CN102584721A - Synthetic method of 2,4-dichloroquinazoline derivative - Google Patents
Synthetic method of 2,4-dichloroquinazoline derivative Download PDFInfo
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Abstract
The invention discloses a synthetic method of a 2, 4-dichloroquinazoline derivative. The invention adopts the technical scheme that a compound (I) reacts with triphosgene completely under the alkaline condition, and then a compound (IV) or a compound (V) is added to generate the 2, 4-dichloroquinazoline derivative. The invention has the benefits that a new preparation method used for producing prazosin drug intermediate products is acquired, so that the synthetic line of prazosin drug is more reasonable, the yield is high, the reaction condition is mild, the operation is simple and convenient and feasible, the product quality is good, and the cost is low. The 2, 4-dichloroquinazoline derivative is suitable for large-scale industrial production.
Description
(1) technical field
The present invention relates to a kind of is the raw material Synthetic 2 to replace 3-(oximido) indole-2-ketone or adjacent aminobenzonitrile and verivate thereof, the compound method of 4-dichloro quinazoline derivant.
(2) background technology
2,4-two chloro-quinazolines have wide biological activity and pharmaceutical activity, are one type of important medicine and fine-chemical intermediate.In recent years, 2, the derived product demand of 4-two chloro-quinazolines increases, and its market outlook are boundless.2,4-dichloro quinazoline derivant can be used for synthetic azoles piperazine class medicine, also can synthesize T cytostatics, adenosine A 2a acceptor inhibitor, HIV-1 suppressor factor, histamine H
4The anti-exciting suppressor factor of acceptor etc.
Azoles piperazine class medicine is α
1Adrenoceptor antagonists, such medicine has been widely used in treatment hypertension, congestive heart failure, irregular pulse, male prostatic hyperplasia, the treatment of numerous diseases such as oncotherapy and prevention, and as a line medicine of hypertension therapeutic.At present commonly used have Prazosin, terazosin and UK-33274, a trimazosin, also has alfuzosin, U.S.A to reach azoles piperazine and bunazosin etc.
A kind of method (CN101747323A) for preparing alfuzosin hydrochloride of report in 2010 such as Li Jiarong, this method is with 2-amino-4, and 5-dimethoxy benzene nitrile is a raw material, warp and DMF condensation; Obtain key intermediate 6,7-dimethoxyquinazoline diketone obtains 2 through chlorination again; 4-two chloro-6, the 7-dimethoxyquinazoline, total recovery is about 69%; Compare with route in the past, though yield increase, but still need obtain through two-step reaction; Secondly reaction needs is reacted in autoclave, and temperature is more than 190 ℃, and Influence on security also makes its application receive than limitations.
Then be raw material among the patent CN101353328A with the veratryl aldehyde, through peroxo-, nitrated, the reduction make 4,5-dimethoxy 2-benzaminic acid; 4,5-dimethoxy 2-benzaminic acid and Zassol cyclization make the quinazoline diones thing, make 2 through the POCl3 chlorination again, 4-two chloro-6,7-dimethoxyquinazoline.Though this method total recovery (48%) still can, the POCl3 that Zassol that synthesis step is long, reaction process need be used severe toxicity and restriction are used, problem of environmental pollution is more serious.
Lee, J.H. etc. (Synlett, 2006,1,65～68) have reported with adjacent aminobenzonitrile and trichloromethylchloroformate and one step of acetonitrile reaction and have made 2 that 4-two chloro-quinazolines, productive rate are 85%.But autoclave compressive reaction and higher temperature of reaction have been used in reaction, and trichloromethylchloroformate has great toxicity, so limited the use of this method widely.
To above situation, the contriver has carried out 2, the exploration of the chemical synthesis process of 4-two chloro-quinazolines; Obtained that a kind of step is short, yield is high, reaction conditions is gentle, easy and simple to handle, cost is low, be suitable for the chemical synthesis process of large-scale application; And in this process, synthesized 6,7-dimethoxy-2,4-two chloro-quinazolines; This midbody can also have alfuzosin, U.S.A to reach azoles piperazine and bunazosin etc. in order to synthetic Prazosin, terazosin and UK-33274, trimazosin.
(3) summary of the invention
Solution required for the present invention be that technical problem is in order to overcome the deficiency of prior art; Provide a kind of 2; The chemical synthesis process of 4-dichloro quinazoline derivant, the more existing method of this method has shortened reactions step and raw material is easy to get, yield high, cost is low, has better industrial applications prospect.
For realizing above-mentioned purpose, the present invention intends and adopts following technical scheme:
A kind of suc as formula 2 shown in (VI), the compound method of 4-dichloro quinazoline derivant, said method is:
In organic solvent A, add suc as formula the triphenylphosphine oxide compounds shown in (I), suc as formula the tertiary amine catalyst shown in (II); Drip the solution that is dissolved in organic solvent A suc as formula two (trichloromethyl) carbonic ethers shown in (III) down at-10～5 ℃ then; Be warming up to 5 ℃～40 ℃ reactions 10 minutes～1 hour after dropwising; Add again suc as formula adjacent aminobenzonitrile compounds shown in (IV) or the 3-shown in formula V (oximido) indole-2-ketone compounds; Be warming up to 80～150 ℃ of reactions 1-8 hour, TLC tracking monitor reaction process; The afterreaction liquid separation and purification that reacts completely obtains suc as formula 2 shown in (VI), 4-dichloro quinazoline derivant;
Said is 1: 0.001～0.01: 0.3～10: 0.3～10 suc as formula the triphenylphosphine oxide compounds shown in (I), suc as formula the tertiary amine catalyst shown in (II), suc as formula two (trichloromethyl) carbonic ethers shown in (III), suc as formula the amount of substance that the feeds intake ratio of the adjacent aminobenzonitrile compounds shown in (IV);
Or said be 1: 0.001～0.01: 0.3～2: 0.3～2 suc as formula the triphenylphosphine oxide compounds shown in (I), suc as formula the tertiary amine catalyst shown in (II), suc as formula two (trichloromethyl) carbonic ethers shown in (III), the amount of substance that the feeds intake ratio of 3-(oximido) indole-2-ketone compounds shown in formula V;
Described organic solvent A is one of following: chlorobenzene, toluene, acetonitrile, YLENE, sym.-tetrachloroethane or orthodichlorobenzene, preferred chlorobenzene or orthodichlorobenzene;
H is not substituted or is substituted basic R on the middle phenyl ring of formula (I)
1Replace substituent R
1Be CH
3, F, OCH
3Or phenyl, preferred methoxyl group, the R on the different positions
1Represent identical substituting group;
In the formula (II), R
2For one of following: CH
2CH
3, CH
2CH
2CH
3Or CH
2CH
2CH
2CH
3, the R on the different positions
2Represent identical substituting group; R
2Be preferably ethyl;
In formula (VI), formula (IV) or the formula V, the H on the phenyl ring be substituted basic Rn singly replace, polysubstituted or be not substituted, n is 0～4 integer; N representes the number of substituent R on the phenyl ring, and during n=0, the H on the expression phenyl ring is not substituted; During n=1, the H of expression on the phenyl ring is substituted that basic R is single to be replaced, n=2～4 o'clock; It is polysubstituted that H on the expression phenyl ring is substituted basic Rn, and the substituent R on different the position of substitution can be identical or different, and said substituent R is CH
3, Cl, Br, F, NO
2, or OCH
3
Concrete, reaction formula is following:
In the formula (VI), the preferred 6-nitro of substituent R n, 6-methyl, 6-bromine, 6-fluorine, 7-fluorine, 8-chlorine, 5,7-dichloro, 6,7-dimethoxy.
The said amount of substance ratio that feeds intake is preferably (I): (II): (III): (IV)=1: 0.003～0.005: 1～2: 1～2 or (I): (II): (III): (V)=1: 0.003～0.005: 1～2: 1～2.
The total consumption of the quality of described organic solvent A is 6～40 times suc as formula the quality of adjacent aminobenzonitrile compounds shown in (IV) or the 3-shown in formula V (oximido) indole-2-ketone compounds, preferred 10～20 times.
Further; In the said method; In organic solvent A, add suc as formula the triphenylphosphine oxide compounds shown in (I), suc as formula the tertiary amine catalyst shown in (II); Preferably drip the solution that is dissolved in organic solvent A suc as formula two (trichloromethyl) carbonic ethers shown in (III) down then at-5～0 ℃; Be warming up to 10～30 ℃ of reactions 20～40 minutes after dropwising, add again suc as formula adjacent aminobenzonitrile compounds shown in (IV) or the 3-shown in formula V (oximido) indole-2-ketone compounds and continue following reaction.
In the said method; Preferably adding suc as formula adjacent aminobenzonitrile compounds shown in (IV) or the 3-shown in formula V (oximido) indole-2-ketone compounds; Be warming up to 100～130 ℃ of reactions 1～4 hour; TLC tracking monitor reaction process, the afterreaction liquid separation and purification that reacts completely obtains suc as formula 2 shown in (VI), 4-dichloro quinazoline derivant.
Said reaction solution separation purification method is: after reaction finished, reaction solution added in the entry, stirred the back standing demix, separated and got organic layer; Water layer extracts with chlorobenzene, merges all organic layers, and the saturated common salt water washing is used in washing again; Use anhydrous sodium sulfate drying, chlorobenzene is reclaimed in underpressure distillation, with the dissolve with ethanol of gained solid with heat, adds sherwood oil; Filter, get filter cake and filtrating, filtrating adds water, divides and removes the alcohol-water layer; Get the underpressure distillation of oil phase layer, make said suc as formula 2 shown in (VI), 4-dichloro quinazoline derivant.
Said filter cake with petroleum ether after the oven dry obtain reclaiming suc as formula the triphenylphosphine oxide compounds shown in (I).
Most preferred, the method for the invention is carried out according to the following steps:
In organic solvent A, add suc as formula the triphenylphosphine oxide compounds shown in (I), suc as formula the tertiary amine catalyst shown in (II); Drip the solution that is dissolved in organic solvent A suc as formula two (trichloromethyl) carbonic ethers shown in (III) down at-5～0 ℃ then; Be warming up to 10～30 ℃ of reactions 20～40 minutes after dropwising; Add again suc as formula adjacent aminobenzonitrile compounds shown in (IV) or the 3-shown in formula V (oximido) indole-2-ketone compounds; Be warming up to 100～130 ℃ of reactions 1～4 hour, TLC tracking monitor reaction process; After reaction finished, reaction solution added in the entry, and standing demix separates and gets organic layer; Water layer extracts with chlorobenzene, merges all organic layers, and the saturated common salt water washing is used in washing again; Use anhydrous sodium sulfate drying, chlorobenzene is reclaimed in underpressure distillation, with the dissolve with ethanol of gained solid with heat, adds sherwood oil; Filter, filter cake and filtrating, filter cake with the thick oven dry of petroleum ether obtain reclaiming suc as formula the triphenylphosphine oxide compounds shown in (I); Filtrating adds water, divides and removes the alcohol-water layer, gets the underpressure distillation of oil phase layer, make said suc as formula 2 shown in (VI), 4-dichloro quinazoline derivant;
The described amount of substance that feeds intake is than being (I): (II): (III): (IV)=1: 0.003～0.005: 1～2: 1～2 or (I): (II): (III): (V)=1: 0.003～0.005: 1～2: 1～2;
Described organic solvent A is chlorobenzene or orthodichlorobenzene; The total consumption of the quality of described organic solvent A is 10～20 times suc as formula the quality of adjacent aminobenzonitrile compounds shown in (IV) or the 3-shown in formula V (oximido) indole-2-ketone compounds.
The present invention can make the preparation of azoles piperazine class medicine prepare by following route, and example hydrochloric acid Prazosin, reaction formula are represented as follows:
Useful achievement of the present invention has been to search out a kind of new chemical synthesis process in order to the midbody of producing azoles piperazine class medicine; Make that synthetic azoles piperazine class medicine route is more reasonable, step is shorter; Having yield height, gentle, easy and simple to handle, the low cost and other advantages of reaction conditions simultaneously, is the method that is suitable for large-scale industrial production.
(4) description of drawings
Fig. 1 embodiment 1 make 2, the nmr spectrum of 4-two chloro-quinazolines.
Fig. 2 embodiment 6 make 6,7-dimethoxy-2, the nmr spectrum of 4-two chloro-quinazolines.
The 7-fluoro-2 that Fig. 3 embodiment 7 makes, the nmr spectrum of 4-two chloro-quinazolines.
Fig. 4 embodiment 8 make 2,4, the nmr spectrum of 8-three chloro-quinazolines.
Fig. 5 embodiment 9 make 2,4,5, the nmr spectrum of 7-tetrachloro quinazoline.
The 6-nitro-2 that Fig. 6 embodiment 10 makes, the nmr spectrum of 4-two chloro-quinazolines.
The 6-methyl-2 that Fig. 7 embodiment 11 makes, the nmr spectrum of 4-two chloro-quinazolines.
Fig. 8 embodiment 12 make 2,4, the nmr spectrum of 6-three chloro-quinazolines.
The 6-bromo-2 that Fig. 9 embodiment 13 makes, the nmr spectrum of 4-two chloro-quinazolines.
(5) embodiment:
Following specific embodiments of the invention describes, but protection scope of the present invention is not limited to these embodiment.
Embodiment 12, the preparation of 4-two chloro-quinazolines
With triphenylphosphine oxide (8.34g, 30mmol), the 20ml chlorobenzene adds in the 100ml there-necked flask, cryosel is bathed (5～0 ℃) down; In reaction flask, add triethylamine (0.01g; 0.1mmol), through constant pressure funnel drip BTC chlorobenzene solution [BTC (and 9.38g, 30mmol)/the 20ml chlorobenzene].Dropwise back normal temperature (20～25 ℃) reaction 30min, add adjacent aminobenzonitrile (3.55g, 30mmol), 120 ℃ of reactions, TLC follows the tracks of detection, reacts 2h and reacts completely.Reaction solution is poured in the 50mL water, stirred, tell organic layer; Water layer extracts with chlorobenzene, merges organic layer, washing; Use the saturated common salt water washing again, use anhydrous sodium sulfate drying, chlorobenzene is reclaimed in underpressure distillation; With the dissolve with ethanol of gained solid, add the 100mL sherwood oil triphenylphosphine oxide is separated out with 10mL heat; Filter, filter cake (triphenylphosphine oxide) is given a baby a bath on the third day after its birth time with sherwood oil, dry triphenylphosphine oxide 7.71g, the recovery 92.5%; Filtrating adds water, and divide and remove the alcohol-water layer, in the sherwood oil product, underpressure distillation gets product 5.23g, and productive rate is 90.0%, 119.3～121.0 ℃ of fusing points,
1H NMR (400MHz, CDCl
3) δ: 8.26 (d, J=8.4Hz, 1H), 8.01-7.97 (m, 2H), 7.76-7.70 (m, 1H). (spectrogram is seen Figure of description one)
Embodiment 22, the preparation of 4-two chloro-quinazolines
With triphenylphosphine oxide (8.34g, 30mmol), the 20ml chlorobenzene adds in the 100ml there-necked flask, cryosel is bathed down; In reaction flask, add triethylamine (0.01g; 0.01mmol), through constant pressure funnel drip BTC chlorobenzene solution [BTC (and 3.08g, 10mmol)/the 10ml chlorobenzene].Dropwise back normal-temperature reaction 30min, (1.62g, 10mmol), 120 ℃ are reacted 2h to add 3-(oximido) indole-2-ketone.Get product 1.89g through separation and purification (with embodiment 1), productive rate is 95.0%.
Embodiment 32, the preparation of 4-two chloro-quinazolines
With triphenylphosphine oxide (0.83g, 3mmol), the 5ml chlorobenzene adds in the 100ml there-necked flask, cryosel is bathed down; In reaction flask, add triethylamine (0.003g; 0.03mmol), through constant pressure funnel drip BTC chlorobenzene solution [BTC (and 9.30g, 30mmol)/the 20ml chlorobenzene].Dropwise back normal-temperature reaction 30min, (3.56g, 30mmol), 120 ℃ are reacted 4h to add adjacent aminobenzonitrile.Get product 4.65g through separation and purification (with embodiment 1), productive rate is 78.0%.
Embodiment 42, the preparation of 4-two chloro-quinazolines
With triphenylphosphine oxide (8.34g, 30mmol), the 20ml chlorobenzene adds in the 100ml there-necked flask, cryosel is bathed down; In reaction flask, add triethylamine (0.01g; 0.1mmol), through constant pressure funnel drip BTC chlorobenzene solution [BTC (and 3.08g, 10mmol)/the 10ml chlorobenzene].Dropwise back normal-temperature reaction 30min, (1.18g, 10mmol), 120 ℃ are reacted 2h to add adjacent aminobenzonitrile.Get product 1.88g through separation and purification (with embodiment 1), productive rate is 94.5%.
Embodiment 52, the preparation of 4-two chloro-quinazolines
With triphenylphosphine oxide (4.18g, 15mmol), the 10ml chlorobenzene adds in the 100ml there-necked flask, cryosel is bathed down; In reaction flask, add triethylamine (0.01g; 0.1mmol), through constant pressure funnel drip BTC chlorobenzene solution [BTC (and 9.35g, 30mmol)/the 20ml chlorobenzene].Dropwise back normal-temperature reaction 30min, (4.86g, 30mmol), 120 ℃ are reacted 2h to add 3-(oximido) indole-2-ketone.Get product 2.39g through separation and purification (with embodiment 1), productive rate is 40.0%.
Embodiment 66,7-dimethoxy-2, the preparation of 4-two chloro-quinazolines
With three (to anisole) phosphine oxide (11.06g, 30mmol), the 25ml chlorobenzene adds in the 100ml there-necked flask, cryosel is bathed down; In reaction flask, add triethylamine (0.01g; 0.1mmol), through constant pressure funnel drip BTC chlorobenzene solution [BTC (and 9.38g, 30mmol)/the 20ml chlorobenzene].Dropwise back normal-temperature reaction 30min, add 5, and 6-dimethoxy-3-(oximido) indole-2-ketone (6.66g, 30mmol), 120 ℃ of reaction 2h.Get product 6.52g through separation and purification (with embodiment 1), productive rate 81.8%, the product fusing point: 161.8～163.7 ℃,
1H NMR (400MHz, CDCl3) δ 7.33 (s, 1H), 7.25 (s, 1H), 4.07 (s, 3H), 4.05 (s, 3H). (spectrogram is seen Figure of description two)
Embodiment 7 7-fluoro-2, the preparation of 4-two chloro-quinazolines
With three (to anisole) phosphine oxide (11.06g, 30mmol), the 20ml chlorobenzene adds in the 100ml there-necked flask, cryosel is bathed down; In reaction flask, add triethylamine (0.01g; 0.1mmol), through constant pressure funnel drip BTC chlorobenzene solution [BTC (and 9.38g, 30mmol)/the 20ml chlorobenzene].Dropwise back normal-temperature reaction 30min, (5.40g, 30mmol), 120 ℃ are reacted 1.5h to add 6-fluoro-3-(oximido) indole-2-ketone.Get product 4.82g through separation and purification (with embodiment 1), productive rate is 74.0%, 142.3～145.1 ℃ of fusing points,
1H NMR (400MHz, CDCl
3) δ 8.29 (dd, J=8.6,5.8Hz, 1H), 7.62 (d, J=8.8Hz, 1H), 7.49 (t, J=8.6Hz, 1H). (spectrogram is seen Figure of description three)
Embodiment 82, and 4, the preparation of 8-three chloro-quinazolines
With three (to anisole) phosphine oxide (11.06g, 30mmol), the 25ml chlorobenzene adds in the 100ml there-necked flask, cryosel is bathed down; In reaction flask, add triethylamine (0.01g; 0.1mmol), through constant pressure funnel drip BTC chlorobenzene solution [BTC (and 9.38g, 30mmol)/the 20ml chlorobenzene].Dropwise back normal-temperature reaction 30min, (5.90g, 30mmol), 120 ℃ are reacted 3h to add 7-chloro-(oximido) indole-2-ketone.Get product 6.48g through separation and purification (with embodiment 1), productive rate is 92.6%, 150.8～152.9 ℃ of fusing points,
1H NMR (400MHz, CDCl
3) δ 8.19 (dd, J=8.8,1.2Hz, 1H), 8.07 (dd, J=7.6,1.2Hz, 1H), 7.65 (dd, J=8.2,7.8Hz, 1H). (spectrogram is seen Figure of description four)
Embodiment 92, and 4,5, the preparation of 7-tetrachloro quinazoline
With three (to anisole) phosphine oxide (11.06g, 30mmol), the 25ml chlorobenzene adds in the 100ml there-necked flask, cryosel is bathed down; In reaction flask, add triethylamine (0.01g; 0.1mmol), through constant pressure funnel drip BTC chlorobenzene solution [BTC (and 9.38g, 30mmol)/the 20ml chlorobenzene].Dropwise back normal-temperature reaction 30min, add 4, and 6-two chloro-3-(oximido) indole-2-ketones (6.93g, 30mmol), 120 ℃ of reaction 3h.Get product 5.31g through separation and purification (with embodiment 1), productive rate is 66.0%.
1H NMR (400MHz, CDCl
3) δ 7.90 (d, J=2.0Hz, 1H), 7.73 (d, J=2.0Hz, 1H). (spectrogram is seen Figure of description five)
Embodiment 10 6-nitros-2, the preparation of 4-two chloro-quinazolines
With three (to anisole) phosphine oxide (11.08g, 30mmol), the 25ml chlorobenzene adds in the 100ml there-necked flask, cryosel is bathed down; In reaction flask, add triethylamine (0.01g; 0.1mmol), through constant pressure funnel drip BTC chlorobenzene solution [BTC (and 9.19g, 30mmol)/the 20ml chlorobenzene].Dropwise back normal-temperature reaction 30min, (6.24g, 30mmol), 120 ℃ are reacted 3h to add 5-nitro-3-(oximido) indole-2-ketone.Get product 3.86g through separation and purification (with embodiment 1), productive rate 52.7%, 121.1～123.4 ℃ of fusing points,
1H NMR (400MHz, CDCl
3) δ 9.16 (dd, J=2.4,0.4Hz, 1H), 8.73 (dd, J=9.2,2.4Hz, 1H), 8.16 (dd, J=9.2,0.4Hz, 1H). (spectrogram is seen Figure of description six)
Embodiment 11 6-methyl-2, the preparation of 4-two chloro-quinazolines
With three (to anisole) phosphine oxide (11.06g, 30mmol), the 25ml chlorobenzene adds in the 100ml there-necked flask, cryosel is bathed down; In reaction flask, add triethylamine (0.01g; 0.1mmol), through constant pressure funnel drip BTC chlorobenzene solution [BTC (and 9.38g, 30mmol)/the 20ml chlorobenzene].Dropwise back normal-temperature reaction 30min, (5.20g, 30mmol), 120 ℃ are reacted 1h to add 5-methyl-3-(oximido) indole-2-ketone.Get product 6.08g through separation and purification (with embodiment 1), productive rate is 95.3%.
1H NMR (400MHz, CDCl
3) δ 8.00 (s, 1H), 7.88 (d, J=8.6Hz, 1H), 7.80 (dd, J=8.6,1.8Hz, 1H), 2.61 (s, 3H). (spectrogram is seen Figure of description seven)
Embodiment 12 2, and 4, the preparation of 6-three chloro-quinazolines
With three (to anisole) phosphine oxide (11.06g, 30mmol), the 25ml chlorobenzene adds in the 100ml there-necked flask, cryosel is bathed down; In reaction flask, add triethylamine (0.01g; 0.1mmol), through constant pressure funnel drip BTC chlorobenzene solution [BTC (and 9.38g, 30mmol)/the 20ml chlorobenzene].Dropwise back normal-temperature reaction 30min, (5.90g, 30mmol), 120 ℃ are reacted 3h to add 5-chloro-(oximido) indole-2-ketone.Get product 5.89g through separation and purification (with embodiment 1), productive rate is 79.80%, 132.5～135.8 ℃ of fusing points,
1H NMR (400MHz, CDCl
3) δ 8.22 (d, J=2.0Hz, 1H), 7.98-7.88 (m, 2H). (spectrogram is seen Figure of description eight)
Embodiment 13 6-bromo-2, the preparation of 4-two chloro-quinazolines
With three (to anisole) phosphine oxide (11.06g, 30mmol), the 25ml chlorobenzene adds in the 100ml there-necked flask, cryosel is bathed down; In reaction flask, add triethylamine (0.01g; 0.1mmol), through constant pressure funnel drip BTC chlorobenzene solution [BTC (and 9.38g, 30mmol)/the 20ml chlorobenzene].Dropwise back normal-temperature reaction 30min, (7.23g, 30mmol), 120 ℃ are reacted 3h to add 5-bromo-(oximido) indole-2-ketone.Get product 5.10g through separation and purification (with embodiment 1), productive rate is 61.2%.131.0～136.1 ℃ of fusing points,
1H NMR (400MHz, CDCl
3) δ 8.40 (d, J=2.0Hz, 1H), 8.04 (dd, J=8.8,2.0Hz, 1H), 7.86 (d, J=8.8Hz, 1H). (spectrogram is seen Figure of description nine)
Claims (9)
1. one kind suc as formula 2 shown in (VI), and the compound method of 4-dichloro quinazoline derivant is characterized in that said method is:
In organic solvent A, add suc as formula the triphenylphosphine oxide compounds shown in (I), suc as formula the tertiary amine catalyst shown in (II); Drip the solution that is dissolved in organic solvent A suc as formula two (trichloromethyl) carbonic ethers shown in (III) down at-10～5 ℃ then; Be warming up to 5 ℃～40 ℃ reactions 10 minutes～1 hour after dropwising; Add again suc as formula adjacent aminobenzonitrile compounds shown in (IV) or the 3-shown in formula V (oximido) indole-2-ketone compounds; Be warming up to 80～150 ℃ of reactions 1-8 hour, TLC tracking monitor reaction process; The afterreaction liquid separation and purification that reacts completely obtains suc as formula 2 shown in (VI), 4-dichloro quinazoline derivant;
Said is 1: 0.001～0.01: 0.3～10: 0.3～10 suc as formula the triphenylphosphine oxide compounds shown in (I), suc as formula the tertiary amine catalyst shown in (II), suc as formula two (trichloromethyl) carbonic ethers shown in (III), suc as formula the amount of substance that the feeds intake ratio of the adjacent aminobenzonitrile compounds shown in (IV);
Or said be 1: 0.001～0.01: 0.3～2: 0.3～2 suc as formula the triphenylphosphine oxide compounds shown in (I), suc as formula the tertiary amine catalyst shown in (II), suc as formula two (trichloromethyl) carbonic ethers shown in (III), the amount of substance that the feeds intake ratio of 3-(oximido) indole-2-ketone compounds shown in formula V;
Described organic solvent A is one of following: chlorobenzene, toluene, acetonitrile, YLENE, sym.-tetrachloroethane or orthodichlorobenzene;
H is not substituted or is substituted basic R on the middle phenyl ring of formula (I)
1Replace substituent R
1Be CH
3, F, OCH
3Or phenyl, the R on the different positions
1Represent identical substituting group;
In the formula (II), R
2For one of following: CH
2CH
3, CH
2CH
2CH
3Or CH
2CH
2CH
2CH
3, the R on the different positions
2Represent identical substituting group;
In formula (VI), formula (IV) or the formula V, the H on the phenyl ring be substituted basic Rn singly replace, polysubstituted or be not substituted, n is 0～4 integer; N representes the number of substituent R on the phenyl ring, and during n=0, the H on the expression phenyl ring is not substituted; During n=1, the H of expression on the phenyl ring is substituted that basic R is single to be replaced, n=2～4 o'clock; It is polysubstituted that H on the expression phenyl ring is substituted basic Rn, and the substituent R on different the position of substitution can be identical or different, and said substituent R is CH
3, Cl, Br, F, NO
2, or OCH
3
2. according to claims 1 described method, it is characterized in that: the described amount of substance that feeds intake is than being (I): (II): (III): (IV)=1: 0.003～0.005: 1～2: 1～2 or (I): (II): (III): (V)=1: 0.003～0.005: 1～2: 1～2.
3. according to claims 1 described method, it is characterized in that: the total consumption of the quality of described organic solvent A is 6～40 times suc as formula the quality of adjacent aminobenzonitrile compounds shown in (IV) or the 3-shown in formula V (oximido) indole-2-ketone compounds.
4. according to claims 1 described method, it is characterized in that described organic solvent A is chlorobenzene or orthodichlorobenzene.
5. according to claims 1 described method, it is characterized in that said reaction solution separation purification method is: after reaction finished, reaction solution added in the entry, stirred the back standing demix; Separate and get organic layer, water layer extracts with chlorobenzene, merges all organic layers, washing; Use the saturated common salt water washing again, use anhydrous sodium sulfate drying, chlorobenzene is reclaimed in underpressure distillation, with the dissolve with ethanol of gained solid with heat; Add sherwood oil, filter, get filter cake and filtrating, filtrating adds water; Divide and to remove the alcohol-water layer, get the underpressure distillation of oil phase layer, make said suc as formula 2 shown in (VI), 4-dichloro quinazoline derivant.
6. method as claimed in claim 5, it is characterized in that after said filter cake is with petroleum ether that oven dry obtains reclaiming suc as formula the triphenylphosphine oxide compounds shown in (I).
7. according to claims 1 described method; It is characterized in that; In organic solvent A, add suc as formula the triphenylphosphine oxide compounds shown in (I), suc as formula the tertiary amine catalyst shown in (II); Drip the solution that is dissolved in organic solvent A suc as formula two (trichloromethyl) carbonic ethers shown in (III) down at-5～0 ℃ then; Be warming up to 10～30 ℃ of reactions 20～40 minutes after dropwising, add again suc as formula adjacent aminobenzonitrile compounds shown in (IV) or the 3-shown in formula V (oximido) indole-2-ketone compounds and continue following reaction.
8. according to claims 1 described method; It is characterized in that; Adding suc as formula adjacent aminobenzonitrile compounds shown in (IV) or the 3-shown in formula V (oximido) indole-2-ketone compounds after, be warming up to 100～130 ℃ the reaction 1～4 hour, TLC tracking monitor reaction process; The afterreaction liquid separation and purification that reacts completely obtains suc as formula 2 shown in (VI), 4-dichloro quinazoline derivant.
9. according to claims 1 described method, it is characterized in that said method is:
In organic solvent A, add suc as formula the triphenylphosphine oxide compounds shown in (I), suc as formula the tertiary amine catalyst shown in (II); Drip the solution that is dissolved in organic solvent A suc as formula two (trichloromethyl) carbonic ethers shown in (III) down at-5～0 ℃ then; Be warming up to 10～30 ℃ of reactions 20～40 minutes after dropwising; Add again suc as formula adjacent aminobenzonitrile compounds shown in (IV) or the 3-shown in formula V (oximido) indole-2-ketone compounds; Be warming up to 100～130 ℃ of reactions 1～4 hour, TLC tracking monitor reaction process; After reaction finished, reaction solution added in the entry, and standing demix separates and gets organic layer; Water layer extracts with chlorobenzene, merges all organic layers, and the saturated common salt water washing is used in washing again; Use anhydrous sodium sulfate drying, chlorobenzene is reclaimed in underpressure distillation, with the dissolve with ethanol of gained solid with heat, adds sherwood oil; Filter, filter cake and filtrating, filter cake with the thick oven dry of petroleum ether obtain reclaiming suc as formula the triphenylphosphine oxide compounds shown in (I); Filtrating adds water, divides and removes the alcohol-water layer, gets the underpressure distillation of oil phase layer, make said suc as formula 2 shown in (VI), 4-dichloro quinazoline derivant;
The described amount of substance that feeds intake is than being (I): (II): (III): (IV)=1: 0.003～0.005: 1～2: 1～2 or (I): (II): (III): (V)=1: 0.003～0.005: 1～2: 1～2;
Described organic solvent A is chlorobenzene or orthodichlorobenzene; The total consumption of the quality of described organic solvent A is 10～20 times suc as formula the quality of adjacent aminobenzonitrile compounds shown in (IV) or the 3-shown in formula V (oximido) indole-2-ketone compounds.
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| Title |
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| JAE HAK LEE ET AL: "Acetonitrile-Mediated Synthesis of 2,4-Dichloroquinoline from 2-Ethynylaniline and 2,4-Dichloroquinazoline from Anthranilonitrile", 《SYNLETT》 * |
| WEIHUI ZHONG ET AL: "Stereoselective Chlorination of New Type Baylis-Hillman Adducts by bis(Trichloromethyl)carbonate with the Aid of Catalytic Amount of Triphenylphosphine Oxide", 《LETTERS IN ORGANIC CHEMISTRY》 * |
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