CN110215933A - A kind of preparation method of respiratory medicine object Ao Dateluo intermediate - Google Patents

A kind of preparation method of respiratory medicine object Ao Dateluo intermediate Download PDF

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CN110215933A
CN110215933A CN201910529179.2A CN201910529179A CN110215933A CN 110215933 A CN110215933 A CN 110215933A CN 201910529179 A CN201910529179 A CN 201910529179A CN 110215933 A CN110215933 A CN 110215933A
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phosphomolybdate
hydroxyl
benzyloxy
nitrate
ethyl ketone
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马海红
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
    • B01J27/14—Phosphorus; Compounds thereof
    • B01J27/186—Phosphorus; Compounds thereof with arsenic, antimony, bismuth, vanadium, niobium, tantalum, polonium, chromium, molybdenum, tungsten, manganese, technetium or rhenium
    • B01J27/188—Phosphorus; Compounds thereof with arsenic, antimony, bismuth, vanadium, niobium, tantalum, polonium, chromium, molybdenum, tungsten, manganese, technetium or rhenium with chromium, molybdenum, tungsten or polonium
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
    • B01J27/14—Phosphorus; Compounds thereof
    • B01J27/186—Phosphorus; Compounds thereof with arsenic, antimony, bismuth, vanadium, niobium, tantalum, polonium, chromium, molybdenum, tungsten, manganese, technetium or rhenium
    • B01J27/188—Phosphorus; Compounds thereof with arsenic, antimony, bismuth, vanadium, niobium, tantalum, polonium, chromium, molybdenum, tungsten, manganese, technetium or rhenium with chromium, molybdenum, tungsten or polonium
    • B01J27/19—Molybdenum
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups

Abstract

The invention belongs to pharmaceutical chemistry technical fields, and in particular to a kind of preparation method of respiratory medicine object Ao Dateluo intermediate.The present invention prepares phosphomolybdate/silica composite nano materials by sol-gel using phosphomolybdate and ethyl orthosilicate as raw material, then carries out sulfonation to it using chlorosulfonic acid and prepares sulfonated phosphomolybdate/silica composite nano materials；It can be used for being catalyzed 1- [2- hydroxyl -5- (benzyloxy) phenyl] ethyl ketone and carry out nitration reaction preparation Ao Dateluo intermediate 1- [2- hydroxyl -3- nitro -5- (benzyloxy) phenyl] ethyl ketone；Solves HNO3/CH3The big defect of waste acid quantity, green, pollution-free in COOH system nitration processes, and nitration reaction yield is up to 93.6%.

Description

A kind of preparation method of respiratory medicine object Ao Dateluo intermediate
Technical field
The invention belongs to pharmaceutical chemistry technical fields, and in particular to a kind of respiratory medicine object Ao Dateluo intermediate Preparation method.
Background technique
Ao Dateluo (Olodaterol) is 2 receptor agonism of a kind of long-acting beta developed by German Boehringer Ingelheim company Agent is ratified to list in July, 2014 through U.S. FDA, and trade name is: StriverdiRespimat, for treating chronic obstruction Property tuberculosis (COPD).
1- [2- hydroxyl -3- nitro -5- (benzyloxy) phenyl] ethyl ketone is the key intermediate for preparing Ao Dateluo, the chemical combination Object is prepared by 1- [2- hydroxyl -5- (benzyloxy) phenyl] ethyl ketone by nitration reaction.Reaction equation such as Scheme1 institute Show:
The nitration reaction mainly uses nitric acid for nitrating agent at present, reacts in acetic acid；Such as Bioorganic& Reaction achieves 74% yield at room temperature in 20 (2010) 1410-1414 of Medicinal Chemistry Letters； German Boehringer Ingelheim company uses HNO in 101208316 A of CN3/CH3COOH system has carried out feather weight production and has put Greatly, 87.2% yield is achieved, HPLC purity is 99.0%.Although yield increases in amplification process, HNO3/ CH3COOH system is strong to equipment corrosion and post-processing is using directly in HNO3/CH3Add elutriation crystalline substance, mistake in COOH system Lock out operation is filtered, causes to generate a large amount of acid waste waters in this way.Environmental Protection in China requires to be continuously improved at present, acid waste water processing cost It continues to increase, so such technique, which must improve, to go into operation.
Iranian scientist is in Journal of the Iranian Chemical Society, 2017,14 (2): 485- With magnetic Fe in 4902O3For core, by hull shape of silica at the magnetic material of core-shell structure, and sulfonic acid is introduced on the surface of the material The shell nuclear magnetism material of functional group's formation sulfonic acid functional；The material can be catalyzed sodium nitrate and carry out nitration to aromatic hydrocarbons, and can return Receipts are applied；The catalysis material has prevented the generation of acid waste water, environmentally protective.But inventor attempts to be catalyzed 1- using the material [2- hydroxyl -5- (benzyloxy) phenyl] ethyl ketone carries out nitration reaction and prepares Ao Dateluo intermediate 1- [2- hydroxyl -3- nitro - 5- (benzyloxy) phenyl] ethyl ketone when the substrate transformation rate be only 45% or so, do not have actual application prospect.
Summary of the invention
It is difficult to understand to prepare treatment chronic obstructive pulmonary disease drug that the object of the present invention is to provide a kind of environmentally protective methods The preparation method of Da Teluo intermediate 1- [2- hydroxyl -3- nitro -5- (benzyloxy) phenyl] ethyl ketone；The present invention with phosphomolybdate and Ethyl orthosilicate prepares phosphomolybdate/silica composite nano materials by sol-gel for raw material, then uses chlorosulfonic acid Sulfonation is carried out to it prepares sulfonated phosphomolybdate/silica composite nano materials；It can be used for being catalyzed 1- [2- hydroxyl -5- (benzyloxy) phenyl] ethyl ketone progress nitration reaction preparation Ao Dateluo intermediate 1- [2- hydroxyl -3- nitro -5- (benzyloxy) Phenyl] ethyl ketone；Solves HNO3/CH3The big defect of waste acid quantity, green, pollution-free in COOH system nitration processes, and nitrifies anti- Answer yield up to 93.6%.
According to an aspect of the present invention, the present invention provides a kind of sulfonated phosphomolybdate/silica composite Nanos The preparation method of material, includes the following steps:
1) by 5.0g Na2MoO4·2H2O is dispersed in 100ml purified water, and the phosphoric acid of 4ml85wt% is then added in water It is reacted for 24 hours at 160 DEG C in thermal response kettle, is cooled to dry phosphomolybdate after room temperature, filtering, acetone washing；Pass through hydro-thermal Phosphomolybdate is prepared in reaction, and phosphomolybdate belongs to polyacid structure, improves the activity of acid catalyzed reaction；
2) by 1.0g phosphomolybdate ultrasonic disperse in 50ml dehydrated alcohol, 0.5g ethyl orthosilicate is then added dropwise, uses The ammonia water conditioning system pH to 9.5-10.5 of 30wt%, then ultrasonic reaction 2-3 days, centrifugation, ethanol washing are dry at room temperature Phosphomolybdate/silica composite nano materials are obtained to constant weight；The present invention is miscellaneous with phosphomolybdate by silica using sol-gel method Phosphomolybdate/silica composite nano materials are prepared in change, and it is further that silica, which is largely coated on the surface of composite material, It carries out sulfonated modification and provides reaction site；
3) that 1.0g phosphomolybdate/silica composite nano materials are placed in ultrasonic disperse in normal heptane is uniform, is cooled to 0 DEG C Hereinafter, chlorosulfonic acid is then added dropwise into system, and after reacting 2-3h to salt-free acid gas evolution at 30-40 DEG C after completion of dropwise addition, mistake Filter, using ethanol rinse, phosphomolybdate/silica composite nano materials for being dried under reduced pressure sulfonated at 50-60 DEG C.
Preferably, the additional amount of chlorosulfonic acid is 5-10mmol in step 3)；The addition of chlorosulfonic acid and phosphomolybdate are being catalyzed Nitrate plays synergistic effect when carrying out nitration to aromatic compound, enhances catalytic capability；Sulphur prepared by the present invention The phosphomolybdate of acidification/silica composite nano materials catalytic activity is compared with Journal of the Iranian Chemical Society, 2017,14 (2): the magnetic Nano material activity reported in 485-490 is high.
According to another aspect of the present invention, it receives the present invention provides a kind of sulfonated phosphomolybdate/silica is compound The purposes of rice material carries out in the presence of solvent and nitrate for being catalyzed 1- [2- hydroxyl -5- (benzyloxy) phenyl] ethyl ketone Nitration reaction prepares Ao Dateluo intermediate 1- [2- hydroxyl -3- nitro -5- (benzyloxy) phenyl] ethyl ketone；Specific steps are as follows:
1) solvent, nitrate and 1- [2- hydroxyl -5- (benzyloxy) phenyl] ethyl ketone are added in reactor to be dispersed with stirring uniformly Afterwards, sulfonated phosphomolybdate/silica composite nano materials are then added and carry out heating reaction；
2) after 1- [2- hydroxyl -5- (benzyloxy) phenyl] ethyl ketone concentration no longer declines in HPLC detection reaction solution, stop stirring It mixes, is cooled to room temperature, filters to isolate sulfonated phosphomolybdate/silica composite nano materials and obtain filtrate；
3) filtrate is carried out post-processing to obtain target product 1- [2- hydroxyl -3- nitro -5- (benzyloxy) phenyl] ethyl ketone.
Preferably, the nitrate be sodium nitrate, potassium nitrate, ammonium nitrate, zinc nitrate, ferric nitrate or calcium nitrate, further Preferably calcium nitrate；
Preferably, the solvent is methylene chloride, methanol, ethyl alcohol, acetic acid, N,N-Dimethylformamide (DMF), dimethyl One of sulfoxide (DMSO) or two kinds and its more than mixed liquor；The further preferably mixing of dimethyl sulfoxide and acetic acid Liquid；Acetic acid can not only provide acidic environment, but also the addition of acetic acid can increase the solubility of nitrate in a solvent, accelerate anti- It answers；
Preferably, the sulfonated phosphomolybdate/silica composite nano materials additional amount is 1- [2- hydroxyl -5- (benzyl Oxygroup) phenyl] ethyl ketone weight 2.0wt%-10wt%；
Preferably, the dosage of the nitrate is the 1.05- of 1- [2- hydroxyl -5- (benzyloxy) phenyl] ethyl ketone mole 1.5 again.
Post-processing of the present invention, which refers to combine using the separation such as concentration, extraction, crystallization and/or means of purification, makes 1- [2- hydroxyl -3- nitro -5- (benzyloxy) phenyl] ethyl ketone is isolated from filtrate with high as far as possible purity and yield.
The present invention prepares sulfonated phosphomolybdate/silica composite nano materials, the phosphomolybdic acid of polyacid structure for the first time Salt and sulfonic group are in catalysis nitrate preparation Ao Dateluo intermediate 1- [2- hydroxyl -3- nitro -5- (benzyloxy) phenyl] ethyl ketone Synergistic effect is played, is had the advantages that compared with nitration reaction condition in the prior art
1) sulfonated phosphomolybdate/silica composite nano materials prepared by the present invention are used to be catalyzed 1- [2- hydroxyl -5- (benzyloxy) phenyl] addition of the ethyl ketone progress nitration reaction without additional nitric acid, greatly reduce the discharge amount of acid waste water；
2) by optimization Catalytic processes, 1- [2- hydroxyl -3- nitro -5- (benzyloxy) phenyl] ethyl ketone product yield is up to 93.6%, with HNO3/CH3COOH system is achieved compared to yield and is obviously improved；
3) sulfonated phosphomolybdate/silica composite nano materials prepared by the present invention can be by simple filtration from reaction It separates in system, and can be applied after recycling.
Specific embodiment
In order to make the objectives, technical solutions and advantages of the present invention clearer, With reference to embodiment, to this Invention is further described.It should be understood that these descriptions are merely illustrative, and it is not intended to limit the scope of the invention.
1- [2- hydroxyl -5- (benzyloxy) phenyl] ethyl ketone is from Jin Jinle (Hunan) Chemical Co., Ltd. in embodiment, HPLC purity is 99.95%；Remaining raw material is commercially available conventional raw material.
HPLC detection method: chromatographic column Agilent C18 (250mmx4.6mm, 5 μm)；Mobile phase A is the phosphorus of 10mmol/L Acid dihydride sodium water solution, Mobile phase B are acetonitrile.Gradient elution is carried out by table 1；Flow velocity is 1.0ml/min, and Detection wavelength is 225nm, column temperature are 30 DEG C.
1 gradient elution program table of table
Embodiment 1
Prepare sulfonated phosphomolybdate/silica composite nano materials:
1) by 5.0g Na2MoO4·2H2O is dispersed in 100ml purified water, and the phosphoric acid of 4ml85wt% is then added in water It is reacted for 24 hours at 160 DEG C in thermal response kettle, is cooled to dry phosphomolybdate after room temperature, filtering, acetone washing；
2) by 1.0g phosphomolybdate ultrasonic disperse in 50ml dehydrated alcohol, 0.5g ethyl orthosilicate is then added dropwise, uses The ammonia water conditioning system pH to 9.5-10.5 of 30wt%, then ultrasonic reaction 2-3 days, centrifugation, ethanol washing are dry at room temperature Phosphomolybdate/silica composite nano materials are obtained to constant weight；
3) that 1.0g phosphomolybdate/silica composite nano materials are placed in ultrasonic disperse in normal heptane is uniform, is cooled to 0 DEG C Hereinafter, 6mmol chlorosulfonic acid is then added dropwise into system, 2-3h is reacted at 30-40 DEG C after completion of dropwise addition and is escaped to salt-free acid gas Afterwards, it filters, using ethanol rinse, phosphomolybdate/silica composite nano materials for being dried under reduced pressure sulfonated at 50-60 DEG C (it is abbreviated as SO3H-PMo/Si)。
Embodiment 2
(SO is abbreviated as to verify sulfonated phosphomolybdate/silica composite nano materials prepared by the present invention3H- PMo/Si catalytic performance), the present invention carry out nitration reaction, tool by substrate of 1- [2- hydroxyl -5- (benzyloxy) phenyl] ethyl ketone Body method is as follows:
Substrate 1- [2- hydroxyl -5- (benzyloxy) phenyl] ethyl ketone (5mmol, 1.21g), sodium nitrate is added in reaction flask (5.5mmol, 0.47g), catalyst SO3H-PMo/Si (0.12g, 10wt%) is dispersed in back flow reaction in 10ml methylene chloride, After 1- [2- hydroxyl -5- (benzyloxy) phenyl] ethyl ketone concentration no longer declines in HPLC detection reaction solution, stop reaction, statistics reaction The area percentage of raw material and product in time and its reaction solution, the results are shown in Table 2:
The catalytic performance of 2 catalyst of table
Note: raw material refers to 1- [2- hydroxyl -5- (benzyloxy) phenyl] ethyl ketone；Product refers to 1- [2- hydroxyl -3- nitro -5- (benzyloxy) phenyl] ethyl ketone；Impurity is all known and unknown impuritie summations in addition to raw material and product；SO3H-Fe2O3/ Si-a refers to using Journal of the Iranian Chemical Society, 2017,14 (2): reports in 485-490 Catalysis material as catalyst, reacted by the condition in embodiment 2；SO3H-Fe2O3/ Si-b refers to using Journal Of the Iranian Chemical Society, 2017,14 (2): the catalysis material reported in 485-490 as catalyst, It is added without methylene chloride, grinding is directly carried out and carries out solvent-free reaction.
Test result shows using the sulfonated phosphomolybdate of catalyst prepared by the present invention/silica composite Nano material Material (is abbreviated as SO3H-PMo/Si it) can effectively be catalyzed 1- [2- hydroxyl -5- (benzyloxy) phenyl] ethyl ketone and generate 1- [2- hydroxyl -3- Nitro -5- (benzyloxy) phenyl] ethyl ketone (conversion ratio is 80% or so)；With the prior art (Journal ofthe Iranian Chemical Society, 2017,14 (2): 485-490) in report catalysis material compare, catalytic activity is higher；Using existing There is the catalysis material in technology, either uses solvent-free grinding (SO3H-Fe2O3/ Si-b) or use methylene chloride reflux (SO3H-Fe2O3/ Si-a), the substrate transformation rate is not high, does not have actual application prospect.
Embodiment 3
Determine that the sulfonated phosphomolybdate/silica composite nano materials prepared using the embodiment of the present invention 1 (are abbreviated as SO3H-PMo/Si it is used as catalyst) in order to further increase catalysis 1- [2- hydroxyl -5- (benzyloxy) phenyl] ethyl ketone preparation 1- The conversion ratio of [2- hydroxyl -3- nitro -5- (benzyloxy) phenyl] ethyl ketone, the present invention is to the reaction dissolvent type of Catalytic processes, nitre Hydrochlorate type and its dosage, the dosage of catalyst are further optimized, the method is as follows:
Substrate 1- [2- hydroxyl -5- (benzyloxy) phenyl] ethyl ketone (5mmol, 1.21g), nitrate is added in reaction flask (1.05-1.5eq is calculated on the basis of substrate mole dosage), catalyst SO3H-PMo/Si (0.5wt%-25wt%, with substrate Calculated on the basis of weight) it is dispersed in 10ml solvent and is stirred to react between 50-60 DEG C, HPLC detects 1- [2- hydroxyl in reaction solution Base -5- (benzyloxy) phenyl] after ethyl ketone concentration no longer declines, stop reaction, count in reaction time and its reaction solution raw material and The area percentage of product, the results are shown in Table 3:
The optimization of 3 catalytic reaction condition of table
Note: DMSO/ acetic acid refers to the mixed liquor of the DMSO of 10 parts by volume and the acetic acid of 1 parts by volume.
Test result shows reaction dissolvent type and nitrating agent type is the key influence factor for influencing catalysis reaction, choosing Select DMSO/ acetic acid mixture (volume ratio 10:1) as solvent, 1.2eq calcium nitrate as nitrating agent, the catalysis of 5.0wt% Agent can almost realize the complete conversion of raw material as reaction condition.
Embodiment 4
The present invention has carried out the amplification research of laboratory scale in feather weight laboratory, provides number for industrialized production According to support, the specific method is as follows:
1) 11L solvent DMSO/ acetic acid mixture (volume is added in the double-layer glass reaction kettle of 20L tool tetrafluoro agitating paddle Than for 10:1), calcium nitrate (393.8g, 2.4mol) and raw material 1- [2- hydroxyl -5- (benzyloxy) phenyl] ethyl ketone (484.5g, After 2mol) being dispersed with stirring uniformly, freshly prepared sulfonated phosphomolybdate/silica composite nano materials are then added (24.2g, 5.0wt%) is warming up to 55 ± 2 DEG C after mixing evenly and carries out heating reaction；
2) progress HPLC detection (calculating by area percentage, starting material left 0.52%) is extracted reaction solution after reacting 4h；Continue Insulation reaction 1h, which is extracted reaction solution, carries out HPLC detection (calculating by area percentage, starting material left 0.12%)；Stop stirring, cooling To room temperature, filters to isolate sulfonated phosphomolybdate/silica composite nano materials and obtain filtrate；
3) 45-50 DEG C is warming up to filtrate, is then added dropwise after purified water occurs crystal into reaction system and stops that guarantor is added dropwise Warm growing the grain 20-30min (about dropwise addition 6.8L)；Continue to be added dropwise to [2- hydroxyl -3- nitro -5- (the benzyloxy of 1- in system after growing the grain Base) phenyl] ethyl ketone concentration no longer declines, is naturally cooling to room temperature, filters, be dried under reduced pressure to obtain 537.8g light yellow solid particle, HPLC content is 99.89% (external standard method), yield 93.6%；A small amount of sample is taken to carry out ESI-MS detection: m/z=288.1 [M+ 1]+；H-NMR (400MHZ, DMSO-d6) δ (ppm): 12.30 (s, 1H), 7.90-7.93 (d, 1H), 7.88-7.87 (d, 1H), 7.48-7.47 (d, 2H), 7.44-7.38 (d, 2H), 7.37-7.39 (dd, 1H), 5.20 (s, 2H), 2.69 (s, 3H).
After using DMSO supersound washing to the sulfonated phosphomolybdate/silica composite nano materials filtered to isolate, 22.2g, the rate of recovery 91.8% are dried to obtain after eluting using acetone；The addition freshly prepared catalyst of 2.0g complements to 24.2g The test of catalyst recovery is carried out according to above-mentioned preparation method, reacts starting material left 0.18% after 5h, after post treatment 1- [2- Hydroxyl -3- nitro -5- (benzyloxy) phenyl] ethyl ketone yield be 93.0%, it is substantially suitable with fresh catalyst catalytic efficiency；So Catalyst prepared by the present invention can carry out recovery in production amplification, further decrease production cost.
Although embodiments of the present invention are described in detail, it should be understood that, without departing from of the invention In the case where spirit and scope, embodiments of the present invention can be made with various changes, replacement and change.

Claims (10)

1. a kind of sulfonated phosphomolybdate/silica composite nano materials preparation method, it is characterised in that: including walking as follows It is rapid:
1) by 5.0g Na2MoO4·2H2O is dispersed in 100ml purified water, and the phosphoric acid that 4ml 85wt% is then added is anti-in hydro-thermal It answers in kettle and is reacted for 24 hours at 160 DEG C, be cooled to dry phosphomolybdate after room temperature, filtering, acetone washing；
2) by 1.0g phosphomolybdate ultrasonic disperse in 50ml dehydrated alcohol, 0.5g ethyl orthosilicate is then added dropwise, using 30wt% Ammonia water conditioning system pH to 9.5-10.5, then ultrasonic reaction 2-3 days at room temperature, centrifugation, ethanol washing are dry to constant weight Obtain phosphomolybdate/silica composite nano materials；
3) that 1.0g phosphomolybdate/silica composite nano materials are placed in ultrasonic disperse in normal heptane is uniform, be cooled to 0 DEG C with Under, chlorosulfonic acid is then added dropwise into system, after reacting 2-3h to salt-free acid gas evolution at 30-40 DEG C after completion of dropwise addition, filtering, Using ethanol rinse, phosphomolybdate/silica composite nano materials for being dried under reduced pressure sulfonated at 50-60 DEG C.
2. preparation method according to claim 1, it is characterised in that: the additional amount of chlorosulfonic acid is 5- in step 3) 10mmol。
3. a kind of sulfonated phosphomolybdate/silica composite Nano of any one of claim 1-2 preparation method preparation The purposes of material, it is characterised in that: in the presence of solvent and nitrate, for being catalyzed 1- [2- hydroxyl -5- (benzyloxy) benzene Base] ethyl ketone progress nitration reaction preparation Ao Dateluo intermediate 1- [2- hydroxyl -3- nitro -5- (benzyloxy) phenyl] ethyl ketone.
4. purposes according to claim 3, it is characterised in that: specifically comprise the following steps:
1) after addition solvent, nitrate and 1- [2- hydroxyl -5- (benzyloxy) phenyl] ethyl ketone are dispersed with stirring uniformly in reactor, so Sulfonated phosphomolybdate/silica composite nano materials are added afterwards and carry out heating reaction；
2) after 1- [2- hydroxyl -5- (benzyloxy) phenyl] ethyl ketone concentration no longer declines in HPLC detection reaction solution, stop stirring, drop It warms to room temperature, filter to isolate sulfonated phosphomolybdate/silica composite nano materials and obtain filtrate；
3) filtrate is carried out post-processing to obtain target product 1- [2- hydroxyl -3- nitro -5- (benzyloxy) phenyl] ethyl ketone.
5. purposes according to claim 4, it is characterised in that: the nitrate is sodium nitrate, potassium nitrate, ammonium nitrate, nitre Sour zinc, ferric nitrate or calcium nitrate, further preferably calcium nitrate.
6. purposes according to claim 5, it is characterised in that: the nitrate is calcium nitrate.
7. purposes according to claim 4, it is characterised in that: the solvent is methylene chloride, methanol, ethyl alcohol, acetic acid, nitrogen One of nitrogen dimethylformamide, dimethyl sulfoxide or two kinds and its more than mixed liquor.
8. purposes according to claim 7, it is characterised in that: the solvent is the mixed liquor of dimethyl sulfoxide and acetic acid.
9. purposes according to claim 4, it is characterised in that: the sulfonated phosphomolybdate/silica composite Nano Material additional amount is the 2.0wt%-10wt% of 1- [2- hydroxyl -5- (benzyloxy) phenyl] ethyl ketone weight.
10. purposes according to claim 4, it is characterised in that: the dosage of the nitrate is 1- [2- hydroxyl -5- (benzyloxy Base) phenyl] 1.05-1.5 times of ethyl ketone mole.
CN201910529179.2A 2019-06-19 2019-06-19 A kind of preparation method of respiratory medicine object Ao Dateluo intermediate Withdrawn CN110215933A (en)

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