CN107573264A - A kind of preparation technology of the sulfonic acid chloride of 3 cyano group, 5 methoxybenzene 1 - Google Patents
A kind of preparation technology of the sulfonic acid chloride of 3 cyano group, 5 methoxybenzene 1 Download PDFInfo
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Abstract
The invention discloses a kind of preparation technology of the sulfonic acid chloride of 3 cyano group, 5 methoxybenzene 1.Comprise the steps of：With 3; 5 dinitrobenzoic acids are raw material; it is substituted the reaction generation nitrobenzoic acid of 3 methoxyl group 5; the nitrobenzoic acid of 3 methoxyl group 5 generates the nitrobenzamide of 3 methoxyl group 5 through amidation process; the nitrobenzamide of the 3 methoxyl group 5 dehydration generation p-nitrile of 3 methoxyl group 5; the p-nitrile of 3 methoxyl group 5 generates the methoxy cyanophenyl of 3 amino 5 through reduction reaction, and the methoxy cyanophenyl of 3 amino 5 obtains the sulfonic acid chloride of 3 cyano group of target compound, 5 methoxybenzene 1 through diazotising and sulfonylation.This route raw material is easy to get, operating condition is gently easily-controllable, and post processing is simple, is adapted to industrialized production.
Description
Technical field
The present invention relates to a kind of preparation technology of 3- cyano group -5- methoxybenzene -1- sulfonic acid chlorides.Belong to organic synthesis, fine
Chemical industry, medicine intermediate field.
Background technology
Sulfonic acid chloride is important electrophilic group, can obtain a variety of derivatives with reactions such as alkali, phenol, alcohol, ammonia.Therefore, sulphonyl
Chlorine class compound is widely used in the synthesis of medicine, agricultural chemicals, dyestuff etc., is a kind of important fine organic chemical industry's intermediate.3-
Cyano group -5- methoxybenzene -1- sulfonic acid chlorides not only contain sulfonic acid chloride group, also contain cyano group.Cyano group is easily hydrolyzed or reduced
Reaction, ester or amine are further generated, is easy to the extension of derivative.Research shows containing 3- cyano group -5- methoxybenzene sulphonyl skeletons
Molecule have that multi-medicament is active, such as regulation or inhibitory enzyme reverse transcriptase, activation glucokinase act on, and are used for synthesis and control
Treat the treatment and prevention medicine of a variety of diseases such as immunologic deficiency syndrome, diabetes, cystic fibrosis.
The preparation technology of document report 3- cyano group -5- methoxybenzene -1- sulfonic acid chlorides is had no at present.
The content of the invention
The technical problem to be solved in the present invention is：A kind of preparation work of 3- cyano group -5- methoxybenzene -1- sulfonic acid chlorides is provided
Skill, solve the problems, such as in the prior art also without its preparation technology.
Technical scheme：A kind of preparation method of 3- cyano group -5- methoxybenzene -1- sulfonic acid chlorides, including：With 3,5-
Dinitrobenzoic acid is raw material, is substituted reaction generation 3- methoxyl group -5- nitrobenzoic acids, 3- methoxyl group -5- nitrobenzoic acids
3- methoxyl group -5- nitrobenzamides, 3- methoxyl group -5- nitrobenzamides dehydration generation 3- methoxies are generated through amidation process
Base -5- p-nitriles, 3- methoxyl group -5- p-nitriles generate 3- amino -5- methoxy cyanophenyls, 3- amino -5- through reduction reaction
Methoxy cyanophenyl obtains target compound 3- cyano group -5- methoxybenzene -1- sulfonic acid chlorides through diazotising and sulfonylation.
(1) step reaction is that 1eq 3,5- dinitrobenzoic acids are dissolved in into dry DMSO, adds 2~8eq first
Sodium alkoxide, 2~24h is reacted at room temperature, then 50~120 DEG C are continued 2~10h of reaction.
(2) step reaction is that 1eq 3- methoxyl group -5- nitrobenzoic acids are dissolved in dry THF, addition 1~
5eq thionyl chlorides, the DMF of the drying of catalytic amount, 0.5~3h of back flow reaction is added dropwise.Reaction finishes, and be concentrated under reduced pressure reaction solution.0
At~10 DEG C, concentrate is slowly added to 25% concentrated ammonia liquor：THF=25~85g：Generated in 100mL mixed liquor 3- methoxyl groups-
5- nitrobenzamides.
(3) step reaction is that 1eq 3- methoxyl group -5- nitrobenzamides are dissolved in DMF, is cooled to -15~5
DEG C, 4~6eq POCl3 is slowly added dropwise, 0.5~1h of insulation reaction, then reacts at room temperature 8~16h and 3- methoxyl groups -5- is made
P-nitrile.
(4) step reaction is that 1eq 3- methoxyl group -5- p-nitriles are dissolved in methanol, addition 0.01~
0.05eq 10% palladium carbon and 1~3eq ammonium acetate, are passed through hydrogen, and 3- amino -5- methoxies are made in 25~40 DEG C of 8~16h of reaction
Base cyanophenyl.
(5) step reaction is that 1eq 3- amino -5- methoxy cyanophenyls are dissolved in into concentrated hydrochloric acid：Acetic acid=2.5:1(v/
V) in mixed solution, 0 DEG C is cooled to, 1~2eq sodium nitrite in aqueous solution is added dropwise, 0.5~1h of insulation reaction, obtains reserve liquid.
Separately 1~2eq stannous chloride is added in glacial acetic acid, control temperature is not higher than 15 DEG C, is passed through SO2Gas, it is slowly added dropwise above-mentioned
3- cyano group -5- methoxybenzene -1- sulfonic acid chlorides are made in reserve liquid, 1~3h of insulation reaction.
Beneficial effects of the present invention：The present invention, for initiation material, is synthesized with 3,5- dinitrobenzoic acids through five four-step reactions
Target compound.This route raw material is easy to get, operating condition is gently easily-controllable, and post processing is simple, is adapted to industrialized production.
Embodiment
Embodiment 1
A.3- the preparation of methoxyl group -5- nitrobenzoic acids
In there-necked flask, 3,5- dinitrobenzoic acids (30.0g, 0.141mol) are dissolved in dry DMSO (300mL), added
Enter sodium methoxide (38.2g, 0.707mol), react at room temperature 10h, then rise to 80 DEG C and continue to react 5h.Reaction finishes, and is cooled to room
Temperature, reaction solution is poured into frozen water, ethyl acetate (100mL × 2) carries miscellaneous, collection aqueous phase, watery hydrochloric acid tune pH=2, ethyl acetate
(200mL × 3) extract, and collect organic phase, anhydrous sodium sulfate drying, and evaporated under reduced pressure solvent obtains 3- methoxyl group -5- nitrobenzoic acids
Solid 25.2g, yield 90.5%.
1H NMR(400MHz,Chloroform-d)δ:11.21(s,1H),8.12(s,1H),8.01(s,1H),7.85
(s,1H),3.89(s,1H)；ESI-MS,m/z:198.01[M+H]+。
B.3- the preparation of methoxyl group -5- nitrobenzamides
In there-necked flask, 3- methoxyl group -5- nitrobenzoic acids (25.0g, 0.127mol) are dissolved in dry THF
In (200mL), thionyl chloride (45.3g, 0.380mol) is added, 2 drip-dry dry DMF, back flow reaction 1h is added dropwise.Reaction finishes,
Be concentrated under reduced pressure reaction solution.At 0 DEG C~10 DEG C, concentrate is slowly added to 25% concentrated ammonia liquor (60.0g, 0.881mol) and THF
In the mixed liquor of (100mL), that is, there is solid generation.Filter, filter cake is eluted with water (50mL × 1), dry 3- methoxyl group -5- nitre
Yl-benzamide 23.7g, yield 95.3%.
1H NMR(400MHz,Chloroform-d)δ:8.28(s,1H),7.88(s,1H),7.49(s,2H),7.32(s,
1H),3.92(s,1H)；ESI-MS,m/z:197.16[M+H]+。
C.3- the preparation of methoxyl group -5- p-nitriles
In there-necked flask, 3- methoxyl group -5- nitrobenzamides (20.0g, 0.102mol) are dissolved in DMF (200mL),
- 15 DEG C are cooled to, POCl3 (78.2g, 0.510mol) is slowly added dropwise, -15 DEG C of reaction 0.5h, then reacts at room temperature 12h.Instead
It should finish, reaction solution is poured into frozen water, that is, separate out solid, filter, dry 3- methoxyl group -5- p-nitrile solid 16.2g,
Yield is 89.2%.
1H NMR(400MHz,Chloroform-d)δ:7.91(s,1H),7.72(s,1H),7.36(s,1H),4.08(s,
3H)；ESI-MS,m/z:179.05[M+H]+。
D.3- the preparation of amino -5- methoxy cyanophenyls
In there-necked flask, 3- methoxyl group -5- p-nitriles (15.0g, 0.084mol) are dissolved in methanol (150mL), added
Enter 10% palladium carbon (3.0g) and ammonium acetate (13.0g, 0.168mol), be passed through hydrogen, 40 DEG C of reaction 8h.Reaction finishes, and filters, filter
Cake is washed with methanol (30mL × 3).Filtrate is collected, is concentrated under reduced pressure, concentrate is poured into 100mL water, ethyl acetate (80mL × 3)
Extraction, organic phase is collected, anhydrous sodium sulfate drying, solvent is removed under reduced pressure and obtains 3- amino -5- methoxy cyanophenyl solid 12.1g, received
Rate is 97.3%.
1H NMR(400MHz,Chloroform-d)δ:7.66(s,1H),7.47(s,1H),6.97(s,1H),6.22(s,
2H,3.88(s,3H)；ESI-MS,m/z:149.05[M+H]+。
E.3- the preparation of cyano group -5- methoxybenzenes -1- sulfonic acid chlorides
In there-necked flask, 3- amino -5- methoxy cyanophenyls (10.0g, 0.068mol) are dissolved in concentrated hydrochloric acid：Acetic acid=2.5:
In 1 (v/v) mixed solution (100mL), 0 DEG C is cooled to, the water (30mL) that natrium nitrosum (5.1g, 0.074mol) is added dropwise is molten
Liquid, insulation reaction 0.5h, obtains reserve liquid.
There-necked flask separately is taken, stannous chloride (7.4g, 0.074mol) is added in glacial acetic acid (30mL), control temperature is not higher than
15 DEG C, it is passed through SO2Gas, above-mentioned reserve liquid, insulation reaction 1h is slowly added dropwise.Reaction finishes, and pours into and solid is separated out in frozen water,
Filter, filter cake obtains 3- cyano group -5- methoxybenzene -1- sulfonic acid chloride white solid 13.9g, yield 88.7% with Gossypol recrystallized from chloroform.
1H NMR(400MHz,Chloroform-d)δ:7.89 (s, 1H), 7.72 (s, 1H), 7.49 (s, 1H), 3.97 (s,
3H)；ESI-MS,m/z:231.98[M+H]+。
Embodiment 2
A.3- the preparation of methoxyl group -5- nitrobenzoic acids
In there-necked flask, 3,5- dinitrobenzoic acids (30.0g, 0.141mol) are dissolved in dry DMSO (300mL), added
Enter sodium methoxide (15.3g, 0.283mol), react at room temperature 24h, then rise to 120 DEG C and continue to react 2h.Reaction finishes, and is cooled to
Room temperature, reaction solution is poured into frozen water, ethyl acetate (100mL × 2) puies forward miscellaneous, collection aqueous phase, watery hydrochloric acid tune pH=2, acetic acid second
Ester (200mL × 3) extracts, and collects organic phase, anhydrous sodium sulfate drying, and evaporated under reduced pressure solvent obtains 3- methoxyl group -5- nitrobenzoyls
Sour solid 24.7g, yield 88.5%.
1H NMR(400MHz,Chloroform-d)δ:11.21(s,1H),8.12(s,1H),8.01(s,1H),7.85
(s,1H),3.89(s,1H)；ESI-MS,m/z:198.01[M+H]+。
B.3- the preparation of methoxyl group -5- nitrobenzamides
In there-necked flask, 3- methoxyl group -5- nitrobenzoic acids (15.0g, 0.076mol) are dissolved in dry THF
In (100mL), thionyl chloride (27.2g, 0.228mol) is added, 2 drip-dry dry DMF, back flow reaction 1h is added dropwise.Reaction finishes,
Be concentrated under reduced pressure reaction solution.At 0 DEG C~10 DEG C, concentrate is slowly added to concentrated ammonia liquor (35.0g, 0.514mol) and THF
In the mixed liquor of (50mL), that is, there is solid generation.Filter, filter cake is eluted with water (25mL × 1), dry 3- methoxyl group -5- nitre
Yl-benzamide 14.1g, yield 94.6%.
1H NMR(400MHz,Chloroform-d)δ:8.28(s,1H),7.88(s,1H),7.49(s,2H),7.32(s,
1H),3.92(s,1H)；ESI-MS,m/z:197.16[M+H]+。
C.3- the preparation of methoxyl group -5- p-nitriles
In there-necked flask, 3- methoxyl group -5- nitrobenzamides (10.0g, 0.051mol) are dissolved in DMF (100mL),
- 15 DEG C are cooled to, POCl3 (39.1g, 0.255mol) is slowly added dropwise, -15 DEG C of reaction 0.5h, then reacts at room temperature 12h.Instead
It should finish, reaction solution is poured into frozen water, that is, separate out solid, filter, dry 3- methoxyl group -5- p-nitrile solid 8.0g,
Yield is 88.5%.
1H NMR(400MHz,Chloroform-d)δ:7.91(s,1H),7.72(s,1H),7.36(s,1H),4.08(s,
3H)；ESI-MS,m/z:179.05[M+H]+。
D.3- the preparation of amino -5- methoxy cyanophenyls
In there-necked flask, 3- methoxyl group -5- p-nitriles (8.0g, 0.045mol) are dissolved in methanol (80mL), added
10% palladium carbon (1.4g) and ammonium acetate (6.9g, 0.090mol), it is passed through hydrogen, 40 DEG C of reaction 8h.Reaction finishes, and filters, filter cake
Washed with methanol (15mL × 3).Filtrate is collected, is concentrated under reduced pressure, concentrate is poured into 50mL water, ethyl acetate (40mL × 3) extraction
Take, collect organic phase, anhydrous sodium sulfate drying, remove solvent under reduced pressure and obtain 3- amino -5- methoxy cyanophenyl solid 6.5g, yield is
98.2%.
1H NMR(400MHz,Chloroform-d)δ:7.66(s,1H),7.47(s,1H),6.97(s,1H),6.22(s,
2H,3.88(s,3H)；ESI-MS,m/z:149.05[M+H]+。
E.3- the preparation of cyano group -5- methoxybenzenes -1- sulfonic acid chlorides
In there-necked flask, 3- amino -5- methoxy cyanophenyls (5.0g, 0.034mol) are dissolved in concentrated hydrochloric acid：Acetic acid=2.5:1
(v/v) in mixed solution (50mL), 0 DEG C is cooled to, water (15mL) solution of natrium nitrosum (2.6g, 0.037mol) is added dropwise,
Insulation reaction 0.5h, obtains reserve liquid.
There-necked flask separately is taken, stannous chloride (3.7g, 0.037mol) is added in glacial acetic acid (15mL), control temperature is not higher than
15 DEG C, it is passed through SO2Gas, above-mentioned reserve liquid, insulation reaction 1h is slowly added dropwise.Reaction finishes, and pours into and solid is separated out in frozen water,
Filter, filter cake obtains 3- cyano group -5- methoxybenzene -1- sulfonic acid chloride white solid 7.0g, yield 89.6% with Gossypol recrystallized from chloroform.
1H NMR(400MHz,Chloroform-d)δ:7.89 (s, 1H), 7.72 (s, 1H), 7.49 (s, 1H), 3.97 (s,
3H)；ESI-MS,m/z:231.98[M+H]+。
Embodiment 3
A.3- the preparation of methoxyl group -5- nitrobenzoic acids
In there-necked flask, 3,5- dinitrobenzoic acids (15.0g, 0.071mol) are dissolved in dry DMSO (150mL), added
Enter sodium methoxide (30.6g, 0.566mol), react at room temperature 2h, then rise to 50 DEG C and continue to react 10h.Reaction finishes, and is cooled to room
Temperature, reaction solution is poured into frozen water, ethyl acetate (50mL × 2) carries miscellaneous, collection aqueous phase, watery hydrochloric acid tune pH=2, ethyl acetate
(100mL × 3) extract, and collect organic phase, anhydrous sodium sulfate drying, and evaporated under reduced pressure solvent obtains 3- methoxyl group -5- nitrobenzoic acids
Solid 12.5g, yield 89.5%.
1H NMR(400MHz,Chloroform-d)δ:11.21(s,1H),8.12(s,1H),8.01(s,1H),7.85
(s,1H),3.89(s,1H)；ESI-MS,m/z:198.01[M+H]+。
B.3- the preparation of methoxyl group -5- nitrobenzamides
In there-necked flask, 3- methoxyl group -5- nitrobenzoic acids (15.0g, 0.076mol) are dissolved in dry THF
In (100mL), thionyl chloride (9.1g, 0.076mol) is added, 2 drip-dry dry DMF, back flow reaction 3h is added dropwise.Reaction finishes, and subtracts
Press concentration of reaction solution.At 0 DEG C~10 DEG C, concentrate is slowly added to 25% concentrated ammonia liquor (15.0g, 0.220mol) and THF
In the mixed liquor of (50mL), that is, there is solid generation.Filter, filter cake is eluted with water (25mL × 1), dry 3- methoxyl group -5- nitre
Yl-benzamide 14.0g, yield 93.6%.
1H NMR(400MHz,Chloroform-d)δ:8.28(s,1H),7.88(s,1H),7.49(s,2H),7.32(s,
1H),3.92(s,1H)；ESI-MS,m/z:197.16[M+H]+。
C.3- the preparation of methoxyl group -5- p-nitriles
In there-necked flask, 3- methoxyl group -5- nitrobenzamides (10.0g, 0.051mol) are dissolved in DMF (100mL),
- 15 DEG C are cooled to, POCl3 (39.1g, 0.255mol) is slowly added dropwise, -15 DEG C of reaction 0.5h, then reacts at room temperature 12h.Instead
It should finish, reaction solution is poured into frozen water, that is, separate out solid, filter, dry 3- methoxyl group -5- p-nitrile solid 8.2g,
Yield is 89.8%.
1H NMR(400MHz,Chloroform-d)δ:7.91(s,1H),7.72(s,1H),7.36(s,1H),4.08(s,
3H)；ESI-MS,m/z:179.05[M+H]+。
D.3- the preparation of amino -5- methoxy cyanophenyls
In there-necked flask, 3- methoxyl group -5- p-nitriles (10.0g, 0.056mol) are dissolved in methanol (100mL), added
Enter 10% palladium carbon (1.8g) and ammonium acetate (8.7g, 0.112mol), be passed through hydrogen, 40 DEG C of reaction 8h.Reaction finishes, and filters, filter
Cake is washed with methanol (15mL × 3).Filtrate is collected, is concentrated under reduced pressure, concentrate is poured into 50mL water, ethyl acetate (40mL × 3)
Extraction, organic phase is collected, anhydrous sodium sulfate drying, solvent is removed under reduced pressure and obtains 3- amino -5- methoxy cyanophenyl solid 8.1g, yield
For 97.6%.
1H NMR(400MHz,Chloroform-d)δ:7.66(s,1H),7.47(s,1H),6.97(s,1H),6.22(s,
2H,3.88(s,3H)；ESI-MS,m/z:149.05[M+H]+。
E.3- the preparation of cyano group -5- methoxybenzenes -1- sulfonic acid chlorides
In there-necked flask, 3- amino -5- methoxy cyanophenyls (5.0g, 0.034mol) are dissolved in concentrated hydrochloric acid：Acetic acid=2.5:1
(v/v) in mixed solution (50mL), 0 DEG C is cooled to, water (15mL) solution of natrium nitrosum (2.6g, 0.037mol) is added dropwise,
Insulation reaction 0.5h, obtains reserve liquid.
There-necked flask separately is taken, stannous chloride (3.7g, 0.037mol) is added in glacial acetic acid (15mL), control temperature is not higher than
15 DEG C, it is passed through SO2Gas, above-mentioned reserve liquid, insulation reaction 1h is slowly added dropwise.Reaction finishes, and pours into and solid is separated out in frozen water,
Filter, filter cake obtains 3- cyano group -5- methoxybenzene -1- sulfonic acid chloride white solid 6.9g, yield 88.1% with Gossypol recrystallized from chloroform.
1H NMR(400MHz,Chloroform-d)δ:7.89 (s, 1H), 7.72 (s, 1H), 7.49 (s, 1H), 3.97 (s,
3H)；ESI-MS,m/z:231.98[M+H]+。
Embodiment 4
A.3- the preparation of methoxyl group -5- nitrobenzoic acids
In there-necked flask, 3,5- dinitrobenzoic acids (30.0g, 0.141mol) are dissolved in dry DMSO (300mL), added
Enter sodium methoxide (38.2g, 0.707mol), react at room temperature 10h, then rise to 80 DEG C and continue to react 5h.Reaction finishes, and is cooled to room
Temperature, reaction solution is poured into frozen water, ethyl acetate (100mL × 2) carries miscellaneous, collection aqueous phase, watery hydrochloric acid tune pH=2, ethyl acetate
(200mL × 3) extract, and collect organic phase, anhydrous sodium sulfate drying, and evaporated under reduced pressure solvent obtains 3- methoxyl group -5- nitrobenzoic acids
Solid 25.3g, yield 90.8%.
1H NMR(400MHz,Chloroform-d)δ:11.21(s,1H),8.12(s,1H),8.01(s,1H),7.85
(s,1H),3.89(s,1H)；ESI-MS,m/z:198.01[M+H]+。
B.3- the preparation of methoxyl group -5- nitrobenzamides
In there-necked flask, 3- methoxyl group -5- nitrobenzoic acids (25.0g, 0.127mol) are dissolved in dry THF
In (200mL), thionyl chloride (75.4g, 0.634mol) is added, 2 drip-dry dry DMF, back flow reaction 1h is added dropwise.Reaction finishes,
Be concentrated under reduced pressure reaction solution.At 0 DEG C~10 DEG C, concentrate is slowly added to 25% concentrated ammonia liquor (85.0g, 1.248mol) and THF
In the mixed liquor of (100mL), that is, there is solid generation.Filter, filter cake is eluted with water (50mL × 1), dry 3- methoxyl group -5- nitre
Yl-benzamide 23.9g, yield 96.1%.
1H NMR(400MHz,Chloroform-d)δ:8.28(s,1H),7.88(s,1H),7.49(s,2H),7.32(s,
1H),3.92(s,1H)；ESI-MS,m/z:197.16[M+H]+。
C.3- the preparation of methoxyl group -5- p-nitriles
In there-necked flask, 3- methoxyl group -5- nitrobenzamides (20.0g, 0.102mol) are dissolved in DMF (200mL),
- 15 DEG C are cooled to, POCl3 (62.5g, 0.408mol) is slowly added dropwise, -15 DEG C of reaction 0.5h, then reacts at room temperature 16h.Instead
It should finish, reaction solution is poured into frozen water, that is, separate out solid, filter, dry 3- methoxyl group -5- p-nitrile solid 15.9g,
Yield is 87.7%.
1H NMR(400MHz,Chloroform-d)δ:7.91(s,1H),7.72(s,1H),7.36(s,1H),4.08(s,
3H)；ESI-MS,m/z:179.05[M+H]+。
D.3- the preparation of amino -5- methoxy cyanophenyls
In there-necked flask, 3- methoxyl group -5- p-nitriles (15.0g, 0.084mol) are dissolved in methanol (150mL), added
Enter 10% palladium carbon (2.7g) and ammonium acetate (13.0g, 0.168mol), be passed through hydrogen, 40 DEG C of reaction 8h.Reaction finishes, and filters, filter
Cake is washed with methanol (30mL × 3).Filtrate is collected, is concentrated under reduced pressure, concentrate is poured into 100mL water, ethyl acetate (80mL × 3)
Extraction, organic phase is collected, anhydrous sodium sulfate drying, solvent is removed under reduced pressure and obtains 3- amino -5- methoxy cyanophenyl solid 12.1g, received
Rate is 96.6%.
1H NMR(400MHz,Chloroform-d)δ:7.66(s,1H),7.47(s,1H),6.97(s,1H),6.22(s,
2H,3.88(s,3H)；ESI-MS,m/z:149.05[M+H]+。
E.3- the preparation of cyano group -5- methoxybenzenes -1- sulfonic acid chlorides
In there-necked flask, 3- amino -5- methoxy cyanophenyls (10.0g, 0.068mol) are dissolved in concentrated hydrochloric acid：Acetic acid=2.5:
In 1 (v/v) mixed solution (100mL), 0 DEG C is cooled to, the water (30mL) that natrium nitrosum (5.1g, 0.074mol) is added dropwise is molten
Liquid, insulation reaction 0.5h, obtains reserve liquid.
There-necked flask separately is taken, stannous chloride (7.4g, 0.074mol) is added in glacial acetic acid (30mL), control temperature is not higher than
15 DEG C, it is passed through SO2Gas, above-mentioned reserve liquid, insulation reaction 1h is slowly added dropwise.Reaction finishes, and pours into and solid is separated out in frozen water,
Filter, filter cake obtains 3- cyano group -5- methoxybenzene -1- sulfonic acid chloride white solid 13.8g, yield 88.1% with Gossypol recrystallized from chloroform.
1H NMR(400MHz,Chloroform-d)δ:7.89 (s, 1H), 7.72 (s, 1H), 7.49 (s, 1H), 3.97 (s,
3H)；ESI-MS,m/z:231.98[M+H]+。
Embodiment 5
A.3- the preparation of methoxyl group -5- nitrobenzoic acids
In there-necked flask, 3,5- dinitrobenzoic acids (30.0g, 0.141mol) are dissolved in dry DMSO (300mL), added
Enter sodium methoxide (38.2g, 0.707mol), react at room temperature 10h, then rise to 80 DEG C and continue to react 5h.Reaction finishes, and is cooled to room
Temperature, reaction solution is poured into frozen water, ethyl acetate (100mL × 2) carries miscellaneous, collection aqueous phase, watery hydrochloric acid tune pH=2, ethyl acetate
(200mL × 3) extract, and collect organic phase, anhydrous sodium sulfate drying, and evaporated under reduced pressure solvent obtains 3- methoxyl group -5- nitrobenzoic acids
Solid 25.4g, yield 91.2%.
1H NMR(400MHz,Chloroform-d)δ:11.21(s,1H),8.12(s,1H),8.01(s,1H),7.85
(s,1H),3.89(s,1H)；ESI-MS,m/z:198.01[M+H]+。
B.3- the preparation of methoxyl group -5- nitrobenzamides
In there-necked flask, 3- methoxyl group -5- nitrobenzoic acids (25.0g, 0.127mol) are dissolved in dry THF
In (200mL), thionyl chloride (45.3g, 0.380mol) is added, 2 drip-dry dry DMF, back flow reaction 1h is added dropwise.Reaction finishes,
Be concentrated under reduced pressure reaction solution.At 0 DEG C~10 DEG C, concentrate is slowly added to 25% concentrated ammonia liquor (60.0g, 0.881mol) and THF
In the mixed liquor of (100mL), that is, there is solid generation.Filter, filter cake is eluted with water (50mL × 1), dry 3- methoxyl group -5- nitre
Yl-benzamide 23.9g, yield 95.9%.
1H NMR(400MHz,Chloroform-d)δ:8.28(s,1H),7.88(s,1H),7.49(s,2H),7.32(s,
1H),3.92(s,1H)；ESI-MS,m/z:197.16[M+H]+。
C.3- the preparation of methoxyl group -5- p-nitriles
In there-necked flask, 3- methoxyl group -5- nitrobenzamides (20.0g, 0.102mol) are dissolved in DMF (200mL),
- 15 DEG C are cooled to, POCl3 (93.8g, 0.612mol) is slowly added dropwise, -15 DEG C of reaction 0.5h, then reacts at room temperature 8h.Instead
It should finish, reaction solution is poured into frozen water, that is, separate out solid, filter, dry 3- methoxyl group -5- p-nitrile solid 16.4g,
Yield is 90.1%.
1H NMR(400MHz,Chloroform-d)δ:7.91(s,1H),7.72(s,1H),7.36(s,1H),4.08(s,
3H)；ESI-MS,m/z:179.05[M+H]+。
D.3- the preparation of amino -5- methoxy cyanophenyls
In there-necked flask, 3- methoxyl group -5- p-nitriles (15.0g, 0.084mol) are dissolved in methanol (150mL), added
Enter 10% palladium carbon (0.9g) and ammonium acetate (19.5g, 0.253mol), be passed through hydrogen, 30 DEG C of reaction 10h.Reaction finishes, and filters,
Filter cake is washed with methanol (30mL × 3).Filtrate to be collected, is concentrated under reduced pressure, concentrate is poured into 100mL water, ethyl acetate (80mL ×
3) extract, collect organic phase, anhydrous sodium sulfate drying, remove solvent under reduced pressure and obtain 3- amino -5- methoxy cyanophenyl solid 11.9g,
Yield is 95.1%.
1H NMR(400MHz,Chloroform-d)δ:7.66(s,1H),7.47(s,1H),6.97(s,1H),6.22(s,
2H,3.88(s,3H)；ESI-MS,m/z:149.05[M+H]+。
E.3- the preparation of cyano group -5- methoxybenzenes -1- sulfonic acid chlorides
In there-necked flask, 3- amino -5- methoxy cyanophenyls (10.0g, 0.068mol) are dissolved in concentrated hydrochloric acid：Acetic acid=2.5:
In 1 (v/v) mixed solution (100mL), 0 DEG C is cooled to, the water (30mL) that natrium nitrosum (5.1g, 0.074mol) is added dropwise is molten
Liquid, insulation reaction 0.5h, obtains reserve liquid.
There-necked flask separately is taken, stannous chloride (7.4g, 0.074mol) is added in glacial acetic acid (30mL), control temperature is not higher than
15 DEG C, it is passed through SO2Gas, above-mentioned reserve liquid, insulation reaction 1h is slowly added dropwise.Reaction finishes, and pours into and solid is separated out in frozen water,
Filter, filter cake obtains 3- cyano group -5- methoxybenzene -1- sulfonic acid chloride white solid 13.8g, yield 88.1% with Gossypol recrystallized from chloroform.
1H NMR(400MHz,Chloroform-d)δ:7.89 (s, 1H), 7.72 (s, 1H), 7.49 (s, 1H), 3.97 (s,
3H)；ESI-MS,m/z:231.98[M+H]+。
Embodiment 6
A.3- the preparation of methoxyl group -5- nitrobenzoic acids
In there-necked flask, 3,5- dinitrobenzoic acids (30.0g, 0.141mol) are dissolved in dry DMSO (300mL), added
Enter sodium methoxide (38.2g, 0.707mol), react at room temperature 10h, then rise to 80 DEG C and continue to react 5h.Reaction finishes, and is cooled to room
Temperature, reaction solution is poured into frozen water, ethyl acetate (100mL × 2) carries miscellaneous, collection aqueous phase, watery hydrochloric acid tune pH=2, ethyl acetate
(200mL × 3) extract, and collect organic phase, anhydrous sodium sulfate drying, and evaporated under reduced pressure solvent obtains 3- methoxyl group -5- nitrobenzoic acids
Solid 25.1g, yield 90.1%.
1H NMR(400MHz,Chloroform-d)δ:11.21(s,1H),8.12(s,1H),8.01(s,1H),7.85
(s,1H),3.89(s,1H)；ESI-MS,m/z:198.01[M+H]+。
B.3- the preparation of methoxyl group -5- nitrobenzamides
In there-necked flask, 3- methoxyl group -5- nitrobenzoic acids (25.0g, 0.127mol) are dissolved in dry THF
In (200mL), thionyl chloride (45.3g, 0.380mol) is added, 2 drip-dry dry DMF, back flow reaction 1h is added dropwise.Reaction finishes,
Be concentrated under reduced pressure reaction solution.At 0 DEG C~10 DEG C, concentrate is slowly added to 25% concentrated ammonia liquor (60.0g, 0.881mol) and THF
In the mixed liquor of (100mL), that is, there is solid generation.Filter, filter cake is eluted with water (50mL × 1), dry 3- methoxyl group -5- nitre
Yl-benzamide 23.6g, yield 94.9%.
1H NMR(400MHz,Chloroform-d)δ:8.28(s,1H),7.88(s,1H),7.49(s,2H),7.32(s,
1H),3.92(s,1H)；ESI-MS,m/z:197.16[M+H]+。
C.3- the preparation of methoxyl group -5- p-nitriles
In there-necked flask, 3- methoxyl group -5- nitrobenzamides (20.0g, 0.102mol) are dissolved in DMF (200mL),
- 15 DEG C are cooled to, POCl3 (78.2g, 0.510mol) is slowly added dropwise, -15 DEG C of reaction 0.5h, then reacts at room temperature 12h.Instead
It should finish, reaction solution is poured into frozen water, that is, separate out solid, filter, dry 3- methoxyl group -5- p-nitrile solid 16.3g,
Yield is 89.8%.
1H NMR(400MHz,Chloroform-d)δ:7.91(s,1H),7.72(s,1H),7.36(s,1H),4.08(s,
3H)；ESI-MS,m/z:179.05[M+H]+。
D.3- the preparation of amino -5- methoxy cyanophenyls
In there-necked flask, 3- methoxyl group -5- p-nitriles (15.0g, 0.084mol) are dissolved in methanol (150mL), added
Enter 10% palladium carbon (4.5g) and ammonium acetate (6.5g, 0.084mol), be passed through hydrogen, 25 DEG C of reaction 16h.Reaction finishes, and filters, filter
Cake is washed with methanol (30mL × 3).Filtrate is collected, is concentrated under reduced pressure, concentrate is poured into 100mL water, ethyl acetate (80mL × 3)
Extraction, organic phase is collected, anhydrous sodium sulfate drying, solvent is removed under reduced pressure and obtains 3- amino -5- methoxy cyanophenyl solid 12.0g, received
Rate is 96.2%.
1H NMR(400MHz,Chloroform-d)δ:7.66(s,1H),7.47(s,1H),6.97(s,1H),6.22(s,
2H,3.88(s,3H)；ESI-MS,m/z:149.05[M+H]+。
E.3- the preparation of cyano group -5- methoxybenzenes -1- sulfonic acid chlorides
In there-necked flask, 3- amino -5- methoxy cyanophenyls (10.0g, 0.068mol) are dissolved in concentrated hydrochloric acid：Acetic acid=2.5:
In 1 (v/v) mixed solution (100mL), 0 DEG C is cooled to, the water (30mL) that natrium nitrosum (4.5g, 0.068mol) is added dropwise is molten
Liquid, insulation reaction 1h, obtains reserve liquid.
There-necked flask separately is taken, stannous chloride (6.7g, 0.068mol) is added in glacial acetic acid (30mL), control temperature is not higher than
15 DEG C, it is passed through SO2Gas, above-mentioned reserve liquid, insulation reaction 3h is slowly added dropwise.Reaction finishes, and pours into and solid is separated out in frozen water,
Filter, filter cake obtains 3- cyano group -5- methoxybenzene -1- sulfonic acid chloride white solid 13.5g, yield 86.6% with Gossypol recrystallized from chloroform.
1H NMR(400MHz,Chloroform-d)δ:7.89 (s, 1H), 7.72 (s, 1H), 7.49 (s, 1H), 3.97 (s,
3H)；ESI-MS,m/z:231.98[M+H]+。
Embodiment 7
A.3- the preparation of methoxyl group -5- nitrobenzoic acids
In there-necked flask, 3,5- dinitrobenzoic acids (30.0g, 0.141mol) are dissolved in dry DMSO (300mL), added
Enter sodium methoxide (38.2g, 0.707mol), react at room temperature 10h, then rise to 80 DEG C and continue to react 5h.Reaction finishes, and is cooled to room
Temperature, reaction solution is poured into frozen water, ethyl acetate (100mL × 2) carries miscellaneous, collection aqueous phase, watery hydrochloric acid tune pH=2, ethyl acetate
(200mL × 3) extract, and collect organic phase, anhydrous sodium sulfate drying, and evaporated under reduced pressure solvent obtains 3- methoxyl group -5- nitrobenzoic acids
Solid 25.4g, yield 91.3%.
1H NMR(400MHz,Chloroform-d)δ:11.21(s,1H),8.12(s,1H),8.01(s,1H),7.85
(s,1H),3.89(s,1H)；ESI-MS,m/z:198.01[M+H]+。
B.3- the preparation of methoxyl group -5- nitrobenzamides
In there-necked flask, 3- methoxyl group -5- nitrobenzoic acids (25.0g, 0.127mol) are dissolved in dry THF
In (200mL), thionyl chloride (45.3g, 0.380mol) is added, 2 drip-dry dry DMF, back flow reaction 1h is added dropwise.Reaction finishes,
Be concentrated under reduced pressure reaction solution.At 0 DEG C~10 DEG C, concentrate is slowly added to 25% concentrated ammonia liquor (60.0g, 0.881mol) and THF
In the mixed liquor of (100mL), that is, there is solid generation.Filter, filter cake is eluted with water (50mL × 1), dry 3- methoxyl group -5- nitre
Yl-benzamide 23.9g, yield 96.0%.
1H NMR(400MHz,Chloroform-d)δ:8.28(s,1H),7.88(s,1H),7.49(s,2H),7.32(s,
1H),3.92(s,1H)；ESI-MS,m/z:197.16[M+H]+。
C.3- the preparation of methoxyl group -5- p-nitriles
In there-necked flask, 3- methoxyl group -5- nitrobenzamides (20.0g, 0.102mol) are dissolved in DMF (200mL),
- 15 DEG C are cooled to, POCl3 (78.2g, 0.510mol) is slowly added dropwise, -15 DEG C of reaction 0.5h, then reacts at room temperature 12h.Instead
It should finish, reaction solution is poured into frozen water, that is, separate out solid, filter, dry 3- methoxyl group -5- p-nitrile solid 16.4g,
Yield is 90.0%.
1H NMR(400MHz,Chloroform-d)δ:7.91(s,1H),7.72(s,1H),7.36(s,1H),4.08(s,
3H)；ESI-MS,m/z:179.05[M+H]+。
D.3- the preparation of amino -5- methoxy cyanophenyls
In there-necked flask, 3- methoxyl group -5- p-nitriles (15.0g, 0.084mol) are dissolved in methanol (150mL), added
Enter 10% palladium carbon (2.7g) and ammonium acetate (13.0g, 0.168mol), be passed through hydrogen, 40 DEG C of reaction 8h.Reaction finishes, and filters, filter
Cake is washed with methanol (30mL × 3).Filtrate is collected, is concentrated under reduced pressure, concentrate is poured into 100mL water, ethyl acetate (80mL × 3)
Extraction, organic phase is collected, anhydrous sodium sulfate drying, solvent is removed under reduced pressure and obtains 3- amino -5- methoxy cyanophenyl solid 12.0g, received
Rate is 96.5%.
1H NMR(400MHz,Chloroform-d)δ:7.66(s,1H),7.47(s,1H),6.97(s,1H),6.22(s,
2H,3.88(s,3H)；ESI-MS,m/z:149.05[M+H]+。
E.3- the preparation of cyano group -5- methoxybenzenes -1- sulfonic acid chlorides
In there-necked flask, 3- amino -5- methoxy cyanophenyls (10.0g, 0.068mol) are dissolved in concentrated hydrochloric acid：Acetic acid=2.5:
In 1 (v/v) mixed solution (100mL), 0 DEG C is cooled to, the water (30mL) that natrium nitrosum (9.3g, 0.135mol) is added dropwise is molten
Liquid, insulation reaction 0.5h, obtains reserve liquid.
There-necked flask separately is taken, stannous chloride (13.4g, 0.135mol) is added in glacial acetic acid (30mL), control temperature is not high
In 15 DEG C, SO is passed through2Gas, above-mentioned reserve liquid, insulation reaction 1h is slowly added dropwise.Reaction finishes, and pours into frozen water and separates out admittedly
Body, filter, filter cake obtains 3- cyano group -5- methoxybenzene -1- sulfonic acid chloride white solid 14.0g with Gossypol recrystallized from chloroform, and yield is
89.8%.
1H NMR(400MHz,Chloroform-d)δ:7.89 (s, 1H), 7.72 (s, 1H), 7.49 (s, 1H), 3.97 (s,
3H)；ESI-MS,m/z:231.98[M+H]+。
Embodiment 8
A.3- the preparation of methoxyl group -5- nitrobenzoic acids
In there-necked flask, 3,5- dinitrobenzoic acids (30.0g, 0.141mol) are dissolved in dry DMSO (300mL), added
Enter sodium methoxide (38.2g, 0.707mol), react at room temperature 10h, then rise to 80 DEG C and continue to react 5h.Reaction finishes, and is cooled to room
Temperature, reaction solution is poured into frozen water, ethyl acetate (100mL × 2) carries miscellaneous, collection aqueous phase, watery hydrochloric acid tune pH=2, ethyl acetate
(200mL × 3) extract, and collect organic phase, anhydrous sodium sulfate drying, and evaporated under reduced pressure solvent obtains 3- methoxyl group -5- nitrobenzoic acids
Solid 25.1g, yield 89.8%.
1H NMR(400MHz,Chloroform-d)δ:11.21(s,1H),8.12(s,1H),8.01(s,1H),7.85
(s,1H),3.89(s,1H)；ESI-MS,m/z:198.01[M+H]+。
B.3- the preparation of methoxyl group -5- nitrobenzamides
In there-necked flask, 3- methoxyl group -5- nitrobenzoic acids (25.0g, 0.127mol) are dissolved in dry THF
In (200mL), thionyl chloride (45.3g, 0.380mol) is added, 2 drip-dry dry DMF, back flow reaction 1h is added dropwise.Reaction finishes,
Be concentrated under reduced pressure reaction solution.At 0 DEG C~10 DEG C, concentrate is slowly added to 25% concentrated ammonia liquor (60.0g, 0.881mol) and THF
In the mixed liquor of (100mL), that is, there is solid generation.Filter, filter cake is eluted with water (50mL × 1), dry 3- methoxyl group -5- nitre
Yl-benzamide 23.5g, yield 94.4%.
1H NMR(400MHz,Chloroform-d)δ:8.28(s,1H),7.88(s,1H),7.49(s,2H),7.32(s,
1H),3.92(s,1H)；ESI-MS,m/z:197.16[M+H]+。
C.3- the preparation of methoxyl group -5- p-nitriles
In there-necked flask, 3- methoxyl group -5- nitrobenzamides (20.0g, 0.102mol) are dissolved in DMF (200mL),
- 15 DEG C are cooled to, POCl3 (78.2g, 0.510mol) is slowly added dropwise, -15 DEG C of reaction 0.5h, then reacts at room temperature 12h.Instead
It should finish, reaction solution is poured into frozen water, that is, separate out solid, filter, dry 3- methoxyl group -5- p-nitrile solid 16.1g,
Yield is 88.5%.
1H NMR(400MHz,Chloroform-d)δ:7.91(s,1H),7.72(s,1H),7.36(s,1H),4.08(s,
3H)；ESI-MS,m/z:179.05[M+H]+。
D.3- the preparation of amino -5- methoxy cyanophenyls
In there-necked flask, 3- methoxyl group -5- p-nitriles (15.0g, 0.084mol) are dissolved in methanol (150mL), added
Enter 10% palladium carbon (2.7g) and ammonium acetate (13.0g, 0.168mol), be passed through hydrogen, 40 DEG C of reaction 8h.Reaction finishes, and filters, filter
Cake is washed with methanol (30mL × 3).Filtrate is collected, is concentrated under reduced pressure, concentrate is poured into 100mL water, ethyl acetate (80mL × 3)
Extraction, organic phase is collected, anhydrous sodium sulfate drying, solvent is removed under reduced pressure and obtains 3- amino -5- methoxy cyanophenyl solid 12.1g, received
Rate is 96.7%.
1H NMR(400MHz,Chloroform-d)δ:7.66(s,1H),7.47(s,1H),6.97(s,1H),6.22(s,
2H,3.88(s,3H)；ESI-MS,m/z:149.05[M+H]+。
E.3- the preparation of cyano group -5- methoxybenzenes -1- sulfonic acid chlorides
In there-necked flask, 3- amino -5- methoxy cyanophenyls (10.0g, 0.068mol) are dissolved in concentrated hydrochloric acid：Acetic acid=2.5:
In 1 (v/v) mixed solution (100mL), 0 DEG C is cooled to, the water (30mL) that natrium nitrosum (7.0g, 0.101mol) is added dropwise is molten
Liquid, insulation reaction 0.5h, obtains reserve liquid.
There-necked flask separately is taken, stannous chloride (10.0g, 0.101mol) is added in glacial acetic acid (30mL), control temperature is not high
In 15 DEG C, SO is passed through2Gas, above-mentioned reserve liquid, insulation reaction 2h is slowly added dropwise.Reaction finishes, and pours into frozen water and separates out admittedly
Body, filter, filter cake obtains 3- cyano group -5- methoxybenzene -1- sulfonic acid chloride white solid 14.0g with Gossypol recrystallized from chloroform, and yield is
89.5%.
1H NMR(400 MHz,Chloroform-d)δ:7.89 (s, 1H), 7.72 (s, 1H), 7.49 (s, 1H), 3.97
(s,3H)；ESI-MS,m/z:231.98[M+H]+。
Claims (7)
- A kind of 1. preparation technology of 3- cyano group -5- methoxybenzene -1- sulfonic acid chlorides, it is characterised in that：Comprise the steps of：(1) with 3,5- dinitrobenzoic acids are raw material, are substituted reaction generation 3- methoxyl group -5- nitrobenzoic acids, (2) 3- methoxyl group -5- nitros Benzoic acid generates 3- methoxyl group -5- nitrobenzamides, the dehydration of (3) 3- methoxyl group -5- nitrobenzamides through amidation process 3- methoxyl group -5- p-nitriles are generated, (4) 3- methoxyl group -5- p-nitriles generate 3- amino -5- methoxybenzenes through reduction reaction Nitrile, (5) 3- amino -5- methoxy cyanophenyls through diazotising and sulfonylation obtain target compound 3- cyano group -5- methoxybenzenes - 1- sulfonic acid chlorides.
- A kind of 2. preparation technology of 3- cyano group -5- methoxybenzene -1- sulfonic acid chlorides according to claim 1, it is characterised in that： Intermediate is 3- methoxyl group -5- nitrobenzoic acids, 3- methoxyl group -5- nitrobenzamides, 3- methoxyl group -5- p-nitriles and 3- Amino -5- methoxy cyanophenyls.
- A kind of 3. preparation technology of 3- cyano group -5- methoxybenzene -1- sulfonic acid chlorides according to claim 1, it is characterised in that： Described (1) step reaction is that 1eq 3,5- dinitrobenzoic acids are dissolved in into dry DMSO, adds 2~8eq sodium methoxide, 50~120 DEG C are risen to after room temperature reaction and continues reaction generation 3- methoxyl group -5- nitrobenzoic acids.
- A kind of 4. preparation technology of 3,5- dimethyl -4- Fang isoxazoles according to claim 1, it is characterised in that：Institute (2) step reaction stated is that 1eq 3- methoxyl group -5- nitrobenzoic acids are dissolved in dry THF, adds 1~5eq protochlorides Sulfone, the DMF of the drying of catalytic amount, back flow reaction is added dropwise；Reaction finishes, and be concentrated under reduced pressure reaction solution；At 0~10 DEG C, it will concentrate Liquid adds 25% concentrated ammonia liquor：THF=25~85g：3- methoxyl group -5- nitrobenzamides are generated in 100mL mixed liquor.
- A kind of 5. preparation technology of 3,5- dimethyl -4- Fang isoxazoles according to claim 1, it is characterised in that：Institute (3) step reaction stated is that 1eq 3- methoxyl group -5- nitrobenzamides are dissolved in DMF, is cooled to -15~5 DEG C, slowly 4~6eq POCl3 is added dropwise, then insulation reaction is warmed to room temperature continues reaction generation 3- methoxyl group -5- p-nitriles.
- A kind of 6. preparation technology of 3,5- dimethyl -4- Fang isoxazoles according to claim 1, it is characterised in that：Institute (4) step reaction stated is that 1eq 3- methoxyl group -5- p-nitriles are dissolved in methanol, adds the 10% of 0.01~0.05eq The ammonium acetate of palladium carbon and 1~3eq, it is passed through hydrogen, 25~40 DEG C of reaction generation 3- amino -5- methoxy cyanophenyls.
- A kind of 7. preparation technology of 3,5- dimethyl -4- Fang isoxazoles according to claim 1, it is characterised in that：Institute (5) step reaction stated is that 1eq 3- amino -5- methoxy cyanophenyls are dissolved in into concentrated hydrochloric acid：Acetic acid=2.5:1 (v/v) mixing In solution, 0 DEG C is cooled to, 1~2eq sodium nitrite in aqueous solution is added dropwise, insulation reaction, obtains reserve liquid；Separately by 1~2eq chlorine Change in cuprous addition glacial acetic acid, control temperature is not higher than 15 DEG C, is passed through SO2Gas, above-mentioned reserve liquid, insulation reaction is slowly added dropwise Generate 3- cyano group -5- methoxybenzene -1- sulfonic acid chlorides.
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