronsted acid such as H in addition2SO4, HF or superpower
Acid ratio such as HF SbF5And HSO3F·SbF5Also it is applied to friedel-crafts acylation.Developed the trifluoro of transition metal later again
Mesylate catalyst, organic molecule catalyst friedel-crafts acylation, have preferable effect.But, no matter Louis
This acid, transition metal salt or organic micromolecule catalyst, its type is all homogeneous catalyst, although it is in numerous chemistry conjunctions
There is in one-tenth field higher activity and selectivity, but such catalyst of great majority report also has the huge of its own
Not enough greatly：Stoichiometric consumption is needed during using lewis acid；Post processing is comparatively laborious, especially using AlCl3When, point liquor ratio
More difficult；Response time is longer；Reaction temperature is typically higher；Severe reaction conditions, multipair greatly water vapor sensitive；Meeting in course of reaction
Produce corrosive gas in a large number, and form substantial amounts of inorganic salt, cause the destruction of environment；And transition metal salt cost is relatively
High；These catalyst all can not recycle and reuse, and economy is not enough；Etc..
On the other hand, because the 2- position of the similar heteroaromatic structure such as pyrroles, furan, thiophene, 3- position have to electrophilic reagent
Very strong activity and the probability of its poly in acid condition, the method that efficiently selectivity carries out the acylation of 2- position at present
Less.
Yang Yonghui. the research of nitrogenous heteroaromatic compound friedel-crafts acylation. Hebei：University Of Hebei, 2011,5-
13. disclose respectively with the modified H- beta-molecular sieve of the acid such as different molecular sieves and oxalic acid, phosphoric acid, hydrochloric acid as catalyst, by pyrroles
With the friedel-crafts acylation of acetic anhydride synthesis of acetyl base pyrroles, reaction is in the single port equipped with reflux condensing tube and nitrogen protection
Carry out in bottle.Optimum reaction condition is：Using phosphoric acid modification H- beta-molecular sieve be catalyst, reaction temperature be 70 DEG C, reaction when
Between be 5h, now the overall selectivity of acetyl pyrrole be 93.8%, 2- acetyl pyrrole selectivity be 76.7%.It is right that reaction needs
Molecular sieve carries out sour modification, carries out intermittent reaction, complex operation using single port bottle, the selectivity of reaction is relatively low, and product divides
More difficult from purification, it is unfavorable for that application is amplified in industrialization.
Content of the invention
For overcoming the deficiencies in the prior art, the present invention proposes a kind of easy and simple to handle, mild condition, yield and 2- position is acylated
The new method that the 2- position of the heteroaromatic compounds that selectivity is high, catalyst need not separate and can be recycled is acylated.
The technical scheme that the 2- position of described heteroaromatic compounds is acylated method includes：In continuous reaction apparatus, fill out
Fill solid acid catalyst, be continuously added to heteroaromatic compounds and acylating reagent, carry out friedel-crafts acylation；
Described heteroaromatic compounds are as shown in structural formula I：
Wherein, X is selected from：NR3, O, S, preferably NR3；
R1、R2Independently selected from：H, substituted or unsubstituted alkyl, or R1、R2Formed together with the carbon atom being connected with it
Aromatic ring；Described alkyl preferably is selected from：-CH3、-CH2CH3、-CH(CH3)2、-C(CH3)3；Preferably, R1、R2It is H or R simultaneously1、R2
Form phenyl ring together with the carbon atom being connected with it；
R3For H or amido protecting group, described amido protecting group preferably is selected from：Ms, Ts, methyl, Boc, Cbz,
Alloc、PMB、Bn、Tfa、Trt、Dmb；
Preferably, described acylating reagent be selected from acyl chlorides and carboxylic acid anhydrides, preferably carboxylic acid anhydrides, carboxylic acid anhydrides preferably be selected from：
Acetic anhydride, 2- monochloroacetic acid anhydride, trifluoroacetic anhydride, benzoyl oxide, more preferably acetic anhydride；
In a preferred embodiment of the present invention, X is NH, during being acylated, can there is acylating reagent excellent
The competitive reaction first reacted with amino, needs to protect this amino with protection group before charging reaction, so described heteroaromatic
The 2- position of compound is acylated method and also includes protecting step on amino；
Another preferred embodiment in, in described formula I, X be NR3, R1、R2It is H or R simultaneously1、R2Connected with it
The carbon atom connecing forms phenyl ring together, and that is, described heteroaromatic compounds are substituted or unsubstituted pyrroles or indole derivativeses；
Preferably, described heteroaromatic compounds and/or acylating reagent solvent dissolve；Described solvent is unwise to acid
The solvent of sense, preferably is selected from：Dichloromethane, 1,2- dichloroethanes, chlorobenzene, Nitrobenzol, carbon tetrachloride；Above-mentioned lysigenous virtue is miscellaneous
The solution concentration of cycle compound and/or acylating reagent is 0.1-2.0mol/L, preferably 0.5-1.5mol/L, it is furthermore preferred that fragrant
The solution concentration of heterocyclic compound is 1.0mol/L, and the solution concentration of acylating reagent is 1.1mol/L；
Described heteroaromatic compounds and acylating reagent add continuous after being separately added into continuous reaction apparatus or mix homogeneously
Reaction unit；
Preferably, the molar ratio of described heteroaromatic compounds and acylating reagent is 1:1.0-2.0；More preferably 1:
1.0-1.5, most preferably 1:1.1；
Preferably, the particle diameter >=1mm of described solid acid catalyst, more preferably 1-5mm, more preferably 1-2mm；
Preferably, the consumption of described solid acid catalyst is the substrate (including heteroaromatic compounds and acylating reagent) that feeds intake
More than 5 times of quality, preferably 5-15 times, more preferably 10 times；
Preferably, described solid acid catalyst is ion exchange resin or zeolite, and described ion exchange resin is preferred
From：Macroporous ion exchange resin Amberlyst-15, perfluorosulfonic acid ion exchanger resin Nafion, more preferably Amberlyst-
15；Described zeolite is preferably H- β zeolite；
In a preferred embodiment of the present invention, described solid acid catalyst is H- β zeolite, described heteroaromatic
The 2- position of compound is acylated the activation step that method also includes catalyst；Preferably, described activation step includes：By H- β
Zeolite is placed in crucible, after baking 3-5 hour at 500-600 DEG C in Muffle furnace, is cooled to standby after room temperature；
Preferably, described reaction temperature is 25-130 DEG C, more preferably 40-100 DEG C, more preferably 55-75 DEG C；
Preferably, the described response time is 0.1-2.0h, more preferably 0.5-1.5h, most preferably 1h；
Described continuous reaction apparatus include cylinder, temperature control system, automatic feed system；
In a preferred embodiment of the present invention, described continuous reaction apparatus are fixed bed reactors, including post
Body, chuck, feed pump, material container, receptor；It is filled with solid acid catalyst, chuck interior circulation circulates in described cylinder
Coolant or heating agent, realize the control of cylinder interior reaction temperature, and feed pump is connected with material container and cylinder entrance, can will react former
Material pumps into the control realizing the response time in cylinder and by adjusting flow velocity, and receptor is connected with cylinder outlet, for receiving post
The reactant liquor that body flows out.
In one embodiment of the invention, said method includes：By macroporous ion exchange resin Amberlyst-15 or
H- β zeolite is filled in the cylinder of continuous reaction apparatus, and the consumption of catalyst is to feed intake 10 times of substrate quality, through sealing
After detection, start dnockout, the amino being dissolved with solvent is from bottom to top pumped into toward in reaction unit by feed pump protected
Azole derivativesWith the anhydride being dissolved with same solvent, the molar ratio of the two is 1:1.1, by flowing through folder
The water of different temperatures of set or heating bath oil adjust reaction temperature, and reaction temperature is 65 DEG C, are controlled instead by adjusting the flow velocity of pump
Answer the response time in continuous reaction apparatus for the liquid, the response time is 1h, the reactant liquor flowing out from cylinder is collected with receptor, beats
Material finishes, system in HPLC detection receptor, after raw material converts completely, solution in receiving bottle is directly thickened to dry obtain final product target
Product.
The present invention also provides a kind of application in chemosynthesis for said method.
It is a kind of synthesis technique of high effective green environmentally friendly that the 2- position of the heteroaromatic compounds that the present invention provides is acylated method,
Employ heterogeneous catalysis, product separates easily, it is to avoid intractable AlCl3Etc. lewis acidic use, prevent to ring
The harm that border is caused；Methods described employs continuous operation, and reaction condition is relatively gentle and the response time is shorter, and catalyst need not
Separate and repeatable utilize, reaction yield can reach more than 95%, reaction selectivity preferably, 2- position be acylated selectivity up to
More than 96%, product purity can reach more than 92%, and easy and simple to handle, cost is relatively low, with the obvious advantage when amplifying production, economic effect
Beneficial prospect is very considerable.
Brief description
Fig. 1 show the catalyst Amberlyst-15 of the embodiment of the present invention 1 use and the construction unit of Nafion resin；
The construction unit of A-Amberlyst-15, the construction unit of B-Nafion resin.
Fig. 2 show the catalyst Amberlyst-15 of the embodiment of the present invention 1 use and the electron scanning of Nafion resin
Electromicroscopic photograph；The construction unit of A-Amberlyst-15, the construction unit of B-Nafion resin.
Fig. 3 show the crystal structure of the catalyst H- β zeolite of the embodiment of the present invention 1 use.
Fig. 4 show the structural representation of the fixed bed reactors of the embodiment of the present invention 1 use；1- successive reaction receives
Device, 2- JO, 3- fixed bed reactors kettle (inclusion chuck), 4- feed pump, 5- bottle for material, 6- temperature measuring point, 7-
JI.
Fig. 5 show the nuclear magnetic spectrogram of the product of embodiment of the present invention 2-5；A-1H nuclear magnetic spectrum, B-13C nuclear-magnetism figure
Spectrum.
Fig. 6 show the nuclear magnetic spectrogram of the product of embodiment of the present invention 6-9；A-1H nuclear magnetic spectrum, B-13C nuclear-magnetism figure
Spectrum.
Specific embodiment
In the present invention, Ms is mesylTs is p-toluenesulfonylBoc is tertbutyloxycarbonylCbz is benzyloxycarbonyl groupAlloc is allyloxycarbonylPMB is to methoxy-benzylBn is benzylTfa is trifluoroacetyl groupTrt is three
BenzylDmb is 2,4- dimethoxy-benzyl
Below in conjunction with the accompanying drawing in the embodiment of the present invention, the technical scheme in the embodiment of the present invention is carried out clear, complete
Site preparation describes it is clear that described embodiment is only a part of embodiment of the present invention, rather than whole embodiments.Based on this
Embodiment in invention, the every other reality that those of ordinary skill in the art are obtained under the premise of not making creative work
Apply example, broadly fall into the scope of protection of the invention.
Embodiment 1：Screening of catalyst
Catalyst to be screened as shown in table 1, is reacted by batch and is obtained, and its concrete operations is as follows by this screening：
Under room temperature, 1- tosyl -1H- pyrroles (10mmol, 1.0eq) is added in there-necked flask, adds appropriate DCM
(50mL) dissolve, be then slowly added into acetic anhydride (20mmol, 2.0eq), after stirring 15min, disposably add solid acid
(100wt%).Said mixture is stirred at room temperature, and TLC monitors, till consumption of raw materials is complete.
Table 1 is the selection result, from experimental result, solid acid and traditional lewis acid such as AlCl3Compare, have completely
Different regioselectivities：Use AlCl3Catalysis can be efficiently obtained by 3- acetylate, and solid acid catalysis, mainly obtain 2-
Acetylate.And in solid acid, H- β zeolite has best 2- position selectivity, and highest reaction conversion ratio.In addition,
Amberlyst-15 and Nafion resin also has good catalytic effect.
The acetylation catalyst screening of table 1N-Ts- pyrroles
A.HPLC external standard yield；
B. it is the yield through silica gel chromatography column purification in bracket.
Amberlyst-15 and Nafion resin is all ion exchange resin, and its physical property is as shown in table 2.
Amberlyst-15 is a kind of macroporous network shape sulfonic acid polyene group ion exchange resin, has 20% divinylbenzene (structure
Unit is shown in Figure 1A), it is acid main to pass through by the acidity decision of benzenesulfonyl, and its open architecture as shown in Figure 2 A, amplifies 100 times
Microstructure.Nafion (perfluorinated sulfonic acid) ion exchange resin is tetrafluoroethene and perfluor -2- (fluorosulfonyl ethyoxyl)-propyl group
The copolymer (construction unit is shown in Figure 1B) of vinyl ethers.After fluosulfonic acid hydrolysis, highly acid end-CF can be generated2CF2SO3H base
Group.The typical relative molecular weight of this copolymer can about 1070 about.Nafion resin is in chemistry (due to its skeleton C-
The stability of F key) and thermodynamically all very stable, can also keep stable more than 280 DEG C.The weak point of Nafion resin is
Its surface area is less.Its open architecture is as shown in Figure 2 B.
Table 2Amberlyst-15 and the physical property of Nafion resin
Another kind solid acid H- β zeolite used in the present invention is a kind of big polarity aluminosilicate containing water rack-like structure
Mineral, are a kind of high silicon materials, and silicone content reaches 93%.Its structure is the homobium of 2 to 3 kinds of polymorphs, has in one
The 12 ring channels three dimension systems that portion communicates with one another, its open architecture is as shown in Figure 3.
Embodiment 2：The continuous preparation of 1- (1- tosyl -1H- pyrroles's -2- base) ethyl ketone
H- β zeolite is placed in crucible, toasts 4 hours at 500-600 DEG C in Muffle furnace, be cooled to after room temperature existing with or
Sealing preserve.
H- β zeolite (500wt%) of activation is placed in the kettle 3 of fixed bed reactors as shown in Figure 4, through overstocked
After the detection of envelope property, start dnockout, the N-Ts- pyrroles dissolved with dichloromethane (10mL) is pumped into by feed pump 4 simultaneously respectively
(2.21g, 10mmol, 1.0eq) and the acetic anhydride (1.12g, 11mmol, 1.1eq) being dissolved with dichloromethane (10mL), in chuck
65 DEG C of circulating water temperature, dnockout speed 1.0mL/min (controls reactant liquor in successive reaction by adjusting the flow velocity of feed pump 4
Response time in device).The reactant liquor receptor 1 flowing out from kettle 3 is collected, and after 1 hour, dnockout finishes, and HPLC detection connects
Receive system in bottle, raw material converts completely, 2- acetylation selectivity 96%, product purity>95%.Will be direct for solution in receptor 1
It is concentrated to dryness and obtain final product target product, yield>96%.
Catalyst in continuous reaction apparatus can be different because of the activity of substrate continuously using 6-10 time.
Embodiment 3：The continuous preparation of 1- (1- tosyl -1H- pyrroles's -2- base) ethyl ketone
Catalyst Amberlyst-15 (500wt%) is placed in the kettle 3 of fixed bed reactors as shown in Figure 4,
After sealing propertytest, start dnockout, the N- being dissolved with dichloromethane (10mL) is pumped into by feed pump 4 simultaneously respectively
Ts- pyrroles (2.21g, 10mmol, 1.0eq) and dissolved with dichloromethane (10mL) acetic anhydride (1.12g, 11mmol,
1.1eq), 65 DEG C of chuck interior circulation coolant-temperature gage, dnockout speed 1.0mL/min.The reactant liquor receptor 1 flowing out from kettle 3 is received
Collection, after 1 hour, dnockout finishes, system in HPLC detection receiving bottle, and raw material converts completely, 2- acetylation selectivity 97%, product
Purity 93%.Solution in receiving bottle is directly thickened to dry obtain final product target product, yield 95%.
Embodiment 4：The continuous preparation of 1- (1- tosyl -1H- pyrroles's -2- base) ethyl ketone
H- β zeolite (500wt%) of activation is placed in the kettle 3 of fixed bed reactors as shown in Figure 4, through overstocked
After the detection of envelope property, start dnockout, by feed pump 4 by N-Ts- pyrroles (2.21g, 10mmol, 1.0eq) and acetic anhydride
It is solid that dichloromethane (20mL) mixed solution of (1.12g, 11mmol, 1.1eq) pumps into catalyst according to the flow velocity 1mL/min setting
Fixed bed, the circulating hot water temperature in chuck is 65 DEG C.The reactant liquor receptor 1 flowing out from kettle 3 is collected, dnockout after 1 hour
Finish, system in HPLC detection receiving bottle, raw material converts completely, 2- acetylation selectivity 96%, product purity>92%.To connect
Receive solution in device 1 to be directly thickened to dry obtain final product target product, yield>95%.
Embodiment 5：The continuous preparation of 1- (1- tosyl -1H- pyrroles's -2- base) ethyl ketone
Amberlyst-15 (500wt%) is placed in the kettle 3 of fixed bed reactors as shown in Figure 4, through overstocked
After the detection of envelope property, start dnockout, by feed pump 4 by N-Ts- pyrroles (2.21g, 10mmol, 1.0eq) and acetic anhydride
It is solid that dichloromethane (20mL) mixed solution of (1.12g, 11mmol, 1.1eq) pumps into catalyst according to the flow velocity 1mL/min setting
Fixed bed, the circulating hot water temperature in chuck is 65 DEG C.The reactant liquor receptor 1 flowing out from kettle 3 is collected, dnockout after 1 hour
Finish, system in HPLC detection receiving bottle, raw material converts completely, product purity 92%.Solution in receptor 1 is directly thickened to
Dry obtain final product target product, yield 95%, 2- acetylation selectivity 96%.
The product of embodiment 2-5：1- (1- tosyl -1H- pyrroles's -2- base) ethyl ketone1H and13C nuclear magnetic spectrum is respectively
As shown in Fig. 5 A and B.
Embodiment 6：The continuous preparation of 1- (1- benzyl -1H- pyrroles's -2- base) ethyl ketone
H- β zeolite (500wt%) of activation is placed in the kettle 3 of fixed bed reactors as shown in Figure 4, through overstocked
Envelope property detection after, start dnockout, by feed pump 4 pump into respectively simultaneously with dichloromethane dissolving N-Bn- pyrroles (16g,
100mmol, 1.0eq) and the acetic anhydride (11.2g, 110mmol, 1.1eq) that dissolved with dichloromethane (100mL), chuck interior circulation
65 DEG C of coolant-temperature gage.The reactant liquor receptor 1 flowing out from kettle 3 is collected, and after 1 hour, dnockout finishes, in HPLC detection receiving bottle
System, raw material converts completely, product purity 93%, 2- acetylation selectivity 98%,.Solution in receptor 1 is directly thickened to
Dry obtain final product target product, yield 95%.
Embodiment 7：The continuous preparation of 1- (1- benzyl -1H- pyrroles's -2- base) ethyl ketone
Catalyst Amberlyst-15 (500wt%) is placed in the kettle 3 of fixed bed reactors as shown in Figure 4,
After sealing propertytest, start dnockout, the N- being dissolved with dichloromethane (50mL) is pumped into by feed pump 4 simultaneously respectively
Bn- pyrroles (16g, 100mmol, 1.0eq) and dissolved with dichloromethane (50mL) acetic anhydride (11.2g, 110mmol,
1.1eq), 65 DEG C of chuck interior circulation coolant-temperature gage.The reactant liquor receptor 1 flowing out from kettle 3 is collected, and after 1 hour, dnockout finishes,
System in HPLC detection receiving bottle, raw material converts completely, product purity 93%, 2- acetylation selectivity 99%,.By receptor 1
Interior solution is directly thickened to dry obtain final product target product, yield 95%.
Embodiment 8：The continuous preparation of 1- (1- benzyl -1H- pyrroles's -2- base) ethyl ketone
H- β zeolite (500wt%) of activation is placed in the kettle 3 of fixed bed reactors as shown in Figure 4, through overstocked
After the detection of envelope property, start dnockout, by feed pump 4 by N-Bn- pyrroles (16g, 100mmol, 1.0eq) and acetic anhydride
Dichloromethane (100mL) mixed solution of (11.2g, 110mmol, 1.1eq) pumps into catalyst according to the flow velocity 1mL/min setting
Fixed bed, the circulating hot water temperature in chuck is 65 DEG C.The reactant liquor receptor 1 flowing out from kettle 3 is collected, and beats after 1 hour
Material finishes, system in HPLC detection receiving bottle, and raw material converts completely, product purity 92%, 2- acetylation selectivity 99%.To connect
Receive solution in device 1 to be directly thickened to dry obtain final product target product, yield>95%.
Embodiment 9：The continuous preparation of 1- (1- benzyl -1H- pyrroles's -2- base) ethyl ketone
Amberlyst-15 (500wt%) is placed in the kettle 3 of fixed bed reactors as shown in Figure 4, through overstocked
After the detection of envelope property, start dnockout, by feed pump 4 by N-Bn- pyrroles (16g, 100mmol, 1.0eq) and acetic anhydride
Dichloromethane (100mL) mixed solution of (11.2g, 110mmol, 1.1eq) pumps into catalyst according to the flow velocity 1mL/min setting
Fixed bed, the circulating hot water temperature in chuck is 65 DEG C.The reactant liquor receptor 1 flowing out from kettle 3 is collected, and beats after 1 hour
Material finishes, system in HPLC detection receiving bottle, and raw material converts completely, product purity ＞ 92%, 2- acetylation product proportion 98%.
Solution in receptor 1 is directly thickened to dry obtain final product target product, yield>95%.
The product of embodiment 6-9：1- (1- benzyl -1H- pyrroles's -2- base) ethyl ketone1H and13C nuclear magnetic spectrum is respectively as Fig. 6 A
With shown in B.
The foregoing is only presently preferred embodiments of the present invention, not in order to limit the present invention, all essences in the present invention
Within god and principle, any modification of being made, equivalent etc., should be included within the scope of the present invention.
Claims (10)
1. a kind of 2- position of heteroaromatic compounds is acylated method, including：In continuous reaction apparatus, filled solid acid catalysiss
Agent, is continuously added to heteroaromatic compounds and acylating reagent, carries out friedel-crafts acylation；
Described heteroaromatic compounds are as shown in structural formula I：
Wherein, X is selected from：NR3、O、S；
R1、R2Independently selected from：H, substituted or unsubstituted alkyl, or R1、R2Form aromatic ring together with the carbon atom being connected with it；
R3For H or amido protecting group.
2. the method for claim 1 is it is characterised in that described X is NR3；And/or, R1、R2It is H or R simultaneously1、R2With
The carbon atom that it is connected forms phenyl ring together；And/or, described amido protecting group is selected from：Ms, Ts, methyl, Boc, Cbz,
Alloc、PMB、Bn、Tfa、Trt、Dmb；And/or,
Described acylating reagent is selected from acyl chlorides and carboxylic acid anhydrides.
3. method as claimed in claim 1 or 2 is it is characterised in that X is NH, the 2- position acyl group of described heteroaromatic compounds
Change method also includes protecting step on amino.
4. the method for claim 1 is it is characterised in that described heteroaromatic compounds and/or acylating reagent solvent
Dissolving, described solvent is the solvent insensitive to acid；And/or,
The molar ratio of described heteroaromatic compounds and acylating reagent is 1:1.0-2.0；And/or,
Particle diameter >=the 1mm of described solid acid catalyst；And/or,
The consumption of described solid acid catalyst is to feed intake more than 5 times of substrate quality；And/or,
Described solid acid catalyst is ion exchange resin or zeolite.
5. method as claimed in claim 4 is it is characterised in that described solvent is selected from：Dichloromethane, 1,2- dichloroethanes,
Chlorobenzene, Nitrobenzol, carbon tetrachloride；And/or,
The molar ratio of described heteroaromatic compounds and acylating reagent is 1:1.0-1.5；And/or,
The particle diameter of described solid acid catalyst is 1-5mm；And/or,
The consumption of described solid acid catalyst is to feed intake 5-15 times of substrate quality；And/or,
Described ion exchange resin is selected from：Macroporous ion exchange resin Amberlyst-15, perfluorosulfonic acid ion exchanger resin
Nafion；And/or,
Described zeolite is preferably H- β zeolite.
6., it is characterised in that described solid acid catalyst is H- β zeolite, described virtue is miscellaneous for method as claimed in claim 5
The 2- position of cycle compound is acylated the activation step that method also includes catalyst.
7. the method as described in any one of claim 4-6 is it is characterised in that the temperature of described acylation reaction is 25-130
℃；And/or, the time of described reaction is 0.1-2.0h.
8. method as claimed in claim 7 is it is characterised in that the temperature of described acylation reaction is 40-100 DEG C；With/
Or, the time of described reaction is 0.5-1.5h.
9. the method as described in any one of claim 4-6 is it is characterised in that described continuous reaction apparatus include cylinder, temperature
Degree control system, automatic feed system.
10. method as claimed in claim 9 is it is characterised in that described continuous reaction apparatus are fixed bed reactors, including
Cylinder, chuck, feed pump, material container, receptor；It is filled with solid acid catalyst, chuck inner recirculation flow in described cylinder
Logical coolant or heating agent, feed pump is connected with material container and cylinder entrance, and receptor is connected with cylinder outlet.
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| CN110860307A (en) * | 2019-11-27 | 2020-03-06 | 吉林大学 | Beta molecular sieve catalyst, preparation method and application thereof in preparation of aromatic ketone by acylation method |
| CN115260023A (en) * | 2022-05-13 | 2022-11-01 | 浙江禾本科技股份有限公司 | Novel synthesis method of 3, 4-dimethoxy-4-chloro-benzophenone |
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