CN103613549A

Movatterモバイル変換

Info

Publication number: CN103613549A
Application number: CN201310473405.2A
Authority: CN
Inventors: 陈志卫; 苏为科; 徐盼云; 袁其亮; 王超; 陈寅镐
Original assignee: ZHEJIANG ZHONGXIN CHEMICALS CO Ltd; Zhejiang University of Technology ZJUT
Current assignee: ZHEJIANG ZHONGXIN CHEMICALS CO Ltd; Zhejiang University of Technology ZJUT
Priority date: 2013-10-11
Filing date: 2013-10-11
Publication date: 2014-03-05
Anticipated expiration: 2033-10-11
Also published as: CN103613549B

Abstract

Translated fromChinese

本发明公开了一种氟喹酮的制备方法，该方法以靛红酸酐为起始原料，首先经硝化、还原、乙酰化合成了关键中间体N-（2-氨基-5-乙酰氨基苯甲酰基）邻甲苯胺，再经氨解、环合、氟交换、脱保护得到目标产物氟喹酮；本发明氟喹酮的制备方法，原料廉价易得，降低了生产成本，革除了现有文献方法中高毒高害试剂氟代乙酰氯的使用，具有安全、环保的优点，同时在氟交换反应中使用四丁基溴化铵作为反应的相转移催化剂，大大提高了该步反应的转化率，由起始原料靛红酸酐制备目标产物氟喹酮的总收率可达60.0%以上。The invention discloses a preparation method of fluoroquinone. In the method, isatoic anhydride is used as a starting material, and the key intermediate N-(2-amino-5-acetylaminobenzidine is firstly synthesized through nitration, reduction and acetylation acyl) o-toluidine, and then through ammonolysis, cyclization, fluorine exchange, and deprotection to obtain the target product fluoroquinone; the preparation method of fluoroquinone of the present invention has cheap and easy-to-obtain raw materials, reduces production costs, and eliminates the existing literature The use of highly toxic and highly harmful reagent fluoroacetyl chloride in the method has the advantages of safety and environmental protection. At the same time, tetrabutylammonium bromide is used as a phase transfer catalyst in the fluorine exchange reaction, which greatly improves the conversion rate of this step. The total yield of the target product fluoroquinone from the starting material isatoic anhydride can reach more than 60.0%.

Description

A kind of preparation method of afloqualone

(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-nitroisatoic anhydride 2 is 1:0.03-0.08 with the mass ratio that feeds intake of Raney's nickel; 5-nitroisatoic 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 KH₂pO₄the aqueous solution (pH3.25)=30:70, V/V).

Embodiment 2

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 KH₂pO₄the 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 KH₂pO₄the 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 KH₂pO₄the 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 KH₂pO₄the 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 KH₂pO₄the 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 KH₂pO₄the aqueous solution (pH3.25)=35:65, V/V).

Embodiment 8

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 KH₂pO₄the 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 purity₂pO₄the aqueous solution (pH3.25)=35:65, V/V).

Embodiment 10

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 KH₂pO₄the 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 KH₂pO₄the aqueous solution (pH3.25)=35:65, V/V);¹h NMR (400MHz, DMSO-d₆): δ=2.01 (s, 3H), 4.81-5.02 (m, 2H), 5.85 (s, 2H), 7.15 (dd, J₁=2.8Hz, J₂=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

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 KH₂pO₄the aqueous solution (pH3.25)=35:65, V/V).

Claims

Translated fromChinese

1.一种氟喹酮的制备方法，其特征在于，所述制备方法包括如下步骤：1. a preparation method of fluoroquinone, is characterized in that, described preparation method comprises the steps:

（1）、将式（1）所示的靛红酸酐溶于质量浓度为95%-98%的浓硫酸中，于0-10℃内缓慢滴加硝化试剂，滴完后保温反应0.5-2h，反应液缓慢倾倒入冰水混合物中，析出黄色固体，抽滤、水洗、真空干燥得式（2）所示的5-硝基靛红酸酐；所述靛红酸酐与硝化试剂的投料物质的量比为1:1.1-1.3；(1) Dissolve the isatoic anhydride shown in formula (1) in concentrated sulfuric acid with a mass concentration of 95%-98%, slowly add the nitrating reagent dropwise at 0-10°C, and keep it warm for 0.5-2h after dropping , the reaction solution was slowly poured into a mixture of ice and water, and a yellow solid was precipitated, filtered with suction, washed with water, and dried in vacuum to obtain 5-nitroisatoic anhydride shown in formula (2); The amount ratio is 1:1.1-1.3;

（2）、将式（2）所示的5-硝基靛红酸酐、有机溶剂A及雷尼镍加入高压釜中，通氢气维持釜内压力为0.5-2.0MPa，搅拌并升温至30-80℃反应0.5-4h，过滤回收雷尼镍，滤液中直接加入乙酸酐，室温下继续搅拌反应0.5-2h，减压浓缩回收溶剂，残留物经真空干燥得式（3）所示的5-乙酰氨基靛红酸酐；所述5-硝基靛红酸酐与雷尼镍的投料质量比为1:0.03-0.08；5-硝基靛红酸酐与乙酸酐的投料物质的量比为1:1.0-1.2；(2) Add 5-nitroisatoic anhydride, organic solvent A and Raney nickel shown in formula (2) into the autoclave, pass hydrogen to maintain the pressure in the autoclave at 0.5-2.0MPa, stir and heat up to 30- React at 80°C for 0.5-4h, filter and recover Raney nickel, add acetic anhydride directly to the filtrate, continue to stir and react at room temperature for 0.5-2h, concentrate under reduced pressure to recover the solvent, and vacuum-dry the residue to obtain the 5- Acetylaminoisatoic anhydride; the mass ratio of 5-nitroisatoic anhydride and Raney nickel is 1:0.03-0.08; the mass ratio of 5-nitroisatoic anhydride and acetic anhydride is 1:1.0 -1.2;

（3）、将式（3）所示的5-乙酰氨基靛红酸酐溶于有机溶剂B中，加入邻甲苯胺，50-110℃内反应3-5h，减压浓缩回收溶剂和过量的邻甲苯胺，残留物经真空干燥得式（4）所示的N-（2-氨基-5-乙酰氨基苯甲酰基）邻甲苯胺；所述5-乙酰氨基靛红酸酐与邻甲苯胺的投料物质的量比为1:1.0-1.5；(3) Dissolve 5-acetylaminoisatoic anhydride represented by formula (3) in organic solvent B, add o-toluidine, react at 50-110°C for 3-5h, concentrate under reduced pressure to recover solvent and excess o-toluidine Toluidine, the residue is vacuum-dried to obtain N-(2-amino-5-acetamidobenzoyl) o-toluidine shown in formula (4); The amount ratio of substances is 1:1.0-1.5;

（4）、将式（4）所示的N-（2-氨基-5-乙酰氨基苯甲酰基）邻甲苯胺溶于冰醋酸中，室温搅拌下缓慢滴加氯乙酰氯，滴加完毕后，搅拌并升温回流反应1-5h，减压浓缩至干，残留物经真空干燥得式（5）所示的6-乙酰氨基-2-氯甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮；所述N-（2-氨基-5-乙酰氨基苯甲酰基）邻甲苯胺与氯乙酰氯的投料物质的量比为1:0.9-1.1；(4) Dissolve N-(2-amino-5-acetylaminobenzoyl) o-toluidine represented by formula (4) in glacial acetic acid, slowly add chloroacetyl chloride dropwise under stirring at room temperature, after the dropwise addition is completed , stirred and heated to reflux for 1-5h, concentrated to dryness under reduced pressure, and the residue was vacuum-dried to obtain 6-acetylamino-2-chloromethyl-3-(2-methylphenyl) represented by formula (5) -4(3H)-1,3-phthalazinone; the ratio of N-(2-amino-5-acetamidobenzoyl) o-toluidine to chloroacetyl chloride is 1:0.9 -1.1;

（5）、将式（5）所示的6-乙酰氨基-2-氯甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮溶于有机溶剂C中，再加入现烘活化过的氟化钾，在季铵盐相转移催化剂的作用下搅拌回流反应1-5h，反应结束后经分离纯化得到式（6）所示的6-乙酰氨基-2-氟甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮；所述6-乙酰氨基-2-氯甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮与氟化钾、季铵盐相转移催化剂的投料物质的量比为1:3.0-5.0:0.1-0.2；(5) Dissolve 6-acetamido-2-chloromethyl-3-(2-methylphenyl)-4(3H)-1,3-naphthyridine represented by formula (5) in In the organic solvent C, add freshly baked and activated potassium fluoride, and stir and reflux for 1-5 hours under the action of a quaternary ammonium salt phase transfer catalyst. After the reaction, separate and purify to obtain 6-acetyl Amino-2-fluoromethyl-3-(2-methylphenyl)-4(3H)-1,3-phthalazinone; the 6-acetylamino-2-chloromethyl-3-( The molar ratio of 2-methylphenyl)-4(3H)-1,3-naphthyridine to potassium fluoride and quaternary ammonium salt phase transfer catalyst is 1:3.0-5.0:0.1-0.2;

（6）、将式（6）所示的6-乙酰氨基-2-氟甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮投入到NaOH的乙醇-水混合溶液中，升温至40-80℃搅拌反应1-3h，反应结束后先减压回收乙醇，水层再用二氯甲烷萃取，有机层减压浓缩至干，所得残留物经异丙醇重结晶，真空干燥后得到式（7）所示的6-氨基-2-氟甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮，即氟喹酮；(6) Put 6-acetylamino-2-fluoromethyl-3-(2-methylphenyl)-4(3H)-1,3-naphthyridine represented by formula (6) into In the ethanol-water mixed solution of NaOH, heat up to 40-80°C and stir for 1-3h. After the reaction is completed, the ethanol is recovered under reduced pressure, the water layer is extracted with dichloromethane, the organic layer is concentrated to dryness under reduced pressure, and the obtained residue is Recrystallized from isopropanol and vacuum dried to obtain 6-amino-2-fluoromethyl-3-(2-methylphenyl)-4(3H)-1,3-diazepine represented by formula (7) Zinones, i.e. fluoroquinones;

2.如权利要求1所述的氟喹酮的制备方法，其特征在于步骤（1）中，所述硝化试剂选自浓硝酸或发烟硝酸。2. The preparation method of fluoroquinone according to claim 1, characterized in that in step (1), the nitrating reagent is selected from concentrated nitric acid or fuming nitric acid.

3.如权利要求1所述的氟喹酮的制备方法，其特征在于步骤（1）中，所述浓硫酸的用量以靛红酸酐的质量计为3-6mL/g；所述硝化试剂为65wt%-68wt%的浓硝酸。3. the preparation method of fluoroquinone as claimed in claim 1 is characterized in that in step (1), the consumption of described vitriol oil is counted as 3-6mL/g with the quality of isatoic anhydride; Described nitrating reagent is 65wt%-68wt% concentrated nitric acid.

4.如权利要求1所述的氟喹酮的制备方法，其特征在于步骤（2）中，所述有机溶剂A选自乙腈、四氢呋喃、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或它们任意比例的混合溶剂；所述有机溶剂A的加入量以5-硝基靛红酸酐的质量计为10-15mL/g。4. the preparation method of fluoroquinone as claimed in claim 1 is characterized in that in step (2), described organic solvent A is selected from acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N- Dimethylacetamide or their mixed solvents in any proportion; the added amount of the organic solvent A is 10-15mL/g based on the mass of 5-nitroisatoic anhydride.

5.如权利要求1所述的氟喹酮的制备方法，其特征在于步骤（3）中，所述有机溶剂B选自乙腈、四氢呋喃、C1-C4的醇或它们任意比例的混合溶剂；所述的机溶剂B的加入量以5-乙酰氨基靛红酸酐的质量计为4-6mL/g。5. the preparation method of fluoroquinone as claimed in claim 1 is characterized in that in step (3), described organic solvent B is selected from the alcohol of acetonitrile, tetrahydrofuran, C1-C4 or their mixed solvent of any proportion; The amount of the organic solvent B added is 4-6 mL/g based on the mass of 5-acetamido isatoic anhydride.

6.如权利要求1所述的氟喹酮的制备方法，其特征在于步骤（4）中，所述冰醋酸的加入量以N-（2-氨基-5-乙酰氨基苯甲酰基）邻甲苯胺计的质量计为4-6mL/g。6. The preparation method of fluoroquinone as claimed in claim 1, is characterized in that in step (4), the addition amount of described glacial acetic acid is N-(2-amino-5-acetylaminobenzoyl) o-methyl The mass of aniline meter is 4-6mL/g.

7.如权利要求1所述的氟喹酮的制备方法，其特征在于步骤（5）中，所述有机溶剂C选自N,N-二甲基甲酰胺、硝基苯、环丁砜、乙腈、苯甲腈或它们任意比例的混合溶剂；所述有机溶剂C的加入量以6-乙酰氨基-2-氯甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮的质量计为4-6mL/g。7. The preparation method of fluoroquinone as claimed in claim 1, characterized in that in step (5), the organic solvent C is selected from N,N-dimethylformamide, nitrobenzene, sulfolane, acetonitrile, Benzonitrile or their mixed solvents in any proportion; - The mass of phthalazinone is 4-6mL/g.

8.如权利要求1所述的氟喹酮的制备方法，其特征在于步骤（5）中，所述季铵盐相转移催化剂选自苯基三甲基溴化铵、苯基三甲基氯化铵、苄基三乙基溴化铵、十六烷基三甲基溴化铵、四丁基溴化铵或四丁基氯化铵。8. the preparation method of fluoroquinone as claimed in claim 1 is characterized in that in step (5), described quaternary ammonium salt phase-transfer catalyst is selected from phenyl trimethyl ammonium bromide, phenyl trimethyl chloride ammonium chloride, benzyltriethylammonium bromide, cetyltrimethylammonium bromide, tetrabutylammonium bromide or tetrabutylammonium chloride.

9.如权利要求1所述的氟喹酮的制备方法，其特征在于步骤（6）中，所述NaOH的乙醇-水混合溶液的溶剂是乙醇、水体积比配比1:0.4-0.6的混合溶液；所述NaOH的乙醇-水混合溶液中NaOH的质量浓度为4%-8%；所述6-乙酰氨基-2-氟甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮与NaOH的投料物质的量比为1:1.5-2.0。9. The preparation method of fluoroquinone as claimed in claim 1, characterized in that in step (6), the solvent of the ethanol-water mixed solution of NaOH is ethanol, water volume ratio ratio 1:0.4-0.6 Mixed solution; the mass concentration of NaOH in the ethanol-water mixed solution of NaOH is 4%-8%; the 6-acetylamino-2-fluoromethyl-3-(2-methylphenyl)-4( The ratio of 3H)-1,3-naphthyridine to NaOH is 1:1.5-2.0.

10.如权利要求1所述的氟喹酮的制备方法，其特征在于步骤（5）中，所述分离纯化的方法为：反应结束后反应液减压浓缩至干，加入二氯甲烷，过滤回收过量的氟化钾，滤液浓缩所得粗品用乙醇重结晶，真空干燥得式（6）所示的6-乙酰氨基-2-氟甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮。10. The preparation method of fluoroquinone as claimed in claim 1, characterized in that in step (5), the method of separation and purification is: after the reaction, the reaction solution is concentrated to dryness under reduced pressure, added dichloromethane, filtered Excess potassium fluoride was recovered, the filtrate was concentrated and the obtained crude product was recrystallized with ethanol, and dried in vacuo to obtain 6-acetylamino-2-fluoromethyl-3-(2-methylphenyl)-4( 3H)-1,3-Naphthyridine.