CN107673994A - A kind of preparation method of arylmethane class compound - Google Patents
A kind of preparation method of arylmethane class compound Download PDFInfo
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- CN107673994A CN107673994A CN201710289064.1A CN201710289064A CN107673994A CN 107673994 A CN107673994 A CN 107673994A CN 201710289064 A CN201710289064 A CN 201710289064A CN 107673994 A CN107673994 A CN 107673994A
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Abstract
The invention discloses a kind of preparation method of arylmethane class compound.Described arylmethane class compound I preparation method, comprises the following steps：In organic solvent, under calcium chloride and water effect, compound I 2 is subjected to de-ester reaction, obtain described compound I, the temperature of the reaction is 130 DEG C of boiling points to the solvent, wherein, R ' and R " one kind arbitrarily in methyl, ethyl, isopropyl and the tert-butyl group independently of one another；N=0 or 1；R1, R2, R3, R4 and R5 are each independently H or electron withdraw group, and wherein at least one is electron withdraw group.The preparation method raw material of the present invention is easy to get, and cost is relatively low, and the three wastes are few, process safety, is adapted to industrialized production.
Description
Technical field
The present invention relates to a kind of preparation method of arylmethane class compound.
Background technology
In the prior art, the common method for taking off ester is reacted for Krapcho decarbonylations (Krapcho decarboxylation)
(A.P.Krapcho et al, Tetrahedron Letters 1967,215), mainly remove has electron withdraw group in β positions
Ester, such as 'beta '-ketoester, malonate, o- cyano group ester and alpha sulfonyl ester.But the characteristics of this method is can only to remove an ester
Base.
Mukund Gurjar provide a kind of improved method in Synthesis, 2000,1659-1661, by de-
Except two ester groups on the aryl malonic acid esters of nitro substitution, arylmethane is obtained.One is provided to introduce methyl on aryl
New method.
But this method is only applicable to react when having strong electrophilic nitro substitution on aryl, and still suffer from sometimes
Conversion not exclusively (only remove an ester group), especially when nitro and malonate are in contraposition, has that conversion ratio is low, yield
The defects of not high.
Therefore, if the scope of applicable substrate can be expanded, and yield is further improved, pole will be brought in chemical field
Big industrial application value.
For example, the fluoro- 4- methyl cyanophenyls of 3- (CAS 170572-49-3) are used to prepare treatment for hypertension, heart failure
Medicine Osilodrostat important source material, synthetic reaction route is as follows：
But the synthetic route and technique of the existing fluoro- 4- methyl cyanophenyls of 3- have more shortcoming：Step is more, it is cumbersome,
Pollution is big, cost is of a relatively high, yield is low, and total recovery only has 40~50%.
The content of the invention
The technical problems to be solved by the invention are to overcome the preparation side of arylmethane class compound in the prior art
The defects of applicable substrate spectrum of method is small, conversion is incomplete, yield is low, and provide a kind of preparation of arylmethane class compound
Method, this method wide application range of substrates, raw material are easy to get, and the three wastes are few, process safety, and high conversion rate, high income, cost are relatively low,
It is adapted to industrialized production.
The invention provides a kind of arylmethane class compound I preparation method, comprise the following steps：In organic solvent
In, under calcium chloride and water effect, compound I-2 is subjected to de-ester reaction, obtains described compound I, the reaction
Temperature be 130 DEG C of boiling points to the solvent,
Wherein, R ' and R " is each independently selected from one kind in methyl, ethyl, isopropyl and the tert-butyl group；
N=0 or 1；
R1、R2、R3、R4And R5H or electron withdraw group are each independently, and wherein at least one is electron withdraw group.
Described electron withdraw group be substituent substituted benzene ring hydrogen after, cause electron density on phenyl ring to drop originally relatively
It is low.
Described compound I-2, is compound I-3 as n=1, is compound I-4 as n=0；
The preferred methyl of described R ' and/or R ".
One or more in the preferred nitro of described electron withdraw group, cyano group and halogen；The preferred fluorine of described halogen or
Chlorine.
Described electron withdraw group is preferably placed at ortho position or contraposition.
The described preferred 2- of compound I-2 (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates, the fluoro- 4- cyano group benzene of 2-
Methyl acetate, 2- (4- cyano group -2- fluorophenyls) -1,3- diethyl malonates or 2- (4- cyano group -2- chlorphenyls) -1,3- malonic acid
Dimethyl ester.
The described fluoro- 4- methyl cyanophenyls of the preferred 3- of compound I or the chloro- 4- methyl cyanophenyls of 3-.
Described organic solvent can be the organic solvent that such de-ester reaction is conventional in this area, be not involved in reaction i.e.
Can, particularly preferably dimethyl sulfoxide (DMSO), DMF, N in the present invention, N- diethyl acetamides and N- crassitudes
One or more in ketone, more preferably N, N- diethyl acetamides.
The mol ratio of described compound I-2 and described water can be the conventional mol ratio of such de-ester reaction of this area,
Such as 1:1~1:5, it is particularly preferably 1 in of the invention:2~1:3.
The mol ratio of described compound I-2 and described calcium chloride can be conventional mole of such de-ester reaction of this area
Than, such as 1:0.5~1:5.0, it is particularly preferably 1 in of the invention:2.0~1:3.0.
The dosage of described organic solvent can be not especially limited, and be carried out as long as not influenceing reaction, you can；Institute in the present invention
The mass ratio preferably 4 of the organic solvent stated and described compound I-2:1.
Preferably 130~160 DEG C, more preferably 140~145 DEG C of described reaction temperature.
The process of described reaction can use the routine monitoring method (such as TLC, HPLC or NMR) in this area to carry out
Monitoring, as reaction end when typically being disappeared using compound I-2 or no longer reacted；The described reaction time can be 20~48 hours,
It is preferred that 20~24 hours.
A kind of preparation method of arylmethane class compound as described above, it may also include the steps of：Organic solvent
In, under alkali effect, compound I-1 and compound I-5 is subjected to substitution reaction, obtains described compound I-3,
Wherein, R ', R ", R1、R2、R3、R4And R5It is defined as above；
N=1；
X is F, Cl, Br or I.
Described electron withdraw group be substituent substituted benzene ring hydrogen after, cause electron density on phenyl ring to drop originally relatively
It is low.
In described substitution reaction, described R ' and/or the preferred methyl of R ".
X preferred F or Cl.
One or more in the preferred nitro of described electron withdraw group, cyano group and halogen；The preferred fluorine of described halogen or
Chlorine.
Described electron withdraw group is preferably placed at ortho position or contraposition.
In described substitution reaction, the described preferred 2- of compound I-3 (4- cyano group -2- fluorophenyls) -1,3- malonic acid two
Methyl esters, 2- (4- cyano group -2- fluorophenyls) -1,3- diethyl malonates or 2- (4- cyano group -2- chlorphenyls) -1,3- malonic acid dimethyls
Ester.
In described substitution reaction, described organic solvent can be the conventional organic solvent of such reaction of this area, with not
Participate in reaction, you can；Particularly preferred dimethyl sulfoxide (DMSO), N,N-dimethylformamide, N, N- diethyl acetamides in the present invention
With the one or more in 1-METHYLPYRROLIDONE, more preferably N, N- diethyl acetamides.
In described substitution reaction, described alkali can be the conventional alkali of such substitution reaction of this area, such as sodium carbonate, carbon
One or more in sour potassium, cesium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide and sodium hydrogen, carbon is particularly preferably in of the invention
One or more in sour sodium, potassium carbonate and sodium hydrogen, more preferably potassium carbonate.
In described substitution reaction, described compound I-1 and described compound I-5 mol ratio can not be limited specifically
It is fixed, it can be selected according to such substitution reaction routine mol ratio for this area, the present invention is preferably 1:1~3:1, more preferably
2:1~3:1.
In described substitution reaction, the dosage of described solvent can be not especially limited, and be carried out as long as not influenceing reaction, i.e.,
Can；In the present invention, the mass ratio preferably 3 of described organic solvent and described compound I-5:1.
In described substitution reaction, the mol ratio of described alkali and described compound I-5 can be not especially limited, can root
Selected according to for the conventional mol ratio of such substitution reaction of this area, the present invention is preferably 1:1~5:1, more preferably 2:1~
3:1。
Described reaction temperature can be conventional temperature in such substitution reaction of this area, preferably 50 in the present invention~
155 DEG C, be more preferably 85~90 DEG C.
In described substitution reaction, the process of described substitution reaction can use the routine monitoring method in this area
(such as TLC, HPLC or NMR) is monitored, as reaction end when typically being disappeared using described compound I-5 or no longer reacted；
The described reaction time is preferably 3~12 hours, is more preferably 4~6 hours.
In described substitution reaction, it is preferred that after the completion of described substitution reaction, described compound I-2 is without isolation
(that is, purifying compound I-2 is not separated or obtains the mixture containing compound I-2；For example, the reaction solution of substitution reaction is not
It is post-treated, or reaction solution progress simply post processing etc. of substitution reaction, obtain the mixture containing compound I-2；It is described
Simple post processing can be filtering, pH regulations etc.), directly carry out described de-ester reaction, prepare described in compound I；Example
Such as, after the reaction solution of described substitution reaction filtered (washing filter cake can be included), described compound I is directly prepared.
It on the basis of common sense in the field is met, above-mentioned each optimum condition, can be combined, it is each preferably real to produce the present invention
Example.
Agents useful for same and raw material of the present invention are commercially available.
The positive effect of the present invention is：The preparation method of the arylmethane class compound of the present invention, substrate are applicable
Scope is wide, raw material is easy to get, is simple to operate, high conversion rate, high income, and cost is relatively low, and the three wastes are few, process safety, suitable for industrialization
Using.
Embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to described reality
Apply among a scope.The experimental method of unreceipted actual conditions in the following example, conventionally and condition, or according to business
Product specification selects.
Embodiment 1：The synthesis of 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates：
100 grams of 3,4- difluorobenzonilyiles, 190 grams of dimethyl malenates (2.0eq), 298 grams of anhydrous carbon are added in 1L four-hole bottles
Sour potassium (3eq) and 300 grams of DMAs, stirring heating, 85~90 DEG C of insulation reactions 4 to 6 hours, (HPLC is monitored,
Conversion ratio>99%) 25~30 DEG C are cooled to, 700 grams of water add reaction, stir 10 minutes, filtering, filtrate layered, water layer second
Acetoacetic ester extracts, and merges organic phase.Concentration organic phase obtains 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenate crude products.
By crude product at 40~45 DEG C, it is dissolved in 120mL methanol, is cooled at 0~5 DEG C, is incubated 1 hour and crystallizes, filtering, 30mL ice
Methanol washs, and is dried in vacuo at 50~55 DEG C and obtains 151.5 grams of 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates, received
Rate 83.9%.
1H NMR(DMSO-d6,400MHz)：3.70(s,6H,-℃H3)；5.34(s,1H,-CH),7.60-7.65(m,
1H,Ar-H)；7.72 (dd, 1H, J1=8.0Hz, J2=1.2Hz, Ar-H)；7.90 (dd, 1H, J1=10.0Hz, J2=
1.2Hz,Ar-H)。
Embodiment 2：The synthesis of the fluoro- 4- methyl cyanophenyls of 3-：
151.5 grams of 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates (1eq) are put into 1L four-hole bottles, are added
21.7 grams of water (2eq), 140.9 gram of 95% anhydrous calcium chloride (2eq) and 606 grams of DMAs, stirring heating, 140
(HPLC is monitored~145 DEG C of insulation reactions, conversion ratio within 20 to 24 hours>99%), it is cooled to 30 DEG C, adds 352.5 grams of water, 303
Gram dichloromethane, about 70.2 grams of concentrated hydrochloric acid is added dropwise, it is organic to be harmonious to system pH=5~7, liquid separation, the extraction of water layer dichloromethane
And the organic phase that is concentrated under reduced pressure, the DMAc concentrates of the fluoro- 4- methyl cyanophenyls of 3- are obtained, continue rectification under vacuum, collect the fluoro- 4- methyl of 3-
Cyanophenyl, to being steamed without product, obtain 70.0 grams of white solids, yield 85.9%.
1H NMR(DMSO-d6,400MHz)：2.29(s,3H,-CH3)；7.50 (t, 1H, J=7.6Hz, Ar-H)；7.58
(dd, 1H, J1=8.0Hz, J2=1.2Hz, Ar-H)；7.74 (dd, 1H, J1=9.6Hz, J2=1.2Hz, Ar-H).
Embodiment 3：The synthesis of the fluoro- 4- methyl cyanophenyls of 3-：
In 50mL four-hole bottles put into the fluoro- 4- cyano group methyl phenylacetate solids of 1.0 grams of 2-, add 0.19 gram of water, 1.15 grams
95% anhydrous calcium chloride and 15 grams of DMAs, stirring heating, 140~145 DEG C of insulation reactions 20 to 24 hours
(HPLC is monitored, conversion ratio>99%) 60-70 DEG C, is cooled to, is concentrated under reduced pressure, post purification is crossed, obtains the fluoro- 4- methyl cyanophenyls of 3-,
0.62 gram of faint yellow solid, yield 89.0%.
Embodiment 4：The synthesis of the fluoro- 4- methyl cyanophenyls of 3-：
168.4 grams of 2- (4- cyano group -2- fluorophenyls) -1,3- diethyl malonates (1eq) are put into 1L four-hole bottles, are added
21.7 grams of water (2eq), 140.9 gram of 95% anhydrous calcium chloride (2eq) and 606 grams of DMAs, stirring heating, 140
~145 DEG C of insulation reactions 20 to 24 hours, 30 DEG C are cooled to, add 352.5 grams of water, 303 grams of dichloromethane, concentrated hydrochloric acid is added dropwise about
70.2 grams, merge to system pH=5~7, liquid separation, the extraction of water layer dichloromethane, organic phase, be concentrated under reduced pressure organic phase, and it is fluoro- to obtain 3-
The DMAc concentrates of 4- methyl cyanophenyls, continue rectification under vacuum, collect the fluoro- 4- methyl cyanophenyls of 3-, to being steamed without product, obtain 58.0
Gram white solid, yield 71.2%.
Embodiment 5：The synthesis of the fluoro- 4- methyl cyanophenyls of 3-：
15.2 grams of 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates (1eq) are put into 1L four-hole bottles, add 2.2
Gram water (2eq), 3.53 gram of 95% anhydrous calcium chloride (0.5eq) and 60.6 grams of DMAs, stirring heating, 140~
145 DEG C of insulation reactions 20 to 24 hours, are cooled to 30 DEG C, HPLC results show that raw material has only converted 76%.Extend the reaction time
By 36 hours, HPLC results showed that raw material has also only converted 93%.
Embodiment 6：The synthesis of the fluoro- 4- methyl cyanophenyls of 3-：
15.2 grams of 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates (1eq) are put into 1L four-hole bottles, add 2.2
Gram water (2eq), 21.2 gram of 95% anhydrous calcium chloride (3eq) and 60.6 grams of DMAs, stirring heating, 140~145
DEG C insulation reaction 20 to 24 hours, is cooled to 30 DEG C, HPLC results show that raw material converts>99%.
Embodiment 7：The synthesis of the fluoro- 4- methyl cyanophenyls of 3-：
15.2 grams of 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates (1eq) are put into 1L four-hole bottles, add 2.2
Gram water (2eq), 14.1 gram of 95% anhydrous calcium chloride (2eq) and 60.6 grams of DMFs, stirring heating, 140~145
DEG C insulation reaction 20 to 24 hours, is cooled to 30 DEG C, HPLC results show that raw material converts>99%.
Embodiment 8：The synthesis of the fluoro- 4- methyl cyanophenyls of 3-：
15.2 grams of 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates (1eq) are put into 1L four-hole bottles, add 2.2
Gram water (2eq), 14.1 gram of 95% anhydrous calcium chloride (2eq) and 60.6 grams of dimethyl sulfoxide (DMSO)s, stirring heating, 140~145 DEG C of insulations
Reaction 20 to 24 hours, is cooled to 30 DEG C, HPLC results show that raw material converts>99%.
Embodiment 9：The synthesis of the fluoro- 4- methyl cyanophenyls of 3-：
15.2 grams of 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates (1eq) are put into 1L four-hole bottles, add 1.1
Gram water (1eq), 14.12 gram of 95% anhydrous calcium chloride (2eq) and 60.6 grams of DMAs, stirring heating, 140~
145 DEG C of insulation reactions 20 to 24 hours, are cooled to 30 DEG C, HPLC results show that raw material has converted 76%.
Embodiment 10：The synthesis of the fluoro- 4- methyl cyanophenyls of 3-：
15.2 grams of 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates (1eq) are put into 1L four-hole bottles, add 3.3
Gram water (3eq), 14.1 gram of 95% anhydrous calcium chloride (2eq) and 60.6 grams of DMAs, stirring heating, 140~145
DEG C insulation reaction 20 to 24 hours, is cooled to 30 DEG C, HPLC results show that raw material has converted 97%.
Embodiment 11：The synthesis of the fluoro- 4- methyl cyanophenyls of 3-：
15.2 grams of 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates (1eq) are put into 1L four-hole bottles, add 2.2
Gram water (2eq), 14.1 gram of 95% anhydrous calcium chloride (2eq) and 60.6 grams of DMAs, stirring heating, 155~160
DEG C insulation reaction 20 to 24 hours, is cooled to 30 DEG C, HPLC results show that raw material has converted 99%.
Embodiment 12：The synthesis of the fluoro- 4- methyl cyanophenyls of 3-：
15.2 grams of 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates (1eq) are put into 1L four-hole bottles, add 2.2
Gram water (2eq), 14.1 gram of 95% anhydrous calcium chloride (2eq) and 60.6 grams of DMAs, stirring heating, 130~135
DEG C insulation reaction 20 to 24 hours, is cooled to 30 DEG C, HPLC results show that raw material has converted 72%.
Embodiment 13：The synthesis of the fluoro- 4- methyl cyanophenyls of 3-：
15.2 grams of 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates (1eq) are put into 1L four-hole bottles, add 3.3
Gram water (3eq), 14.1 gram of 95% anhydrous calcium chloride (2eq) and 60.6 grams of DMAs, stirring heating, 155~160
DEG C insulation reaction 20 to 24 hours, is cooled to 30 DEG C, HPLC results show that raw material converts>99%.
Embodiment 14：The synthesis of the fluoro- 4- methyl cyanophenyls of 3-：
15.2 grams of 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates (1eq) are put into 1L four-hole bottles, add 5.5
Gram water (5eq), 14.1 gram of 95% anhydrous calcium chloride (2eq) and 60.6 grams of DMAs, stirring heating, 155~160
DEG C insulation reaction 20 to 24 hours, is cooled to 30 DEG C, HPLC results show that raw material converts>87%.
Embodiment 15：The synthesis of 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates：
10.0 grams of 3,4- difluorobenzonilyiles, 10.0 grams of dimethyl malenates (1.05eq), 29.8 grams of nothings are added in 1L four-hole bottles
Aqueous carbonate potassium (3eq) and 30.0 grams of DMAs, stirring heating, 85~90 DEG C of insulation reactions 4 to 6 hours, HPLC
As a result show, raw material has converted 89%.
Embodiment 16：The synthesis of 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates：
10.0 grams of 3,4- difluorobenzonilyiles, 28.5 grams of dimethyl malenates (3eq), 29.8 grams of anhydrous carbon are added in 1L four-hole bottles
Sour potassium (3eq) and 30.0 grams of DMAs, stirring heating, 85~90 DEG C of insulation reactions 4 to 6 hours, HPLC results
It has been shown that, raw material convert>99%.
Embodiment 17：The synthesis of 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates：
10.0 grams of 3,4- difluorobenzonilyiles, 19.0 grams of dimethyl malenates (2eq), 29.8 grams of anhydrous carbon are added in 1L four-hole bottles
Sour potassium (3eq) and 30.0 grams of DMFs, stirring heating, 85~90 DEG C of insulation reactions 4 to 6 hours, HPLC results
It has been shown that, raw material convert>99%.
Embodiment 18：The synthesis of 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates：
10.0 grams of 3,4- difluorobenzonilyiles, 19.0 grams of dimethyl malenates (2eq), 29.8 grams of anhydrous carbon are added in 1L four-hole bottles
Sour potassium (3eq) and 30.0 grams of dimethyl sulfoxide (DMSO)s, stirring heating, 85~90 DEG C of insulation reactions 4 to 6 hours, HPLC results shows, original
Material converts>99%.
Embodiment 19：The synthesis of 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates：
10.0 grams of 3,4- difluorobenzonilyiles, 19.0 grams of dimethyl malenates (2eq), 22.8 grams of anhydrous carbon are added in 1L four-hole bottles
Sour sodium (3eq) and 30.0 grams of DMAs, stirring heating, 85~90 DEG C of insulation reactions 4 to 6 hours, HPLC results
It has been shown that, raw material have converted 88%.
Embodiment 20：The synthesis of 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates：
10.0 grams of 3,4- difluorobenzonilyiles, 19.0 grams of dimethyl malenates (2eq), 8.6 grams of sodium hydrogen are added in 1L four-hole bottles
(3eq) and 30.0 grams of DMAs, stirring, 15~20 DEG C of insulation reactions 4 to 6 hours, HPLC results are shown, raw material
Convert 95%.
Embodiment 21：The synthesis of 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates：
10.0 grams of 3,4- difluorobenzonilyiles, 19.0 grams of dimethyl malenates (2eq), 19.9 grams of anhydrous carbon are added in 1L four-hole bottles
Sour potassium (2eq) and 30.0 grams of DMAs, stirring heating, 85~90 DEG C of insulation reactions 4 to 6 hours, HPLC results
It has been shown that, raw material have converted 90%.
Embodiment 22：The synthesis of 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates：
10.0 grams of 3,4- difluorobenzonilyiles, 19.0 grams of dimethyl malenates (2eq), 49.7 grams of anhydrous carbon are added in 1L four-hole bottles
Sour potassium (5eq) and 30.0 grams of DMAs, stirring heating, 85~90 DEG C of insulation reactions 4 to 6 hours, HPLC results
It has been shown that, raw material convert>99%.
Embodiment 23：The synthesis of 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates：
10.0 grams of 3,4- difluorobenzonilyiles, 19.0 grams of dimethyl malenates (2eq), 19.0 grams of anhydrous carbon are added in 1L four-hole bottles
Sour potassium (3eq) and 30.0 grams of DMAs, stirring heating, 50~55 DEG C of insulation reactions 4 to 6 hours, HPLC results
It has been shown that, raw material have converted 62%.
Embodiment 24：The synthesis of 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates：
10.0 grams of 3,4- difluorobenzonilyiles, 19.0 grams of dimethyl malenates (2eq), 19.0 grams of anhydrous carbon are added in 1L four-hole bottles
Sour potassium (3eq) and 30.0 grams of DMAs, stirring heating, 150~155 DEG C of insulation reactions 4 to 6 hours, HPLC knots
Fruit shows that raw material converts>99%.
Embodiment 25：The synthesis of 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates：
10.0 grams of 3,4- difluorobenzonilyiles, 19.0 grams of dimethyl malenates (2eq), 19.0 grams of anhydrous carbon are added in 1L four-hole bottles
Sour potassium (3eq) and 30.0 grams of DMAs, stirring heating, 85~90 DEG C of insulation reactions 3 hours, HPLC results show
Show, raw material has converted 94%.
Embodiment 26：The synthesis of 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates：
10.0 grams of 3,4- difluorobenzonilyiles, 19.0 grams of dimethyl malenates (2eq), 19.0 grams of anhydrous carbon are added in 1L four-hole bottles
Sour potassium (3eq) and 30.0 grams of DMAs, stirring heating, 85~90 DEG C of insulation reactions 12 hours, HPLC results show
Show, raw material converts>99%.
Embodiment 27：The synthesis of the chloro- 4- methyl cyanophenyls of 3-：
161.4 grams of 2- (4- cyano group -2- chlorphenyls) -1,3- dimethyl malenates (1eq) are put into 1L four-hole bottles, are added
21.7 grams of water (2eq), 140.9 gram of 95% anhydrous calcium chloride (2eq) and 606 grams of DMAs, stirring heating, 140
~145 DEG C of insulation reactions 20 to 24 hours, 30 DEG C are cooled to, add 352.5 grams of water, 303 grams of dichloromethane, concentrated hydrochloric acid is added dropwise about
70.2 grams, merge to system pH=5~7, liquid separation, the extraction of water layer dichloromethane, organic phase, be concentrated under reduced pressure organic phase, and it is fluoro- to obtain 3-
The DMAc concentrates of 4- methyl cyanophenyls, continue rectification under vacuum, collect the chloro- 4- methyl cyanophenyls of 3-, to being steamed without product, obtain 75.9
Gram white solid, yield 83.0%.
Comparative example 1：The synthesis of the fluoro- 4- methyl cyanophenyls of 3-：
151.5 grams of 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates (1eq) are put into 1L four-hole bottles, are added
21.7 grams of water (2eq), 114.8 grams of anhydrous magnesium chlorides (2eq) and 606 grams of DMAs, stirring heating, 140~145
DEG C insulation reaction 20 to 24 hours, HPLC results show that raw material has only converted 47%.Extend the reaction time to 36 hours, HPLC
As a result show, raw material has also only converted 55%, yield<50%.
Comparative example 2：The synthesis of the fluoro- 4- methyl cyanophenyls of 3-：
15.2 grams of 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates (1eq) are put into 1L four-hole bottles, add 2.2
Gram water (2eq), 14.1 gram of 95% anhydrous calcium chloride (2eq) and 60.6 grams of DMAs, stirring heating, 120~125
DEG C insulation reaction 20 to 24 hours, is cooled to 30 DEG C, HPLC results show that raw material converts<10%.
Claims (10)
1. a kind of arylmethane class compound I preparation method, comprises the following steps：In organic solvent, in calcium chloride and water
Under effect, compound I-2 is subjected to de-ester reaction, obtains described compound I, the temperature of the reaction for 130 DEG C extremely
The boiling point of the solvent,
Wherein, R ' and R " is each independently selected from one kind in methyl, ethyl, isopropyl and the tert-butyl group；
N=0 or 1；
R1、R2、R3、R4And R5H or electron withdraw group are each independently, and wherein at least one is electron withdraw group.
2. arylmethane class compound I as claimed in claim 1 preparation method, it is characterised in that described R ' and/or R "
For methyl；
And/or described electron withdraw group is the one or more in nitro, cyano group and halogen；
And/or described electron withdraw group is located at ortho position or contraposition.
3. arylmethane class compound I as claimed in claim 2 preparation method, it is characterised in that described compound I-2
For 2- (4- cyano group -2- fluorophenyls) -1,3- dimethyl malenates, the fluoro- 4- cyano group methyl phenylacetates of 2-, 2- (4- cyano group -2- fluorobenzene
Base) -1,3- diethyl malonates or 2- (4- cyano group -2- chlorphenyls) -1,3- dimethyl malenates；
And/or described compound I is the fluoro- 4- methyl cyanophenyls of 3- or the chloro- 4- methyl cyanophenyls of 3-.
4. the preparation method of the arylmethane class compound I as described in any one of claims 1 to 3, it is characterised in that described
Organic solvent is dimethyl sulfoxide (DMSO), N,N-dimethylformamide, N, one in N- diethyl acetamides and 1-METHYLPYRROLIDONE
Kind is a variety of；
And/or the mol ratio of described compound I-2 and described water is 1:1~1:5；
And/or the mol ratio of described compound I-2 and described calcium chloride is 1:0.5~1:5.0；
And/or described organic solvent and described compound I-2 mass ratio are 4:1；
And/or described reaction temperature is 130~160 DEG C.
5. arylmethane class compound I as claimed in claim 4 preparation method, it is characterised in that described organic solvent
For N, N- diethyl acetamides；
And/or the mol ratio of described compound I-2 and described water is 1:2~1:3；
And/or the mol ratio of described compound I-2 and described calcium chloride is 1:2.0~1:3.0；
And/or described reaction temperature is 140~145 DEG C.
6. the preparation method of the arylmethane class compound I as described in any one of claims 1 to 3, it is characterised in that also include
Following steps：In organic solvent, under alkali effect, compound I-1 and compound I-5 are subjected to substitution reaction, obtained described
Compound I-3,
Wherein, R ', R ", R1、R2、R3、R4And R5Definition as described in any one of claims 1 to 3；
N=1；
X is F, Cl, Br or I.
7. arylmethane class compound I as claimed in claim 6 preparation method, it is characterised in that described substitution reaction
In, described R ' and/or R " they are methyl；
And/or X is F or Cl；
And/or described electron withdraw group is the one or more in nitro, cyano group and halogen；
And/or described electron withdraw group is located at ortho position or contraposition.
8. arylmethane class compound I as claimed in claim 7 preparation method, it is characterised in that described substitution reaction
In, described organic solvent is dimethyl sulfoxide (DMSO), DMF, N, N- diethyl acetamides and N- crassitudes
One or more in ketone；
And/or described alkali is one in sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide and sodium hydrogen
Kind is a variety of.
9. arylmethane class compound I as claimed in claim 8 preparation method, it is characterised in that described substitution reaction
In, described compound I-1 and described compound I-5 mol ratio is 1:1~3:1；
And/or described organic solvent and described compound I-5 mass ratio are 3:1；
And/or described alkali and described compound I-5 mol ratio are 1:1~5:1；
And/or described reaction temperature is 50~155 DEG C.
10. arylmethane class compound I as claimed in claim 9 preparation method, it is characterised in that described substitution reaction
In, described compound I-1 and described compound I-5 mol ratio 2:1~3:1；
And/or described alkali and described compound I-5 mol ratio are 2:1~3:1；
And/or described reaction temperature is 85~90 DEG C.
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| CN115160134A (en) * | 2022-08-10 | 2022-10-11 | 无锡科华生物科技有限公司 | Preparation method of 4-bromo-2-methyl benzoate |
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| CN115160134A (en) * | 2022-08-10 | 2022-10-11 | 无锡科华生物科技有限公司 | Preparation method of 4-bromo-2-methyl benzoate |
| CN115160134B (en) * | 2022-08-10 | 2023-10-10 | 无锡科华生物科技有限公司 | Preparation method of 4-bromo-2-methyl benzoate |
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