CN103613549A - Afloqualone preparation method - Google Patents
Afloqualone preparation method Download PDFInfo
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- CN103613549A CN103613549A CN201310473405.2A CN201310473405A CN103613549A CN 103613549 A CN103613549 A CN 103613549A CN 201310473405 A CN201310473405 A CN 201310473405A CN 103613549 A CN103613549 A CN 103613549A
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- isatoic anhydride
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
- C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
Abstract
The present invention discloses a afloqualone preparation method, which comprises: adopting an isatin anhydride as a starting raw material, carrying out nitration, reduction and acetylation to synthesize a key intermediate N-(2-amino-5-acetylaminobenzoyl)o-toluidine, and then carrying out aminolysis, cyclization, fluorine exchange and deprotection to obtain the target product afloqualone. The afloqualone preparation method has characteristics of cheap and easily-available raw materials, production cost reduction, elimination of use of highly-toxic and highly-harmful reagent fluoroacetyl chloride in the existing literature method, safety and environmental protection. In addition, tetrabutyl ammonium bromide is adopted as the phase transfer catalyst of the fluorine exchange reaction so as to substantially improve the conversion rate of the fluorine exchange reaction, and the total yield of the target product afloqualone prepared from the starting raw material isatin anhydride can be more than 60.0%.
Description
(1) technical field
The present invention relates to a kind of 6-amino-2-methyl fluoride-3-(2-aminomethyl phenyl)-4(3H) preparation method of-quinazoline ketone (abbreviation afloqualone), particularly a kind ofly take isatoic anhydride and prepare the method for afloqualone as starting raw material.
(2) background technology
Afloqualone nineteen eighty-three, by day Honda limit, Co., Ltd. developed in Japanese Initial Public Offering, through the clinical application of two more than ten years, proved the relaxant that there is good efficacy on an opposite, musculi colli spasm.As muscle relaxant, afloqualone Main Function makes the hyperfunction state of muscular tone alleviate compared with position widely in the upper maincenter of ridge.Its maincenter muscle relaxant activities is approximately 22-29 times of mephenesin, is 8-10 times of chlormezanone.Compare with known muscle relaxant, side effect and the toxicity of afloqualone are all less, have good security.
Before the present invention provides, the main synthetic method of afloqualone:
1) US3966731 has reported and take N-(2-amino-5-nitro benzoyl) Ortho Toluidine is raw material; after elder generation and fluoro-acetic chloride condensation, under acetic anhydride effect, cyclization generates 6-nitro-2-methyl fluoride-3-(2-aminomethyl phenyl again)-4(3H)-1; 3-phthalazone, finally under Pd-C katalysis, hydro-reduction obtains afloqualone.Reaction process route is as Fig. 1.
This technique total recovery reaches 66.6%, but this technique has been used fluoro-acetic chloride, and this compound boiling point is low, and toxicity is large, corrodibility is large and expensive, not yet industrialization at present.
2) JP51105083 has reported and take N-(2-amino-5-nitro benzoyl) Ortho Toluidine is raw material; first generate 2-chloromethyl-3-(2-aminomethyl phenyl with the direct cyclization of chloroacetyl chloride)-6-nitro-4 (3H)-quinazolinone, then carries out fluorine exchange and reduction reaction and generates the finished product afloqualone.Reaction process route is as Fig. 2.
This technique total recovery 41.1%, chloroacetyl chloride substitutes fluoro-acetic chloride for this method, operate safer, but in this technique is carried out to proof procedure, find that crucial fluorine exchange step nitro also can be replaced by fluorine simultaneously, cause this step reaction yield very low, production cost is high.
3) JP51105082 has reported that take N-(2-amino-5-nitro benzoyl) Ortho Toluidine is raw material, first with chloroacetyl chloride cyclization, then carries out upper protection after nitroreduction, then carries out fluorine exchange and hydrolysis deprotection obtains the finished product afloqualone.Reaction process route is as Fig. 3.
This technique total recovery 28%, this method is used chloroacetyl chloride replacement fluorine Acetyl Chloride 98Min. equally, but not only increased fluorine permutoid reaction, has also increased upper protection and deprotection reaction, and reactions steps is many, and total recovery is lower, and cost is high.This technique is carried out finding to find dechlorination phenomenon in the logical During Hydrogen Reducing of Pd-C in proof procedure, cause the yield of this step reaction very low.As shown in Figure 4.
(3) summary of the invention
The object of the present invention is to provide that a kind of reaction conditions is gentle, easy and simple to handle, product yield is high, production cost is low, the preparation method of the afloqualone of green safety.
For achieving the above object, the technical solution used in the present invention is:
A preparation method for afloqualone, comprises the steps:
(1), isatoic anhydride 1 is dissolved in the vitriol oil that mass concentration is 95%-98%, in 0-10 ℃, slowly drip nitrating agent, drip off rear insulation reaction 0.5-2h, reaction solution slowly pours in mixture of ice and water, separate out yellow solid, suction filtration, washing, vacuum-drying obtain 5-nitro isatoic anhydride 2; Described isatoic anhydride 1 feeds intake amount of substance than being 1:1.1-1.3 with nitrating agent;
(2), 5-nitro isatoic anhydride 2, organic solvent A and Raney's nickel are added in autoclave, it is 0.5-2.0MPa that logical hydrogen maintains still internal pressure, stir and be warming up to 30-80 ℃ of reaction 0.5-4h, filtered and recycled Raney's nickel, in filtrate, directly add diacetyl oxide, under room temperature, continue stirring reaction 0.5-2h, concentrating under reduced pressure reclaims solvent, and residue obtains 5-kharophen isatoic anhydride 3 through vacuum-drying; Described 5-nitro isatoic anhydride 2 is 1:0.03-0.08 with the mass ratio that feeds intake of Raney's nickel; 5-nitro isatoic anhydride 2 feeds intake amount of substance than being 1:1.0-1.2 with diacetyl oxide;
(3), 5-kharophen isatoic anhydride 3 is dissolved in organic solvent B, add Ortho Toluidine, in 50-110 ℃, react 3-5h, concentrating under reduced pressure reclaims solvent and excessive Ortho Toluidine, and residue obtains N-(2-amino-5-kharophen benzoyl through vacuum-drying) Ortho Toluidine 4; Described 5-kharophen isatoic anhydride 3 feeds intake amount of substance than being 1:1.0-1.5 with Ortho Toluidine;
(4), by N-(2-amino-5-kharophen benzoyl) Ortho Toluidine 4 is dissolved in Glacial acetic acid, under stirring at room, slowly drip chloroacetyl chloride, after dropwising, stir and temperature rising reflux reaction 1-5h, be evaporated to dry, residue obtains 6-acetylaminohydroxyphenylarsonic acid 2-chloromethyl-3-(2-aminomethyl phenyl through vacuum-drying)-4(3H)-quinazoline ketone 5; Described N-(2-amino-5-kharophen benzoyl) Ortho Toluidine 4 is 1:0.9-1.1 with the amount of substance ratio that feeds intake of chloroacetyl chloride;
(5), by 6-acetylaminohydroxyphenylarsonic acid 2-chloromethyl-3-(2-aminomethyl phenyl)-4(3H)-1,3-phthalazone 5 is dissolved in organic solvent C, the Potassium monofluoride that adds again existing baking to activate, stirring and refluxing reaction 1-5h under the effect of quaternary ammonium salt phase transfer catalyst, reaction finishes to obtain 6-acetylaminohydroxyphenylarsonic acid 2-methyl fluoride-3-(2-aminomethyl phenyl by separation and purification)-4(3H)-quinazoline ketone 6; Described 6-acetylaminohydroxyphenylarsonic acid 2-chloromethyl-3-(2-aminomethyl phenyl)-4(3H)-quinazoline ketone 5 is 1:3.0-5.0:0.1-0.2 with the amount of substance ratio that feeds intake of Potassium monofluoride, quaternary ammonium salt phase transfer catalyst;
(6), by 6-acetylaminohydroxyphenylarsonic acid 2-methyl fluoride-3-(2-aminomethyl phenyl)-4(3H)-1,3-phthalazone 6 is put in the alcohol-water mixing solutions of NaOH, be warming up to 40-80 ℃ of stirring reaction 1-3h, reaction finishes rear first decompression recycling ethanol, and water layer is used dichloromethane extraction again, and organic layer is evaporated to dry, gained residue is through Virahol recrystallization, after vacuum-drying, obtain 6-amino-2-methyl fluoride-3-(2-aminomethyl phenyl)-4(3H)-quinazoline ketone 7, i.e. afloqualone.
In preparation method's step (1) of afloqualone of the present invention, the consumption of the described vitriol oil is counted 3-6mL/g with the quality of isatoic anhydride 1; Described nitrating agent is selected from concentrated nitric acid or nitrosonitric acid; The concentrated nitric acid that preferred described nitrating agent is 65wt%-68wt%.
In step of the present invention (2), described organic solvent A is selected from the mixed solvent of acetonitrile, tetrahydrofuran (THF), DMF, N,N-dimethylacetamide or their arbitrary proportions; Preferred described organic solvent A is tetrahydrofuran (THF); The add-on of described organic solvent A is counted 10-15mL/g with the quality of 5-nitro isatoic anhydride 2; Preferred described 5-nitro isatoic anhydride 2 is 1:0.03-0.05 with the mass ratio that feeds intake of Raney's nickel; Preferably 5-nitro isatoic anhydride 2 is 1:1.0-1.1 with the amount of substance ratio that feeds intake of diacetyl oxide.
In step of the present invention (3), described organic solvent B is selected from the alcohol of acetonitrile, tetrahydrofuran (THF), C1-C4 or the mixed solvent of their arbitrary proportions; Preferred described organic solvent B is ethanol; The add-on of described machine solvent B is counted 4-6mL/g with the quality of 5-kharophen isatoic anhydride 3; Preferred described 5-kharophen isatoic anhydride 3 feeds intake amount of substance than being 1:1.1-1.3 with Ortho Toluidine.
In step of the present invention (4), the add-on of described Glacial acetic acid is in N-(2-amino-5-kharophen benzoyl) quality of Ortho Toluidine 4 counts 4-6mL/g; Preferred described N-(2-amino-5-kharophen benzoyl) Ortho Toluidine 4 is 1:0.95-1.05 with the amount of substance ratio that feeds intake of chloroacetyl chloride.
In step of the present invention (5), described organic solvent C is selected from the mixed solvent of DMF, oil of mirbane, tetramethylene sulfone, acetonitrile, cyanobenzene or their arbitrary proportions; Preferred described organic solvent C is acetonitrile; The add-on of described organic solvent C is with 6-acetylaminohydroxyphenylarsonic acid 2-chloromethyl-3-(2-aminomethyl phenyl)-4(3H) quality of-quinazoline ketone 5 counts 4-6mL/g; Described quaternary ammonium salt phase transfer catalyst is selected from phenyl trimethylammonium bromide, phenyl trimethyl ammonium chloride, benzyl triethyl ammonium bromide, cetyl trimethylammonium bromide, Tetrabutyl amonium bromide or tetrabutylammonium chloride; Preferred described quaternary ammonium salt phase transfer catalyst is Tetrabutyl amonium bromide; Preferred described 6-acetylaminohydroxyphenylarsonic acid 2-chloromethyl-3-(2-aminomethyl phenyl)-4(3H)-quinazoline ketone 5 is 1:3.0-3.5:0.1-0.15 with the amount of substance ratio that feeds intake of Potassium monofluoride, quaternary ammonium salt phase transfer catalyst.
In step of the present invention (5), the method of described separation and purification is: reaction finishes rear reaction solution and is evaporated to dry, add methylene dichloride, the Potassium monofluoride that filtered and recycled is excessive, filtrate concentrates gained crude product ethyl alcohol recrystallization, vacuum-drying obtains 6-acetylaminohydroxyphenylarsonic acid 2-methyl fluoride-3-(2-aminomethyl phenyl)-4(3H)-quinazoline ketone 6.
In step of the present invention (6), the solvent of the alcohol-water mixing solutions of described NaOH is the mixing solutions of ethanol, water volume ratio proportioning 1:0.4-0.6; In the alcohol-water mixing solutions of described NaOH, the mass concentration of NaOH is 4%-8%; Described 6-acetylaminohydroxyphenylarsonic acid 2-methyl fluoride-3-(2-aminomethyl phenyl)-4(3H)-quinazoline ketone 6 is 1:1.5-2.0 with the amount of substance ratio that feeds intake of NaOH.
Compared with prior art, positively effect of the present invention is take that isatoic anhydride cheap and easy to get is as the synthetic key intermediate N-(2-amino-5-kharophen benzoyl of starting raw material) Ortho Toluidine, greatly reduce production cost.The use of having got rid of the high evil of high poison reagent fluoro-acetic chloride in existing literature method, has advantages of safety, environmental protection.In fluorine permutoid reaction, use Tetrabutyl amonium bromide as the phase-transfer catalyst of reaction, greatly improved the transformation efficiency of this step reaction.The total recovery of being prepared target product afloqualone by starting raw material isatoic anhydride can reach more than 60.0%.
(4) accompanying drawing explanation
Fig. 1 is the reaction process route of the synthetic afloqualone of US3966731 report;
Fig. 2 is the reaction process route of the synthetic afloqualone of JP51105083 report;
Fig. 3 is the reaction process route of the synthetic afloqualone of JP51105082 report;
Fig. 4 is that in the reaction process route of synthetic afloqualone of JP51105082 report, Pd-C leads to hydrogen reduction reaction process.
(5) embodiment:
With specific embodiment, be used for further illustrating technical scheme of the present invention below, but protection scope of the present invention is not limited to this:
Embodiment 1
Synthesizing of 5-nitro isatoic anhydride 2
In 250mL there-necked flask, add the vitriol oil (100mL), under mechanical stirring, in the time of 0-10 ℃, slowly add isatoic anhydride 1 (30.0g, 0.18mol), after stirring and dissolving, drip 65% concentrated nitric acid (21.4g, 0.22mol), holding temperature 0-10 ℃, 1h dropwises, and insulation continues reaction 1h, stop stirring, reaction solution is slowly poured in 300mL mixture of ice and water, stirred 20min, solid is fully separated out, filter, washing, obtains 5-nitro isatoic anhydride 2 (37.5g, yield: 97.9%) after being dried.M.p.264.8-265.5 ℃; It is that 98.4%(moving phase is acetonitrile that HPLC measures purity: 20mmol/L KH
2pO
4the aqueous solution (pH3.25)=30:70, V/V).
Synthesizing of 5-nitro isatoic anhydride 2
In 250mL there-necked flask, add the vitriol oil (100mL), under mechanical stirring, in the time of 0-10 ℃, slowly add isatoic anhydride 1 (30.0g, 0.18mol), after stirring and dissolving, drip 98% nitrosonitric acid (14.2g, 0.22mol), holding temperature 0-5 ℃, 1h dropwises, and insulation continues reaction 1h, stop stirring, reaction solution is slowly poured in 300mL mixture of ice and water, stirred 20min, solid is fully separated out, filter, washing, obtains 5-nitro isatoic anhydride 2 (37.0g, yield: 96.6%) after being dried.M.p.263.8-265.3 ℃; It is that 97.2%(moving phase is acetonitrile that HPLC measures purity: 20mmol/L KH
2pO
4the aqueous solution (pH3.25)=30:70, V/V).
Embodiment 3
Synthesizing of 5-kharophen isatoic anhydride 3
In 500mL autoclave, add successively 5-nitro isatoic anhydride 2 (20.0g, 96.0mmol), tetrahydrofuran (THF) (200mL), Raney's nickel (1.00g, purchase is from Aladdin reagent (Shanghai) Co., Ltd., article No. is R111435, specification is 500g, 20-40 order, other embodiment of this specification sheets Raney's nickel used is identical therewith), first use nitrogen replacement air three times, after checking resistance to air loss, use again hydrogen exchange nitrogen three times, it is 2.0Mpa that logical hydrogen maintains pressure, at 60 ℃, react 2h, stopped reaction, filtering Raney's nickel, at ambient temperature, in filtrate, add aceticanhydride (9.79g, 96.0mmol), concentrating under reduced pressure after stirring reaction 1h, the dry 5-kharophen isatoic anhydride 3 (20.1g that obtain, yield: 95.0%).M.p.215.1-216.0 ℃; It is that 98.0%(moving phase is acetonitrile that HPLC measures purity: 20mmol/L KH
2pO
4the aqueous solution (pH3.25)=50:50, V/V).
Embodiment 4
Synthesizing of 5-kharophen isatoic anhydride 3
In 500mL autoclave, add successively 5-nitro isatoic anhydride 2 (20.0g, 96.0mmol), acetonitrile (200mL), Raney's nickel (0.80g), first use nitrogen replacement air three times, after checking resistance to air loss, use hydrogen exchange nitrogen three times, it is 1.0Mpa that logical hydrogen maintains pressure, at 50 ℃, reacts 4h again, stopped reaction, filtering Raney's nickel at ambient temperature, adds aceticanhydride (9.79g in filtrate, 96.0mmol), concentrating under reduced pressure after stirring reaction 1h, dry 5-kharophen isatoic anhydride 3 (19.9g, the yield: 94.0%) of obtaining.M.p.214.5-215.9 ℃; It is that 97.0%(moving phase is acetonitrile that HPLC measures purity: 20mmol/L KH
2pO
4the aqueous solution (pH3.25)=50:50, V/V).
Embodiment 5
N-(2-amino-5-kharophen benzoyl) Ortho Toluidine 4 is synthetic
In 100mL there-necked flask, add successively 5-kharophen isatoic anhydride 3 (8.00g; 36.3mmol); Ortho Toluidine (4.27g; 39.9mmol), ethanol (40mL), temperature rising reflux reaction 4h; react complete; be cooled to room temperature, concentrating under reduced pressure reclaims ethanol and obtains N-(2-amino-5-kharophen benzoyl) Ortho Toluidine 4 (9.79g, yield: 95.0%).M.p.209.6-210.9 ℃; It is that 98.8%(moving phase is acetonitrile that HPLC measures purity: 20mmol/L KH
2pO
4the aqueous solution (pH3.25)=25:75, V/V).
Embodiment 6
N-(2-amino-5-kharophen benzoyl) Ortho Toluidine 4 is synthetic
In 100mL there-necked flask, add successively 5-kharophen isatoic anhydride 3 (8.00g; 36.3mmol); Ortho Toluidine (5.05g; 47.2mmol), tetrahydrofuran (THF) (40mL), temperature rising reflux reaction 4h; react complete; be cooled to room temperature, concentrating under reduced pressure reclaims tetrahydrofuran (THF) and obtains N-(2-amino-5-kharophen benzoyl) Ortho Toluidine 4 (9.70g, yield: 94.2%).M.p.208.9-210.9 ℃; It is that 97.8%(moving phase is acetonitrile that HPLC measures purity: 20mmol/L KH
2pO
4the aqueous solution (pH3.25)=25:75, V/V).
Embodiment 7
6-acetylaminohydroxyphenylarsonic acid 2-chloromethyl-3-(2-aminomethyl phenyl)-4(3H)-quinazoline ketone 5 is synthetic
In 100mL there-necked flask; add successively Glacial acetic acid (40mL), N-(2-amino-5-kharophen benzoyl) Ortho Toluidine 4 (8.00g; 28.3mmol); under stirring at room, slowly drip chloroacetyl chloride (3.20g; 28.3mmol); 20min dropwises; after stirring temperature rising reflux 4h; be cooled to room temperature; concentrating under reduced pressure reclaims Glacial acetic acid and obtains pale solid; dry 6-acetylaminohydroxyphenylarsonic acid 2-chloromethyl-3-(2-aminomethyl phenyl that obtains)-4(3H)-quinazoline ketone 5 (8.88g, yield: 92.0%).M.p.208.9-210.0 ℃; It is that 97.5%(moving phase is acetonitrile that HPLC measures purity: 20mmol/L KH
2pO
4the aqueous solution (pH3.25)=35:65, V/V).
Embodiment 8
6-acetylaminohydroxyphenylarsonic acid 2-chloromethyl-3-(2-aminomethyl phenyl)-4(3H)-quinazoline ketone 5 is synthetic
In 100mL there-necked flask; add successively Glacial acetic acid (40mL), N-(2-amino-5-kharophen benzoyl) Ortho Toluidine 4 (8.00g; 28.3mmol); under stirring at room, slowly drip chloroacetyl chloride (3.50g; 31.1mmol); 20min dropwises; after stirring temperature rising reflux 4h; be cooled to room temperature; concentrating under reduced pressure reclaims Glacial acetic acid and obtains pale solid; dry 6-acetylaminohydroxyphenylarsonic acid 2-chloromethyl-3-(2-aminomethyl phenyl that obtains)-4(3H)-quinazoline ketone 5 (8.69g, yield: 90.1%).M.p.208.5-210.0 ℃; It is that 96.5%(moving phase is acetonitrile that HPLC measures purity: 20mmol/L KH
2pO
4the aqueous solution (pH3.25)=35:65, V/V).
Embodiment 9
6-acetylaminohydroxyphenylarsonic acid 2-methyl fluoride-3-(2-aminomethyl phenyl)-4(3H)-quinazoline ketone 6 is synthetic
In bis-mouthfuls of round-bottomed flasks of 100mL, add successively 6-acetylaminohydroxyphenylarsonic acid 2-chloromethyl-3-(2-aminomethyl phenyl)-4(3H)-1,3-phthalazone 5 (7.50g, 22mmol), anhydrous acetonitrile (40mL), the existing Potassium monofluoride (3.83g activating that dries, 66mmol) with catalyzer Tetrabutyl amonium bromide (0.71g, 2.2mmol), after stirring and refluxing 4h, reaction is finished concentrating under reduced pressure and is reclaimed acetonitrile to dry, resistates adds 30mL methylene dichloride, the KF that filtered and recycled is excessive.Filtrate dichloromethane layer concentrating under reduced pressure obtains crude product.Add 20mL ethyl alcohol recrystallization to obtain 6-acetylaminohydroxyphenylarsonic acid 2-methyl fluoride-3-(2-aminomethyl phenyl)-4(3H)-quinazoline ketone 6 (6.45g, yield: 90.2%).M.p. 249.3-250.3 ℃; It is that 97.6%(moving phase is acetonitrile: 20mmol/LKH that HPLC measures purity
2pO
4the aqueous solution (pH3.25)=35:65, V/V).
Embodiment 10
6-acetylaminohydroxyphenylarsonic acid 2-methyl fluoride-3-(2-aminomethyl phenyl)-4(3H)-quinazoline ketone 6 is synthetic
In bis-mouthfuls of round-bottomed flasks of 100mL, add successively 6-acetylaminohydroxyphenylarsonic acid 2-chloromethyl-3-(2-aminomethyl phenyl)-4(3H)-1,3-phthalazone 5 (7.50g, 22mmol), anhydrous tetramethylene sulfone (40mL), the existing Potassium monofluoride (3.83g activating that dries, 66mmol) with catalyzer Tetrabutyl amonium bromide (0.71g, 2.2mmol), return stirring 4h, reaction is finished concentrating under reduced pressure and is reclaimed tetramethylene sulfone to dry, resistates adds 30mL methylene dichloride, the KF that filtered and recycled is excessive.Filtrate dichloromethane layer concentrating under reduced pressure obtains crude product.Add 20mL ethyl alcohol recrystallization to obtain 6-acetylaminohydroxyphenylarsonic acid 2-methyl fluoride-3-(2-aminomethyl phenyl)-4(3H)-quinazoline ketone 6 (6.30g, yield: 88.2%).M.p.249.3-250.3 ℃; It is that 97.1%(moving phase is acetonitrile that HPLC measures purity: 20mmol/L KH
2pO
4the aqueous solution (pH3.25)=35:65, V/V).
Embodiment 11
6-amino-2-methyl fluoride-3-(2-aminomethyl phenyl)-4(3H)-quinazoline ketone 7 is synthetic
In bis-mouthfuls of flasks of 100mL, add sodium hydroxide (0.92g, 23.0mmol), add again 7.50mL water and 15.0mL ethanol to make it to dissolve, finally add 6-acetylaminohydroxyphenylarsonic acid 2-methyl fluoride-3-(2-aminomethyl phenyl)-4(3H)-quinazoline ketone 6 (5.00g, 15.4mmol).At 70 ℃, stir after 2h, first concentrating under reduced pressure reclaims ethanol, and water layer is used dichloromethane extraction (20mL * 2) again.Merge organic layer, be evaporated to dry brown sticky oily matter, add 25mL Virahol recrystallization to obtain 6-amino-2-methyl fluoride-3-(2-aminomethyl phenyl)-4(3H)-quinazoline ketone 7 (3.86g, yield: 88.5%).M.p.194.5-195.5 ℃; It is that 99.3%(moving phase is acetonitrile that HPLC measures purity: 20mmol/L KH
2pO
4the aqueous solution (pH3.25)=35:65, V/V);
1h NMR (400MHz, DMSO-d
6): δ=2.01 (s, 3H), 4.81-5.02 (m, 2H), 5.85 (s, 2H), 7.15 (dd, J
1=2.8Hz, J
2=8.8Hz, 1H), 7.23 (d, J=2.8Hz, 1H), 7.35-7.44 (m, 4H), 7.51 (d, J=8.8Hz, 1H); MS (ESI): m/z (%)=284[M+H]
+.
Embodiment 12
6-amino-2-methyl fluoride-3-(2-aminomethyl phenyl)-4(3H)-quinazoline ketone 7 is synthetic
In bis-mouthfuls of flasks of 100mL, add sodium hydroxide (1.23g, 30.8mol), add again 7.50mL water and 15.0mL ethanol to make it to dissolve, finally add 6-acetylaminohydroxyphenylarsonic acid 2-methyl fluoride-3-(2-aminomethyl phenyl)-4(3H)-quinazoline ketone 6 (5.00g, 15.4mmol).At 70 ℃, stir after 2h, first concentrating under reduced pressure reclaims ethanol, and water layer is used dichloromethane extraction (20mL * 2) again.Merge organic layer, be evaporated to dry brown sticky oily matter, add 25mL Virahol recrystallization to obtain 6-amino-2-methyl fluoride-3-(2-aminomethyl phenyl)-4(3H)-quinazoline ketone 7 (3.71g, yield: 85.0%).M.p.194.2-195.7 ℃; It is that 99.0%(moving phase is acetonitrile that HPLC measures purity: 20mmol/L KH
2pO
4the aqueous solution (pH3.25)=35:65, V/V).
Claims (10)
1. a preparation method for afloqualone, is characterized in that, described preparation method comprises the steps:
(1), the isatoic anhydride shown in formula (1) is dissolved in the vitriol oil that mass concentration is 95%-98%, in 0-10 ℃, slowly drip nitrating agent, drip off rear insulation reaction 0.5-2h, reaction solution slowly pours in mixture of ice and water, separate out yellow solid, suction filtration, washing, vacuum-drying obtain the 5-nitro isatoic anhydride shown in formula (2); Described isatoic anhydride feeds intake amount of substance than being 1:1.1-1.3 with nitrating agent;
(2), 5-nitro isatoic anhydride, organic solvent A and Raney's nickel shown in formula (2) are added in autoclave, it is 0.5-2.0MPa that logical hydrogen maintains still internal pressure, stir and be warming up to 30-80 ℃ of reaction 0.5-4h, filtered and recycled Raney's nickel, in filtrate, directly add diacetyl oxide, under room temperature, continue stirring reaction 0.5-2h, concentrating under reduced pressure reclaims solvent, and residue obtains the 5-kharophen isatoic anhydride shown in formula (3) through vacuum-drying; The mass ratio that feeds intake of described 5-nitro isatoic anhydride and Raney's nickel is 1:0.03-0.08; 5-nitro isatoic anhydride feeds intake amount of substance than being 1:1.0-1.2 with diacetyl oxide;
(3), the 5-kharophen isatoic anhydride shown in formula (3) is dissolved in organic solvent B, add Ortho Toluidine, in 50-110 ℃, react 3-5h, concentrating under reduced pressure reclaims solvent and excessive Ortho Toluidine, and residue obtains the N-(2-amino-5-kharophen benzoyl shown in formula (4) through vacuum-drying) Ortho Toluidine; Described 5-kharophen isatoic anhydride feeds intake amount of substance than being 1:1.0-1.5 with Ortho Toluidine;
(4), by the N-(2-amino-5-kharophen benzoyl shown in formula (4)) Ortho Toluidine is dissolved in Glacial acetic acid, under stirring at room, slowly drip chloroacetyl chloride, after dropwising, stir and temperature rising reflux reaction 1-5h, be evaporated to dry, residue obtains the 6-acetylaminohydroxyphenylarsonic acid 2-chloromethyl-3-(2-aminomethyl phenyl shown in formula (5) through vacuum-drying)-4(3H)-quinazoline ketone; Described N-(2-amino-5-kharophen benzoyl) Ortho Toluidine is 1:0.9-1.1 with the amount of substance ratio that feeds intake of chloroacetyl chloride;
(5), by the 6-acetylaminohydroxyphenylarsonic acid 2-chloromethyl-3-(2-aminomethyl phenyl shown in formula (5))-4(3H)-1,3-phthalazone is dissolved in organic solvent C, the Potassium monofluoride that adds again existing baking to activate, stirring and refluxing reaction 1-5h under the effect of quaternary ammonium salt phase transfer catalyst, reaction finishes to obtain the 6-acetylaminohydroxyphenylarsonic acid 2-methyl fluoride-3-(2-aminomethyl phenyl shown in formula (6) by separation and purification)-4(3H)-quinazoline ketone; Described 6-acetylaminohydroxyphenylarsonic acid 2-chloromethyl-3-(2-aminomethyl phenyl)-4(3H)-quinazoline ketone is 1:3.0-5.0:0.1-0.2 with the amount of substance ratio that feeds intake of Potassium monofluoride, quaternary ammonium salt phase transfer catalyst;
(6), by the 6-acetylaminohydroxyphenylarsonic acid 2-methyl fluoride-3-(2-aminomethyl phenyl shown in formula (6))-4(3H)-1,3-phthalazone is put in the alcohol-water mixing solutions of NaOH, be warming up to 40-80 ℃ of stirring reaction 1-3h, reaction finishes rear first decompression recycling ethanol, water layer is used dichloromethane extraction again, organic layer is evaporated to dry, gained residue is through Virahol recrystallization, after vacuum-drying, obtain the 6-amino-2-methyl fluoride-3-(2-aminomethyl phenyl shown in formula (7))-4(3H)-1,3-phthalazone, i.e. afloqualone;
2. the preparation method of afloqualone as claimed in claim 1, is characterized in that in step (1), described nitrating agent is selected from concentrated nitric acid or nitrosonitric acid.
3. the preparation method of afloqualone as claimed in claim 1, is characterized in that in step (1), the consumption of the described vitriol oil is counted 3-6mL/g with the quality of isatoic anhydride; Described nitrating agent is the concentrated nitric acid of 65wt%-68wt%.
4. the preparation method of afloqualone as claimed in claim 1, is characterized in that, in step (2), described organic solvent A is selected from the mixed solvent of acetonitrile, tetrahydrofuran (THF), DMF, N,N-dimethylacetamide or their arbitrary proportions; The add-on of described organic solvent A is counted 10-15mL/g with the quality of 5-nitro isatoic anhydride.
5. the preparation method of afloqualone as claimed in claim 1, is characterized in that in step (3), and described organic solvent B is selected from the alcohol of acetonitrile, tetrahydrofuran (THF), C1-C4 or the mixed solvent of their arbitrary proportions; The add-on of described machine solvent B is counted 4-6mL/g with the quality of 5-kharophen isatoic anhydride.
6. the preparation method of afloqualone as claimed in claim 1, is characterized in that in step (4), and the add-on of described Glacial acetic acid is in N-(2-amino-5-kharophen benzoyl) quality of Ortho Toluidine counts 4-6mL/g.
7. the preparation method of afloqualone as claimed in claim 1, is characterized in that, in step (5), described organic solvent C is selected from the mixed solvent of DMF, oil of mirbane, tetramethylene sulfone, acetonitrile, cyanobenzene or their arbitrary proportions; The add-on of described organic solvent C is with 6-acetylaminohydroxyphenylarsonic acid 2-chloromethyl-3-(2-aminomethyl phenyl)-4(3H) quality of-quinazoline ketone counts 4-6mL/g.
8. the preparation method of afloqualone as claimed in claim 1, it is characterized in that, in step (5), described quaternary ammonium salt phase transfer catalyst is selected from phenyl trimethylammonium bromide, phenyl trimethyl ammonium chloride, benzyl triethyl ammonium bromide, cetyl trimethylammonium bromide, Tetrabutyl amonium bromide or tetrabutylammonium chloride.
9. the preparation method of afloqualone as claimed in claim 1, is characterized in that in step (6), and the solvent of the alcohol-water mixing solutions of described NaOH is the mixing solutions of ethanol, water volume ratio proportioning 1:0.4-0.6; In the alcohol-water mixing solutions of described NaOH, the mass concentration of NaOH is 4%-8%; Described 6-acetylaminohydroxyphenylarsonic acid 2-methyl fluoride-3-(2-aminomethyl phenyl)-4(3H)-quinazoline ketone is 1:1.5-2.0 with the amount of substance ratio that feeds intake of NaOH.
10. the preparation method of afloqualone as claimed in claim 1, it is characterized in that in step (5), the method of described separation and purification is: reaction finishes rear reaction solution and is evaporated to dry, add methylene dichloride, the Potassium monofluoride that filtered and recycled is excessive, filtrate concentrates gained crude product ethyl alcohol recrystallization, and vacuum-drying obtains the 6-acetylaminohydroxyphenylarsonic acid 2-methyl fluoride-3-(2-aminomethyl phenyl shown in formula (6))-4(3H)-quinazoline ketone.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106397338A (en) * | 2016-08-31 | 2017-02-15 | 安徽省润生医药股份有限公司 | High yield preparation method of afloqualone |
| CN106496144A (en) * | 2016-08-31 | 2017-03-15 | 安徽省润生医药股份有限公司 | A kind of synthesis technique of afloqualone |
| CN106496145A (en) * | 2016-08-31 | 2017-03-15 | 安徽省润生医药股份有限公司 | A kind of preparation method of afloqualone |
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| CN106496144A (en) * | 2016-08-31 | 2017-03-15 | 安徽省润生医药股份有限公司 | A kind of synthesis technique of afloqualone |
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