CN102002013B - Preparation method of 6-amino-7-fluoro-1,4-benzoxazine-3(4H)-ketone - Google Patents
Preparation method of 6-amino-7-fluoro-1,4-benzoxazine-3(4H)-ketone Download PDFInfo
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- CN102002013B CN102002013B CN2010102540839A CN201010254083A CN102002013B CN 102002013 B CN102002013 B CN 102002013B CN 2010102540839 A CN2010102540839 A CN 2010102540839A CN 201010254083 A CN201010254083 A CN 201010254083A CN 102002013 B CN102002013 B CN 102002013B
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- 0 C*OCC(COc(cc(c([N+]([O-])=O)c1)F)c1[N+]([O-])=O)=O Chemical compound C*OCC(COc(cc(c([N+]([O-])=O)c1)F)c1[N+]([O-])=O)=O 0.000 description 1
- ACRJQDSLPSTNBF-UHFFFAOYSA-N C=C(COc(c(N)c1)cc(F)c1N)O Chemical compound C=C(COc(c(N)c1)cc(F)c1N)O ACRJQDSLPSTNBF-UHFFFAOYSA-N 0.000 description 1
- GOSTWBRYGHVBQC-UHFFFAOYSA-N C=C(COc(c([N+]([O-])=O)c1)cc(F)c1[N+]([O-])=O)O Chemical compound C=C(COc(c([N+]([O-])=O)c1)cc(F)c1[N+]([O-])=O)O GOSTWBRYGHVBQC-UHFFFAOYSA-N 0.000 description 1
- HDCXZAXEAGQCOZ-UHFFFAOYSA-N CC(C[O](C)c(c(N)c1)cc(F)c1N)=O Chemical compound CC(C[O](C)c(c(N)c1)cc(F)c1N)=O HDCXZAXEAGQCOZ-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides a preparation method of 6-amino-7-fluoro-1,4-benzoxazine-3(4H)-ketone, which comprises the following steps: taking 2-(5-fluoro-2,4-dinitrobenzene oxygen) acetic acid as an initial raw material; carrying out hydrogenation reaction to generate 2-(5-fluoro-2,4-diaminobenzene oxygen) acetic acid; and then, carrying out cyclization reaction to obtain the 6-amino-7-fluoro-1,4-benzoxazine-3(4H)-ketone.
Description
Technical field
The present invention relates to the fluoro-Isosorbide-5-Nitrae-benzo of 6-amino-7-
The preparation method of piperazine-3 (4H)-one.
Background technology
Fluoro-Isosorbide-5-Nitrae-the benzo of 6-amino-7-
Piperazine-3 (4H)-one is a kind of important pesticide intermediate, for the preparation of weedicide flumioxazin (speed is received).The synthetic existing multiple synthetic method of flumioxazin, as Lyga, John W. etc., at Pesticide Science, summarize the synthetic of flumioxazin in 1999,55 (3), 281-287; As explained the fluoro-4-proyl-Isosorbide-5-Nitrae of 6-amino-7--benzo in U.S. Pat 5108488 and U.S. Pat 4640707
Piperazine-3 (4H)-one and the reaction of 3,4,5,6-tetrahydrophthalic anhydride make.Explained the fluoro-Isosorbide-5-Nitrae-benzo of 6-amino-7-in U.S. Pat 5238908 and U.S. Pat 5393735
Piperazine-3 (4H)-one and propargyl bromide obtain the fluoro-4-proyl-Isosorbide-5-Nitrae of 6-amino-7--benzo under the effect of sodium hydrogen
Piperazine-3 (4H)-one.
U.S. Pat 4803270 has been explained 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetic acid and ester hydrogenation under palladium/carbon or platinum/carbon catalysis obtains the fluoro-Isosorbide-5-Nitrae-benzo of 6-amino-7-
Piperazine-3 (4H)-one.Takemoto, Ichik etc. are at Bioscience Biotechnology and Biochemistry, 1994,58 (4), (5-fluoro-2 to have reported equally 2-in 788-789, the 4-2,4-dinitrophenoxy) acetic acid and ester thereof hydrogenation under palladium/carbon or platinum/carbon catalysis obtains the fluoro-Isosorbide-5-Nitrae-benzo of 6-amino-7-
Piperazine-3 (4H)-one.The method that these two pieces of documents are reported exists palladium/carbon or platinum/carbon consumption and the excessive problem of solvent load, is difficult to industrialization.
U.S. Pat 4803270,5238908 and European patent EP 237899 have reported that 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetic acid and ester thereof take iron powder and acetic acid as reductive agent is reduced and close ring, obtain the fluoro-Isosorbide-5-Nitrae-benzo of 6-amino-7-
Piperazine-3 (4H)-one.This method exists three wastes shortcoming large, that yield is lower also to be difficult for industrialization.
European patent EP 535613 has been reported 2-, and (5-fluoro-2, the 4-2,4-dinitrophenoxy) butylacetate take toluene as the additional methyl alcohol of main solvent and acetic acid be secondary solvent, a small amount of palladium/carbon of take under 60-70 ℃ of condition obtains the fluoro-Isosorbide-5-Nitrae-benzo of 6-amino-7-of high yield as the reaction of catalyzer hydro-reduction
Piperazine-3 (4H)-one.Exist product and palladium/carbon separation difficulty although this method yield is higher, solvent and palladium/carbon are difficult to the problem of recovery.
In sum, prior art is at the fluoro-Isosorbide-5-Nitrae-benzo of preparation 6-amino-7-
Have 3 deficiencies in the method for piperazine-3 (4H)-one: 1, technique is more complicated, and the industrialization difficulty is larger; 2, the more expensive or poor stability of raw material ratio; 3, reaction conversion ratio and product yield are lower.
Summary of the invention
In order to overcome deficiency of the prior art, inventors of the present invention develop one be easy to that industrialization, raw material are cheap and easy to get, reaction yield and the higher fluoro-Isosorbide-5-Nitrae-benzo of 6-amino-7-of product content
The preparation method of piperazine-3 (4H)-one.
The invention provides the fluoro-Isosorbide-5-Nitrae-benzo of 6-amino-7-
The preparation method of piperazine-3 (4H)-one (compound III) comprises and comprising the following steps:
With 2-, (5-fluoro-2, the 4-2,4-dinitrophenoxy) acetic acid is starting raw material, with 2-, (5-fluoro-2, the 4-2,4-dinitrophenoxy) acetic acid or its salt are the hydrogenation substrate, use hydrogen is hydrogenant agent, and under the existence of hydrogenation catalyst, (5-fluoro-2 to generate 2-through hydrogenation, 4-diaminobenzene oxygen) acetic acid or its salt, reaction formula is as follows:
Then remove by filter described hydrogenation catalyst, the pH value of filtrate be adjusted to 1-7, carry out ring-closure reaction, be shown below:
Gained solution is basified to the pH value for 8-10, makes the fluoro-Isosorbide-5-Nitrae-benzo of 6-amino-7-
Piperazine 3 (4H)-one.
According to an aspect of the present invention, wherein, the substrate of described hydrogenation can be 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetic acid or its salt, and suitable salt has sodium salt, sylvite, ammonium salt, organic amine salt; Particular certain cancers.
According to another aspect of the present invention, wherein, in described hydrogenation, use metal hydrogenation catalyst, described catalyzer can be the metal hydrogenation catalysts such as palladium/carbon, platinum/carbon, Raney's nickel, preferred palladium/carbon, the more preferably palladium/carbon of 1%-20% content, most preferably 5% palladium/carbon.Wherein, the consumption of described metal hydrogenation catalyst can be the 1%-50% of 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetic acid weight, preferably 10%-15%.
According to another aspect of the present invention, wherein, the hydrogen pressure in described hydrogenation can be 1-100kg/cm
2, preferred 10-50kg/cm
2, more preferably 20-30kg/cm
2
According to another aspect of the present invention, wherein, the temperature of reaction of described hydrogenation can be-20-100 ℃, preferably 10-50 ℃, more preferably 15-25 ℃.
According to another aspect of the present invention, wherein, described hydrogenation can carry out in any solvent that can be used for hydrogenation, and preferred solvent is tetrahydrofuran (THF), methyl alcohol, water and their mixture, the more preferably mixture of first alcohol and water.In the present invention, in the mixture of first alcohol and water used, the ratio of methyl alcohol and water is 10: 1-1: 3, be preferably 2: 1-1: 2.
According to another aspect of the present invention, wherein, described ring-closure reaction can carry out in acidity or neutrallty condition, under the condition that is 1-7 in the pH value, carries out, and preferably in the pH value, under the condition for 1-3, carries out.
According to another aspect of the present invention, wherein, can use acid to regulate the pH value of ring-closure reaction, preferably use strong acid to regulate the pH value of ring-closure reaction.Described strong acid is selected from one or more in the mineral acid such as hydrochloric acid, sulfuric acid, phosphoric acid or the organic acids such as trifluoroacetic acid, tosic acid, and preferred strong acid is sulfuric acid.
According to another aspect of the present invention, wherein, after ring-closure reaction, use at least one compound be selected from sodium bicarbonate, saleratus, sodium carbonate, salt of wormwood, ammoniacal liquor, triethylamine to be alkalized, preferably use sodium bicarbonate.
Adopt present method to prepare the fluoro-Isosorbide-5-Nitrae-benzo of 6-amino-7-
Piperazine-3 the most significant the advantage of (4H)-one is: technique is simple, reaction conditions relaxes and is easy to industrialization.Select raw material cheap and easy to get.Reaction yield is high.
Embodiment
Below in conjunction with embodiment, the present invention will be described, but the present invention is not limited to following embodiment.
Embodiment 1
Fluoro-Isosorbide-5-Nitrae-the benzo of 6-amino-7-
The preparation of piperazine-3 (4H)-one:
Hydrogenation: to adding 2-in the autoclave of 2L, (5-fluoro-2, the 4-2,4-dinitrophenoxy) acetic acid (60g, 0.23mol), the mixture that solvent system is methyl alcohol (300mL) and water (300mL), hydrogenation catalyst is 5%Pd/C (8g).Close autoclave, use vacuum and nitrogen (10kg/cm
2) displaced air 3-5 time.Keep hydrogen pressure at 20kg/cm
2Carry out hydrogenation under room temperature, in the present embodiment, the substrate of hydrogenation is 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetic acid.Hydrogenation carries out 8 hours, when hydrogen pressure remains unchanged in 30 minutes, can be considered as having reacted.
Ring-closure reaction: the mixture that will obtain in hydrogenation under nitrogen atmosphere filters, to remove Pd/C.In filtrate, add hydrochloric acid to adjust pH to 1, carry out ring-closure reaction under acidic conditions, stirring at room 1 hour, be basified to pH=8-10 with sodium bicarbonate, separates out the reddish-brown solid, filters, and drying, obtain title compound (37.3g, productive rate 80%), purity 90%.
Embodiment 2
Fluoro-Isosorbide-5-Nitrae-the benzo of 6-amino-7-
The preparation of piperazine-3 (4H)-one:
Hydrogenation: to adding 2-in the autoclave of 2L, (5-fluoro-2, the 4-2,4-dinitrophenoxy) acetic acid (60g, 0.23mol), the mixture that solvent system is methyl alcohol (300mL) and water (300mL), hydrogenation catalyst is 5%Pd/C (8g).Close autoclave, use vacuum and nitrogen (10kg/cm
2) displaced air 3-5 time.Keep hydrogen pressure at 30kg/cm
2, carry out hydrogenation under 10 ℃, in the present embodiment, the substrate of hydrogenation is 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetic acid.Hydrogenation carries out 8 hours, when hydrogen pressure remains unchanged in 30 minutes, can be considered as having reacted.
Ring-closure reaction: the mixture that will obtain in hydrogenation under nitrogen atmosphere filters, to remove Pd/C.In filtrate, add hydrochloric acid to adjust pH to 1, carry out ring-closure reaction under acidic conditions, stirring at room 1 hour, be basified to pH=8-10 with sodium bicarbonate, separates out the reddish-brown solid, filters, and drying, obtain title compound (36.8g, productive rate 79%), purity>92%.
Embodiment 3
Fluoro-Isosorbide-5-Nitrae-the benzo of 6-amino-7-
The preparation of piperazine-3 (4H)-one:
Hydrogenation: to adding 2-in the autoclave of 2L, (5-fluoro-2, the 4-2,4-dinitrophenoxy) acetic acid (60g, 0.23mol), the mixture that solvent system is methyl alcohol (300mL) and water (300mL), hydrogenation catalyst is 5%Pd/C (12g).Close autoclave, use vacuum and nitrogen (10kg/cm
2) displaced air 3-5 time.Keep hydrogen pressure at 20kg/cm
2, carry out hydrogenation under 20 ℃, in the present embodiment, the substrate of hydrogenation is 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetic acid.Hydrogenation carries out 8 hours, when hydrogen pressure remains unchanged in 30 minutes, can be considered as having reacted.
Ring-closure reaction: the mixture that will obtain in hydrogenation under nitrogen atmosphere filters, to remove Pd/C.In filtrate, add hydrochloric acid to adjust pH to 1, carry out ring-closure reaction under acidic conditions, stirring at room 1 hour, be basified to pH=8-10 with sodium bicarbonate, separates out the reddish-brown solid, filters, and drying, obtain title compound (39.6g, productive rate 85%), purity>96%.
Embodiment 4
Fluoro-Isosorbide-5-Nitrae-the benzo of 6-amino-7-
The preparation of piperazine-3 (4H)-one:
Hydrogenation: to adding 2-in the autoclave of 2L, (5-fluoro-2, the 4-2,4-dinitrophenoxy) acetic acid (60g, 0.23mol), the mixture that solvent system is tetrahydrofuran (THF) (300mL) and water (300mL), hydrogenation catalyst is 5%Pd/C (8g).Close autoclave, use vacuum and nitrogen (10kg/cm
2) displaced air 3-5 time.Keep hydrogen pressure at 30kg/cm
2, carry out hydrogenation under 20 ℃, in the present embodiment, the substrate of hydrogenation is 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetic acid.Hydrogenation carries out 8 hours, when hydrogen pressure remains unchanged in 30 minutes, can be considered as having reacted.
Ring-closure reaction: the mixture that will obtain in hydrogenation under nitrogen atmosphere filters, to remove Pd/C.In filtrate, add hydrochloric acid to adjust pH to 1, carry out ring-closure reaction under acidic conditions, stirring at room 1 hour, be basified to pH=8-10 with sodium bicarbonate, separates out the reddish-brown solid, filters, and drying, obtain title compound (32.6g, productive rate 70%), purity>86%.
Embodiment 5
Fluoro-Isosorbide-5-Nitrae-the benzo of 6-amino-7-
The preparation of piperazine-3 (4H)-one:
Hydrogenation: to adding 2-in the autoclave of 2L, (5-fluoro-2, the 4-2,4-dinitrophenoxy) acetic acid (60g, 0.23mol), the mixture that solvent system is tetrahydrofuran (THF) (300mL) and water (300mL), hydrogenation catalyst is 5%Pd/C (12g).Close autoclave, use vacuum and nitrogen (10kg/cm
2) displaced air 3-5 time.Keep hydrogen pressure at 20kg/cm
2, carry out hydrogenation under 20 ℃, in the present embodiment, the substrate of hydrogenation is 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetic acid.Hydrogenation carries out 8 hours, when hydrogen pressure remains unchanged in 30 minutes, can be considered as having reacted.
Ring-closure reaction: the mixture that will obtain in hydrogenation under nitrogen atmosphere filters, to remove Pd/C.In filtrate, add hydrochloric acid to adjust pH to 1, carry out ring-closure reaction under acidic conditions, stirring at room 1 hour, be basified to pH=8-10 with sodium bicarbonate, separates out the reddish-brown solid, filters, and drying, obtain title compound (37.8g, productive rate 81%), purity>93%.
Embodiment 6
Fluoro-Isosorbide-5-Nitrae-the benzo of 6-amino-7-
The preparation of piperazine-3 (4H)-one:
Hydrogenation: to adding 2-in the autoclave of 2L, (5-fluoro-2, the 4-2,4-dinitrophenoxy) acetic acid (60g, 0.23mol), the mixture that solvent system is methyl alcohol (300mL) and tetrahydrofuran (THF) (300mL), hydrogenation catalyst is 1%Pd/C (30g).Close autoclave, use vacuum and nitrogen (10kg/cm
2) displaced air 3-5 time.Keep hydrogen pressure at 10kg/cm
2, carry out hydrogenation under 100 ℃, in the present embodiment, the substrate of hydrogenation is 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetic acid.Hydrogenation carries out 8 hours, when hydrogen pressure remains unchanged in 30 minutes, can be considered as having reacted.
Ring-closure reaction: the mixture that will obtain in hydrogenation under nitrogen atmosphere filters, to remove Pd/C.In filtrate, add sulfuric acid to adjust pH to 3, carry out ring-closure reaction under acidic conditions, stirring at room 1 hour, be basified to pH=8-10 with sodium bicarbonate, separates out the reddish-brown solid, filters, and drying, obtain title compound (30.4g, productive rate 47%), purity>65%.
Embodiment 7
Fluoro-Isosorbide-5-Nitrae-the benzo of 6-amino-7-
The preparation of piperazine-3 (4H)-one:
Hydrogenation: to adding 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetic acid (60g, 0.23mol) in the autoclave of 2L, solvent system is tetrahydrofuran (THF) (600mL), and hydrogenation catalyst is 20%Pd/C (0.6g).Close autoclave, use vacuum and nitrogen (10kg/cm
2) displaced air 3-5 time.Keep hydrogen pressure at 50kg/cm
2, carry out hydrogenation under-20 ℃, in the present embodiment, the substrate of hydrogenation is 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetic acid.Hydrogenation carries out 8 hours, when hydrogen pressure remains unchanged in 30 minutes, can be considered as having reacted.
Ring-closure reaction: the mixture that will obtain in hydrogenation under nitrogen atmosphere filters, to remove Pd/C.In filtrate, add phosphoric acid to adjust pH to 5, carry out ring-closure reaction under acidic conditions, stirring at room 1 hour, be basified to pH=8-10 with sodium bicarbonate, separates out the reddish-brown solid, filters, and drying, obtain title compound (28.3g, productive rate 31%), purity>46%.
Embodiment 8
Fluoro-Isosorbide-5-Nitrae-the benzo of 6-amino-7-
The preparation of piperazine-3 (4H)-one:
Hydrogenation: to adding 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetic acid (60g, 0.23mol) in the autoclave of 2L, solvent system is methyl alcohol (600mL), and hydrogenation catalyst is 10%Pt/C (6g).Close autoclave, use vacuum and nitrogen (10kg/cm
2) displaced air 3-5 time.Keep hydrogen pressure at 30kg/cm
2, carry out hydrogenation under 50 ℃, in the present embodiment, the substrate of hydrogenation is 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetic acid.Hydrogenation carries out 8 hours, when hydrogen pressure remains unchanged in 30 minutes, can be considered as having reacted.
Ring-closure reaction: the mixture that will obtain in hydrogenation under nitrogen atmosphere filters, to remove Pd/C.In filtrate, add trifluoroacetic acid to adjust pH to 2, carry out ring-closure reaction under acidic conditions, stirring at room 1 hour, be basified to pH=8-10 with sodium bicarbonate, separate out the reddish-brown solid, filter drying, obtain title compound (39.5g, productive rate 93%), purity>99%.
Embodiment 9
Fluoro-Isosorbide-5-Nitrae-the benzo of 6-amino-7-
The preparation of piperazine-3 (4H)-one:
Hydrogenation: to adding 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetic acid (60g, 0.23mol) in the autoclave of 2L, solvent system is water (600mL), and hydrogenation catalyst is Raney's nickel (12g).Close autoclave, use vacuum and nitrogen (10kg/cm
2) displaced air 3-5 time.Keep hydrogen pressure at 100kg/cm
2, carry out hydrogenation under 15 ℃, in the present embodiment, the substrate of hydrogenation is 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetic acid.Hydrogenation carries out 8 hours, when hydrogen pressure remains unchanged in 30 minutes, can be considered as having reacted.
Ring-closure reaction: the mixture that will obtain in hydrogenation under nitrogen atmosphere filters, to remove Pd/C.In filtrate, add tosic acid to adjust pH to 4, carry out ring-closure reaction under acidic conditions, stirring at room 1 hour, be basified to pH=8-10 with sodium bicarbonate, separate out the reddish-brown solid, filter drying, obtain title compound (34.6g, productive rate 70%), purity>85%.
The result of embodiment 2-9 is referring to table 1.
Embodiment 10
Fluoro-Isosorbide-5-Nitrae-the benzo of 6-amino-7-
The preparation of piperazine-3 (4H)-one:
Hydrogenation: to adding 2-in the autoclave of 2L, (5-fluoro-2, the 4-2,4-dinitrophenoxy) acetic acid (60g, 0.23mol), sodium bicarbonate (19.4g, 0.23mol), the mixture that solvent system is methyl alcohol (500mL) and water (100mL), hydrogenation catalyst is 5%Pd/C (8g).Close autoclave, use vacuum and nitrogen (10kg/cm
2) displaced air 3-5 time.Keep hydrogen pressure at 20kg/cm
2Carry out hydrogenation under room temperature, in the present embodiment, the substrate of hydrogenation is 2-(5-fluoro-2,4-2,4-dinitrophenoxy) sodium acetate.Hydrogenation carries out 8 hours, when hydrogen pressure, remains unchanged in 30 minutes, can be considered as having reacted.
Ring-closure reaction: the mixture that will obtain in hydrogenation under nitrogen atmosphere filters, to remove Pd/C.In filtrate, add hydrochloric acid to adjust pH to 1, carry out ring-closure reaction under acidic conditions, stirring at room 1 hour, be basified to pH=8-10 with sodium bicarbonate, separates out the reddish-brown solid, filters, and drying, obtain title compound (37.2g, 85%), purity 96%.
Embodiment 11
Fluoro-Isosorbide-5-Nitrae-the benzo of 6-amino-7-
The preparation of piperazine-3 (4H)-one:
Hydrogenation: to adding 2-in the autoclave of 2L, (5-fluoro-2, the 4-2,4-dinitrophenoxy) acetic acid (60g, 0.23mol), sodium bicarbonate (19.4g, 0.23mol), the mixture that solvent system is methyl alcohol (400mL) and water (200mL), hydrogenation catalyst is 5%Pd/C (8g).Close autoclave, use vacuum and nitrogen (10kg/cm
2) displaced air 3-5 time.Keep hydrogen pressure at 30kg/cm
2, carry out hydrogenation under 10 ℃, in the present embodiment, the substrate of hydrogenation is 2-(5-fluoro-2,4-2,4-dinitrophenoxy) sodium acetate.Hydrogenation carries out 8 hours, when hydrogen pressure, remains unchanged in 30 minutes, can be considered as having reacted.
Ring-closure reaction: the mixture that will obtain in hydrogenation under nitrogen atmosphere filters, to remove Pd/C.In filtrate, add hydrochloric acid to adjust pH to 1, carry out ring-closure reaction under acidic conditions, stirring at room 1 hour, be basified to pH=8-10 with sodium bicarbonate, separates out the reddish-brown solid, filters, and drying, obtain title compound (36.3g, 83%), purity 96%.
Embodiment 12
Fluoro-Isosorbide-5-Nitrae-the benzo of 6-amino-7-
The preparation of piperazine-3 (4H)-one:
Hydrogenation: to adding 2-in the autoclave of 2L, (5-fluoro-2, the 4-2,4-dinitrophenoxy) acetic acid (60g, 0.23mol), sodium bicarbonate (19.4g, 0.23mol), the mixture that solvent system is methyl alcohol (200mL) and water (400mL), hydrogenation catalyst is 5%Pd/C (12g).Close autoclave, use vacuum and nitrogen (10kg/cm
2) displaced air 3-5 time.Keep hydrogen pressure at 20kg/cm
2, carry out hydrogenation under 20 ℃, in the present embodiment, the substrate of hydrogenation is 2-(5-fluoro-2,4-2,4-dinitrophenoxy) sodium acetate.Hydrogenation carries out 8 hours, when hydrogen pressure, remains unchanged in 30 minutes, can be considered as having reacted.
Ring-closure reaction: the mixture that will obtain in hydrogenation under nitrogen atmosphere filters, to remove Pd/C.In filtrate, add hydrochloric acid to adjust pH to 1, carry out ring-closure reaction under acidic conditions, stirring at room 1 hour, be basified to pH=8-10 with sodium bicarbonate, separates out the reddish-brown solid, filters, and drying, obtain title compound (39.4g, 90%), purity>97%.
Embodiment 13
Fluoro-Isosorbide-5-Nitrae-the benzo of 6-amino-7-
The preparation of piperazine-3 (4H)-one:
Hydrogenation: to adding 2-in the autoclave of 2L, (5-fluoro-2, the 4-2,4-dinitrophenoxy) acetic acid (60g, 0.23mol), sodium bicarbonate (19.4g, 0.23mol), the mixture that solvent system is tetrahydrofuran (THF) (300mL) and water (300mL), hydrogenation catalyst is 5%Pd/C (8g).Close autoclave, use vacuum and nitrogen (10kg/cm
2) displaced air 3-5 time.Keep hydrogen pressure at 30kg/cm
2, carry out hydrogenation under 20 ℃, in the present embodiment, the substrate of hydrogenation is 2-(5-fluoro-2,4-2,4-dinitrophenoxy) sodium acetate.Hydrogenation carries out 8 hours, when hydrogen pressure, remains unchanged in 30 minutes, can be considered as having reacted.
Ring-closure reaction: the mixture that will obtain in hydrogenation under nitrogen atmosphere filters, to remove Pd/C.In filtrate, add hydrochloric acid to adjust pH to 1, carry out ring-closure reaction under acidic conditions, stirring at room 1 hour, be basified to pH=8-10 with sodium bicarbonate, separates out the reddish-brown solid, filters, and drying, obtain title compound (32.8g, 75%), purity>90%.
Embodiment 14
Fluoro-Isosorbide-5-Nitrae-the benzo of 6-amino-7-
The preparation of piperazine-3 (4H)-one:
Hydrogenation: to adding 2-in the autoclave of 2L, (5-fluoro-2, the 4-2,4-dinitrophenoxy) acetic acid (60g, 0.23mol), sodium bicarbonate (19.4g, 0.23mol), the mixture that solvent system is tetrahydrofuran (THF) (300mL) and water (300mL), hydrogenation catalyst is 5%Pd/C (12g).Close autoclave, use vacuum and nitrogen (10kg/cm
2) displaced air 3-5 time.Keep hydrogen pressure at 20kg/cm
2, carry out hydrogenation under 20 ℃, in the present embodiment, the substrate of hydrogenation is 2-(5-fluoro-2,4-2,4-dinitrophenoxy) sodium acetate.Hydrogenation carries out 8 hours, when hydrogen pressure, remains unchanged in 30 minutes, can be considered as having reacted.
Ring-closure reaction: the mixture that will obtain in hydrogenation under nitrogen atmosphere filters, to remove Pd/C.In filtrate, add hydrochloric acid to adjust pH to 1, carry out ring-closure reaction under acidic conditions, stirring at room 1 hour, be basified to pH=8-10 with sodium bicarbonate, separates out the reddish-brown solid, filters, and drying, obtain title compound (36.8g, 84%), purity>93%.
Embodiment 15
Fluoro-Isosorbide-5-Nitrae-the benzo of 6-amino-7-
The preparation of piperazine-3 (4H)-one:
Hydrogenation: to adding 2-in the autoclave of 2L, (5-fluoro-2, the 4-2,4-dinitrophenoxy) acetic acid (60g, 0.23mol), saleratus (23.0g, 0.23mol), the mixture that solvent system is methyl alcohol (300mL) and tetrahydrofuran (THF) (300mL), hydrogenation catalyst is 1%Pd/C (30g).Close autoclave, use vacuum and nitrogen (10kg/cm
2) displaced air 3-5 time.Keep hydrogen pressure at 10kg/cm
2, carry out hydrogenation under 100 ℃, in the present embodiment, the substrate of hydrogenation is 2-(5-fluoro-2,4-2,4-dinitrophenoxy) potassium acetate.Hydrogenation carries out 8 hours, when hydrogen pressure, remains unchanged in 30 minutes, can be considered as having reacted.
Ring-closure reaction: the mixture that will obtain in hydrogenation under nitrogen atmosphere filters, to remove Pd/C.In filtrate, add sulfuric acid to adjust pH to 3, carry out ring-closure reaction under acidic conditions, stirring at room 1 hour, be basified to pH=8-10 with saleratus, separates out the reddish-brown solid, filters, and drying, obtain title compound (31.7g, 55%), purity>73%.
Embodiment 16
Fluoro-Isosorbide-5-Nitrae-the benzo of 6-amino-7-
The preparation of piperazine-3 (4H)-one:
Hydrogenation: to adding 2-in the autoclave of 2L, (5-fluoro-2, the 4-2,4-dinitrophenoxy) acetic acid (60g, 0.23mol), bicarbonate of ammonia (18.2g, 0.23mol), solvent system is tetrahydrofuran (THF) (600mL), and hydrogenation catalyst is 20%Pd/C (0.6g).Close autoclave, use vacuum and nitrogen (10kg/cm
2) displaced air 3-5 time.Keep hydrogen pressure at 50kg/cm
2, carry out hydrogenation under-20 ℃, in the present embodiment, the substrate of hydrogenation is 2-(5-fluoro-2,4-2,4-dinitrophenoxy) ammonium acetate.Hydrogenation carries out 8 hours, when hydrogen pressure, remains unchanged in 30 minutes, can be considered as having reacted.
Ring-closure reaction: the mixture that will obtain in hydrogenation under nitrogen atmosphere filters, to remove Pd/C.In filtrate, add phosphoric acid to adjust pH to 5, carry out ring-closure reaction under acidic conditions, stirring at room 1 hour, be basified to pH=8-10 with saleratus, separates out the reddish-brown solid, filters, and drying, obtain title compound (30.5g, 37%), purity>51%.
Embodiment 17
Fluoro-Isosorbide-5-Nitrae-the benzo of 6-amino-7-
The preparation of piperazine-3 (4H)-one:
Hydrogenation: to adding 2-in the autoclave of 2L, (5-fluoro-2, the 4-2,4-dinitrophenoxy) acetic acid (60g, 0.23mol), triethylamine (23.2g, 0.23mol), solvent system is methyl alcohol (150mL) and water (450mL), and hydrogenation catalyst is Pt/C (6g).Close autoclave, use vacuum and nitrogen (10kg/cm
2) displaced air 3-5 time.Keep hydrogen pressure at 30kg/cm
2, carry out hydrogenation under 50 ℃, in the present embodiment, the substrate of hydrogenation is 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetic acid triethylamine salt.Hydrogenation carries out 8 hours, when hydrogen pressure, remains unchanged in 30 minutes, can be considered as having reacted.
Ring-closure reaction: the mixture that will obtain in hydrogenation under nitrogen atmosphere filters, to remove Pd/C.In filtrate, add trifluoroacetic acid to adjust pH to 2, carry out ring-closure reaction under acidic conditions, stirring at room 1 hour, be basified to pH=8-10 with triethylamine, separates out the reddish-brown solid, filters, and drying, obtain title compound (38.6g, 90%), purity>98%.
Embodiment 18
Fluoro-Isosorbide-5-Nitrae-the benzo of 6-amino-7-
The preparation of piperazine-3 (4H)-one:
Hydrogenation: to adding 2-in the autoclave of 2L, (5-fluoro-2, the 4-2,4-dinitrophenoxy) acetic acid (60g, 0.23mol), sodium bicarbonate (19.4g, 0.23mol), solvent system is methyl alcohol (545mL) and water (55mL), and hydrogenation catalyst is Raney's nickel (12g).Close autoclave, use vacuum and nitrogen (10kg/cm
2) displaced air 3-5 time.Keep hydrogen pressure at 100kg/cm
2, carrying out hydrogenation under 15 ℃, then in the present embodiment, the substrate of hydrogenation is 2-(5-fluoro-2,4-2,4-dinitrophenoxy) sodium acetate.Hydrogenation carries out 8 hours, when hydrogen pressure, remains unchanged in 30 minutes, can be considered as having reacted.
Ring-closure reaction: the mixture that will obtain in hydrogenation under nitrogen atmosphere filters, to remove Pd/C.In filtrate, add tosic acid to adjust pH to 7, carry out ring-closure reaction under acidic conditions, stirring at room 1 hour, be basified to pH=8-10 with sodium bicarbonate, separates out the reddish-brown solid, filters, and drying, obtain title compound (34.3g, 66%), purity 81%.
The result of embodiment 10-18 is referring to table 2.
Although below describe in conjunction with specific embodiments the present invention in detail, scope of the present invention is not subject to the restriction of these specific embodiments.Those skilled in the art can make various modifications, changes and improvements and not deviate from the spirit and scope of the invention the above embodiment of the present invention.Therefore, all such modifications, changes and improvements are all in the scope of the application's claims.
Claims (22)
1.6-the fluoro-Isosorbide-5-Nitrae-benzo of amino-7-
Piperazine-3(4H) preparation method of-one comprises the following steps:
With 2-, (5-fluoro-2, the 4-2,4-dinitrophenoxy) acetic acid is starting raw material, with 2-, (5-fluoro-2, the 4-2,4-dinitrophenoxy) acetic acid or its salt are the hydrogenation substrate, use hydrogen is hydrogenant agent, and under the existence of metal hydrogenation catalyst, (5-fluoro-2 to generate 2-at the solvent for hydrogenation through hydrogenation, 4-diaminobenzene oxygen) acetic acid or its salt
Remove by filter described metal hydrogenation catalyst,
The pH value of filtrate is adjusted to 1-7, carries out ring-closure reaction,
By the solution after ring-closure reaction alkalize to the pH value be 8 – 10, make the fluoro-Isosorbide-5-Nitrae-benzo of 6-amino-7-
Piperazine-3(4H)-one.
2. preparation method as claimed in claim 1, wherein, the salt of described 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetic acid is sodium salt, sylvite, ammonium salt or the organic amine salt of 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetic acid.
3. preparation method as claimed in claim 1, wherein, the salt of described 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetic acid is the sodium salt of 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetic acid.
4. preparation method as claimed in claim 1, wherein, described metal hydrogenation catalyst is selected from palladium/carbon, platinum/carbon or Raney's nickel, the 1%-50% that described metal hydrogenation catalyst consumption is 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetic acid weight.
5. preparation method as claimed in claim 4, wherein, described metal hydrogenation catalyst is palladium/carbon.
6. preparation method as claimed in claim 4, wherein, described metal hydrogenation catalyst is 1%-20% palladium/carbon.
7. preparation method as claimed in claim 4, wherein, described metal hydrogenation catalyst is 5% palladium/carbon.
8. preparation method as claimed in claim 4, wherein, the 10%-15% that described metal hydrogenation catalyst consumption is 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetic acid weight.
9. preparation method as claimed in claim 1, wherein, in described hydrogenation, the pressure of hydrogen is 1-100kg/cm
2.
10. preparation method as claimed in claim 9, wherein, in described hydrogenation, the pressure of hydrogen is 10-50kg/cm
2.
11. preparation method as claimed in claim 9, wherein, in described hydrogenation, the pressure of hydrogen is 20-30kg/cm
2.
12. preparation method as claimed in claim 1, wherein, in described hydrogenation, the hydrogenation temperature is-20-100 ℃.
13. preparation method as claimed in claim 12, wherein, in described hydrogenation, the hydrogenation temperature is 10-50 ℃.
14. preparation method as claimed in claim 12, wherein, in described hydrogenation, the hydrogenation temperature is 15-25 ℃.
15. preparation method as described in claim 1, wherein, the described solvent for hydrogenation is selected from the mixture of any one or they of tetrahydrofuran (THF), methyl alcohol, water.
16. preparation method as described in claim 15, wherein, the mixture that the described solvent for hydrogenation is methanol/water.
17. preparation method as claimed in claim 15, wherein, in the mixture of described methanol/water, methyl alcohol and water volume ratio are 10:1-1:3.
18. preparation method as claimed in claim 15, wherein, in the mixture of described methanol/water, methyl alcohol and water volume ratio are 2:1-1:2.
19. preparation method as claimed in claim 1, wherein, be adjusted to 1 – 3 by the pH value of filtrate, carries out described ring-closure reaction.
20. preparation method as claimed in claim 1, wherein, in described ring-closure reaction, use strong acid for adjusting pH value, wherein, described strong acid is selected from one or more in hydrochloric acid, sulfuric acid or phosphoric acid.
21. preparation method as claimed in claim 20, wherein, described strong acid is sulfuric acid.
22. preparation method as claimed in claim 1, wherein, use one or more compounds that are selected from sodium bicarbonate, saleratus, sodium carbonate, salt of wormwood, ammoniacal liquor, triethylamine to carry out described alkalization.
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| RU2673237C2 (en) * | 2014-01-29 | 2018-11-23 | Сумитомо Кемикал Компани, Лимитед | Method of obtaining purified compound |
| CN103880771B (en) * | 2014-04-03 | 2016-03-16 | 北京颖泰嘉和生物科技股份有限公司 | The fluoro-4-proyl-Isosorbide-5-Nitrae-benzoxazine-3(4H of 6-amino-7-) preparation method of-one |
| CN103965181A (en) * | 2014-05-22 | 2014-08-06 | 黑龙江大学 | Preparation method of flumioxazin |
| CN104130128B (en) * | 2014-07-21 | 2016-08-24 | 浙江省诸暨合力化学对外贸易有限公司 | The synthetic method of phenoxy acetic acid ester and intermediate thereof |
| CN104610186B (en) * | 2015-02-05 | 2016-11-30 | 北京颖泰嘉和生物科技股份有限公司 | Purify method and the preparation method of flumioxazin of amino benzoxazinone crude product |
| CN110240545B (en) * | 2018-03-08 | 2022-04-26 | 迈克斯(如东)化工有限公司 | Preparation method of 2- (5-fluoro-2, 4-dinitrophenoxy) acetic acid |
| CN113912561B (en) * | 2021-11-04 | 2023-04-07 | 山东京博农化科技股份有限公司 | Synthetic method of 6-amino-7-fluoro-2H-1, 4-benzoxazine-3 (4H) -ketone |
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| US4803270A (en) * | 1986-03-10 | 1989-02-07 | Sumitomo Chemical Company, Limited | Process of producing fluoroaniline derivatives |
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| SU612932A1 (en) * | 1976-04-05 | 1978-06-30 | Предприятие П/Я А-7815 | 4-amino-2,3-dihydro-1,4-benzoxazine-3-ons as semiproducts for synthesis of 2-carboxymethoxyarylhydrazones and 1,5-di-(2-carboxymethoxyaryl) formazanes and method of obtaining same |
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| Ichiki Takemoto et al.Synthesis of a Fluorobenzoxazine Derivative and Its Analogues.《Biosci.Biotech.Biochem.》.1994,第58卷(第4期),788-789. * |
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