CN108686687B - A kind of preparation method of rheumatism bone disease drug Actarit intermediate - Google Patents
A kind of preparation method of rheumatism bone disease drug Actarit intermediate Download PDFInfo
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- B01J37/34—Irradiation by, or application of, electric, magnetic or wave energy, e.g. ultrasonic waves ; Ionic sputtering; Flame or plasma spraying; Particle radiation
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Abstract
The invention belongs to pharmaceutical technology fields, and in particular to a kind of preparation method of rheumatism bone disease drug Actarit intermediate.The present invention uses nano-silicon nitride for carrier for the first time, is modified to obtain a kind of zinc modification Pd catalyst of silicon carbide load to active Pd as modifying agent using zinc salt；Paranitrophenylacetic acid reduction can be effectively catalyzed using the zinc modification Pd catalyst that silicon carbide prepared by the present invention loads and prepare equal amido phenenyl acid, catalyst amount be substrate paranitrophenylacetic acid ten thousand/several fully reacting can be made to convert.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of preparation of rheumatism bone disease drug Actarit intermediate
Method.
Background technique
Actarit (actarit), the entitled 4- acetamidophenylacetic acid of chemistry, is Japanese Nippon Shinyaku company
The immunomodulator of research and development is listed in Japan for 1994 for the first time, and clinic is mainly used for treating chronic rheumatoid arthritis.This product
It can inhibit and prevent the progressive of joint bone, cartilage to destroy, activate patient's T lymphocyte, enhance proleulzin, to inhibit to become
State reaction.
The molecular formula of equal amido phenenyl acid is C8H9NO2, No. CAS is 1197-55-3, and molecular weight 151.16, fusing point is
199-200 DEG C, equal amido phenenyl acid is dissolved in alcohol, lye, is slightly soluble in hot water, equal amido phenenyl acid is frequently as synthesis material medicine Acker
The intermediate of his benefit uses.
Equal amido phenenyl acid is prepared by its corresponding nitro compounds paranitrophenylacetic acid reduction in equal amido phenenyl acid, reacts
Formula is as shown in Scheme 1:
There are two main classes for the synthetic method of the compound of currently available technology report, and one kind is the side using electronation
Method, as, using iron chloride as catalyst, restored using hydrazine hydrate as reducing agent to paranitrophenylacetic acid in 106083631 A of CN,
But hydrazine hydrate is more toxic；Nie Lijuan et al. (Chinese Journal of Pharmaceuticals, 2008, the phase of volume 39 the 12nd, page 894, Acker
The synthesis of his benefit) in use ammonium sulfide for reducing agent, but coproduction by-product aqueous solution containing sulphur simple substance is difficult to handle, and does not meet green
The requirement of chemical industry；University Of Hebei Zhang Xue (University Of Hebei's journal (natural science edition), 2008, the phase of volume 28 the 2nd, 178-181 pages,
The synthesis of Actarit) it is restored in Fe/AcOH system, but can equally generate a large amount of reluctant iron content waste waters.
Second class method is precious metal catalyst method, document Tetrahedron Letters, 1984,25 (32): 3415-
3418, A general procedure for mild and rapaid reduction of aliphatic and
aromatic nitro compounds using ammonium formate as a catalytic hydrogen
Using Pd/C as catalyst in transfer agent, ammonium formate is that hydrogen donor carries out turning hydrogen reaction, and reaction 5-10min yield is
86%, the system is more environmentally friendly, but yield is not high, and catalyst amount is big；Use Pd/C for catalysis in 102224130 B of CN
Agent, at 40-50 DEG C, 0.1-0.6 Ba Chao pressure reduction 4- nitro phenyl acetic acid obtain 4- aminophenyl acetic acid, then improve temperature
With pressure at 50-60 DEG C, 1-4 bars 4- aminocyclohexyl guanidine-acetic acid, be easy to produce so carrying out catalytic hydrogenation using Pd/C merely
Raw de- armaticity by-product, needs strict control reaction condition；Document ChemCatChem 2014,6,3153-3159, Mild and
Selective Hydrogenation of Nitro Compounds using Palladium Nanoparticles
In Supported on Amino-Functionalized Mesocellular Foam with PEG-PPG-PEG polymer be original
Material prepares mesostructured cellular foam (MCF), and then using 3- TSL 8330 is modifying agent to mesoporous foam material
Material be grafted aminopropyl grafting mesostructured cellular foam (AmP-MCF), final load Pd nanoparticle obtains catalyst, this is urged
Agent can efficient catalytic 4- nitro phenyl acetic acid obtain 4- aminophenyl acetic acid, reaction 1.5h yield reaches 99% under room temperature normal pressure,
It is the current highest catalysis process of yield reported in the literature, but the preparation process of catalyst and its carrier is very numerous in this method
It is trivial, and mesostructured cellular foam (AmP-MCF) morphology and size being grafted to catalyst nano palladium and carrier aminopropyl is more demanding.
So developing a kind of catalyst system of simple and effective to be catalyzed paranitrophenylacetic acid reduction and p-aminophenyl is prepared
Acetic acid has great importance for preparing Actarit drug.
Summary of the invention
The purpose of the present invention is overcome precious metal catalyst paranitrophenylacetic acid reduction in the prior art to prepare p-aminophenyl second
Deficiency in acid provides a kind of catalysis process of simple and effective, and the present invention uses nano-silicon nitride for carrier for the first time, is with zinc salt
Modifying agent is modified active Pd to obtain a kind of zinc modification Pd catalyst of silicon carbide load；Using carbonization prepared by the present invention
The zinc modification Pd catalyst of silicon load can effectively be catalyzed paranitrophenylacetic acid reduction and prepare equal amido phenenyl acid, and catalyst amount is
The ten thousand of substrate paranitrophenylacetic acid/several can be such that fully reacting converts.
According to an aspect of the present invention, the present invention provides a kind of preparations of the zinc modification Pd catalyst of silicon carbide load
Method includes the following steps:
By nanometer silicon carbide, PdCl2And ZnCl2The ultrasonic mixing 12h or more in the mixed solution of second alcohol and water composition, so
Aqueous sodium carbonate regulation system pH=8-9 is used afterwards, and the reduction of sodium borohydride aqueous dispersions is added dropwise, continues to stir after completion of dropwise addition
6-8h, then filtering is washed in filtrate without chloride ion, the zinc modification Pd catalyst of dry silicon carbide load；According to molar ratio
It calculates, ZnCl2:PdCl2=1:6-10；
Preferably, the mole dosage of the sodium borohydride is PdCl2And ZnCl23-5 times of the sum of mole；In the present invention
Sodium borohydride mole dosage with can be by PdCl2And ZnCl2Reduction completely, the mole dosage of sodium borohydride of the present invention
Using PdCl2And ZnCl2Three to five times of moles total number；
Preferably, the nanometer silicon carbide and PdCl2Weight ratio be 1:0.25-0.35；By controlling PdCl2Addition
Amount is to adjust catalyst activity；
Preferably, it is calculated according to molar ratio, ZnCl2:PdCl2=1:8；
According to another aspect of the present invention, the present invention provides a kind of use of the zinc modification Pd catalyst of silicon carbide load
On the way, equal amido phenenyl acid is prepared for being catalyzed paranitrophenylacetic acid reduction in the presence of solvent and hydrogen donor.
Preferably, the dosage of the zinc modification Pd catalyst of the silicon carbide load is the 0.2%- of paranitrophenylacetic acid weight
2.0%wt；The zinc modification Pd catalyst of silicon carbide load prepared by the present invention is under conditions of isopropanol is as hydrogen donor, reaction
Active high, catalyst amount is few；
Preferably, the reaction temperature that the catalysis paranitrophenylacetic acid reduction prepares equal amido phenenyl acid is 30-70 DEG C, into
One step is preferably 45-50 DEG C；
Preferably, the solvent is methanol, ethyl alcohol, isopropanol, acetonitrile or tetrahydrofuran, further preferably acetonitrile；
Preferably, the hydrogen donor is sodium formate, potassium formate, ammonium formate or isopropanol, further preferably ammonium formate.
The present invention has the advantage that
1) present invention is modified traditional Pd./C, prepares using nanometer silicon carbide as carrier, the Pd nanometer of zinc modification from
Son is the zinc modification Pd catalyst that the silicon carbide of active component loads；
2) preparation method of catalyst of the present invention is simple, high catalytic efficiency；
2) the zinc modification Pd catalyst for the silicon carbide load that the present invention prepares can the reduction of efficient catalytic paranitrophenylacetic acid
Equal amido phenenyl acid is prepared, catalyst efficiency is high, and catalyst amount is few；The present invention is using nanometer silicon carbide as carrier, using zinc pair
Palladium is modified, and is greatly improved catalyst reaction activity, is reduced the dosage of catalyst, catalyst amount is only
Tetrahedron Letters, 1984,25 (32): in 3415-3418 1/10th hereinafter, catalysis i.e. prepared by the present invention
The catalytic activity of the more traditional Pd/C of agent improves an order of magnitude.
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.
HPLC detection method is according to the prior art " " Journal of Chinese Hospital Pharmacy ", 2002,22 (10): 593- in embodiment
Introduction in 595, high effective liquid chromatography for measuring new immunomodulator Actarit and 3 kinds of intermediates contents " is detected.
Nanometer silicon carbide derives from Beijing Deco Dao Jin Science and Technology Ltd., model DK-SiC-001, and average grain diameter is
40nm, specific surface area 40m2/g.10%wt Pd/C is from Shaanxi Ruike New Materials Co., Ltd., specific surface area
920m2/g；For paranitrophenylacetic acid from lark prestige Science and Technology Ltd., HPLC purity is 99.68%；Remaining raw material is city
Sell conventional raw material.
Embodiment 1
Prepare the zinc modification Pd catalyst of silicon carbide load:
By nanometer silicon carbide 10.0g, PdCl2(2.5g, 14.1mmol) and ZnCl2(0.32g, 2.35mmol) is in 100ml second
Ultrasonic mixing 12h or more in alcohol/water composition mixed solution (volume ratio 1:1), then adjusts body using aqueous sodium carbonate
It is pH=8-9, sodium borohydride aqueous dispersions (100ml contains sodium borohydride 80mmol) reduction is added dropwise, continues to stir after completion of dropwise addition
6-8h, then filtering is washed in filtrate without chloride ion, be dried in vacuo at 40 DEG C silicon carbide load zinc modification Pd catalyst.
Embodiment 2
By nanometer silicon carbide 10.0g, PdCl2(3.5g, 19.7mmol) and ZnCl2(0.34g, 2.46mmol) is in 100ml second
Ultrasonic mixing 12h or more in alcohol/water composition mixed solution (volume ratio 1:1), then adjusts body using aqueous sodium carbonate
It is pH=8-9, sodium borohydride aqueous dispersions (100ml contains sodium borohydride 80mmol) reduction is added dropwise, continues to stir after completion of dropwise addition
6-8h, then filtering is washed in filtrate without chloride ion, be dried in vacuo at 40 DEG C silicon carbide load zinc modification Pd catalyst.
Embodiment 3
The zinc modification Pd catalyst of the silicon carbide load prepared using embodiment 2 carries out catalyst performance assessment, side as representative
Method is as follows:
By substrate paranitrophenylacetic acid (5mmol, 0.91g), catalyst (0.10g ,~10.0%wt), ammonium formate
(20mmol, 1.26g) reacts in 10ml methanol, and HPLC detects turn of substrate paranitrophenylacetic acid in reaction solution after reaction
The selectivity of rate and product equal amido phenenyl acid, the results are shown in Table 1:
1 catalyst catalytic performance of table
| Reaction temperature/DEG C | Reaction time/min | Conversion ratio/% | Selectivity/% |
| 30 | 60 | 86.3 | 99.2 |
| 50 | 15 | 93.8 | 99.6 |
Test result shows that the zinc modification Pd catalyst of silicon carbide load prepared by the present invention under heating conditions can have
Effect catalysis paranitrophenylacetic acid prepares equal amido phenenyl acid.
Embodiment 4
The zinc modification Pd of the silicon carbide load prepared using embodiment 2 is as catalyst, and the present invention is to hydrogen donor type, solvent
Type and the dosage of catalyst are optimized, the method is as follows:
By substrate paranitrophenylacetic acid (10mmol, 1.81g), catalyst (2.0mg-181mg, 0.1%wt~10.0%
Wt), hydrogen donor (40mmol) reacts at 50 DEG C in 20ml solvent, HPLC detection after reaction in reaction solution substrate to nitre
The conversion ratio of base phenylacetic acid and the selectivity of product equal amido phenenyl acid, the results are shown in Table 2:
2 reaction condition optimization of table
The above result shows that the zinc modification Pd catalyst of silicon carbide prepared by the present invention load can be catalyzed a variety of hydrogen donors into
Row reaction achieves good results, it is contemplated that ammonium formate forms gas after turning hydrogen reaction, pollution-free, the preferred formic acid of the present invention
Ammonium is as hydrogen donor；Solvent has larger impact effect to the conversion ratio of substrate, when selected acetonitrile as solvent, ammonium formate as hydrogen
Researcher has surprisingly found that when donor, at this time the catalytic performance highest of catalyst, even if the additional amount of catalyst is substrate pair
When the 0.2%wt of nitrophenyl-acetic acid weight, substrate is almost also able to achieve complete conversion.
Embodiment 5
Substrate paranitrophenylacetic acid (1mol, 181.1g), catalyst (2 side of embodiment are added in 5L double-layer glass reaction kettle
Method preparation, 0.91g, 0.50%wt), ammonium formate (4mol, 252g) be stirred to react at 45-50 DEG C in 3.0L acetonitrile solvent,
Reaction 30min after extract reaction solution carry out HPLC detection (area percentage: substrate paranitrophenylacetic acid 0.08%, product 99.5%,
Surplus impurity), it is cooled to room temperature, uses aperture to isolate catalyst for 0.5 micron of organic filtering with microporous membrane, filtrate is 40
It is concentrated to dryness to obtain concentrate at DEG C, 50ml purified water, 1ml glacial acetic acid and 650ml isopropanol are then added in concentrate
It is heated to 50-60 DEG C of stirring 20-30min, 0-5 DEG C is then cooled to, filtering, dry obtains target product p-aminophenyl second to constant weight
Sour 144.8g, yield 95.8%；HPLC purity is 99.85%；1H-NMR (400MHz, d6-DMSO): δ=6.89 (m, 2H),
6.50(m,2H),3.33(s,2H).MS(ESI):[M+H+],152.07。
Comparative example 1
In order to verify the catalytic performance of traditional Pd/C, the present invention uses commercially available 10%Pd/C (the auspicious section's new material share in Shaanxi
Co., Ltd) in strict accordance with Tetrahedron Letters, 1984,25 (32): the introduction in 3415-3418 carries out repeating examination
Test, actual conditions are as follows: by substrate paranitrophenylacetic acid (5mmol, 0.91g), 10%wt Pd/C (0.25g ,~27.5%
Wt), ammonium formate (20mmol, 1.26g) reacts at 25-30 DEG C under nitrogen protection in 10ml methanol, reacts timing 10min
After extract reaction solution analysis and (counted according to area percentage, substrate paranitrophenylacetic acid 0.88%, product equal amido phenenyl acid
98.96%, surplus is impurity)；Analysis is extracted reaction solution after the reaction was continued 20min (to be counted according to area percentage, substrate pair
Nitrophenyl-acetic acid 0.87%, product equal amido phenenyl acid 98.96%, surplus are impurity), therefore reaction reaches balance, using tradition
Pd/C is reacted using ammonium formate as hydrogen donor at room temperature, at a normal reaches the 27.5% of substrate weight even if catalyst amount,
Substrate conversion can not be made complete；Therefore the zinc modification Pd poor catalyst activity of tradition Pd/C silicon carbide load more prepared by the present invention.
Comparative example 2
Influence for confirmatory reaction condition to catalyst, the present invention is according to the condition in embodiment 5, using commercially available 10%
Pd/C (Shaanxi Ruike New Materials Co., Ltd.) carries out catalysis reaction, and actual conditions are as follows: by substrate paranitrophenylacetic acid
(10mmol, 1.81g), 10%wt Pd/C (9.0mg ,~0.5%wt), ammonium formate (40mmol, 2.5g) in 20ml acetonitrile in
It is reacted at 50 DEG C, HPLC monitoring reaction, 60min extracts reaction solution monitoring, and substrate paranitrophenylacetic acid is 32.8%, and target product is
66.9%, surplus is impurity.
By the reaction result of comparative example 1 and 2 it is found that the zinc modification Pd catalyst of silicon carbide prepared by the present invention load is being urged
During change paranitrophenylacetic acid reduction prepares equal amido phenenyl acid, the more traditional Pd/C catalyst of catalytic activity is high, catalysis
The minimum some thousandths of for substrate dosage of agent dosage can be such that fully reacting converts.
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 (7)
1. a kind of purposes of the zinc modification Pd catalyst of silicon carbide load, it is characterised in that: the zinc of the silicon carbide load changes
Property Pd catalyst prepare equal amido phenenyl acid for being catalyzed paranitrophenylacetic acid reduction in the presence of solvent and hydrogen donor；It is described
Solvent is methanol, ethyl alcohol, isopropanol, acetonitrile or tetrahydrofuran；The hydrogen donor is sodium formate, potassium formate, ammonium formate or isopropyl
Alcohol；
The preparation method of the zinc modification Pd catalyst of silicon carbide load, includes the following steps: nanometer silicon carbide, PdCl2With
ZnCl2Then the ultrasonic mixing 12h or more in the mixed solution of second alcohol and water composition uses aqueous sodium carbonate regulation system pH
The reduction of sodium borohydride aqueous dispersions is added dropwise in=8-9, continues to stir 6-8h after completion of dropwise addition, then filtering is washed in filtrate without chlorine
Ion, the zinc modification Pd catalyst of dry silicon carbide load；It is calculated according to molar ratio, ZnCl2:PdCl2=1:6-10。
2. a kind of purposes of the zinc modification Pd catalyst of silicon carbide load according to claim 1, it is characterised in that: described
The mole dosage of sodium borohydride is PdCl2And ZnCl23-5 times of the sum of mole.
3. a kind of purposes of the zinc modification Pd catalyst of silicon carbide load according to claim 1, it is characterised in that: described
Nanometer silicon carbide and PdCl2Weight ratio be 1:0.25-0.35.
4. a kind of purposes of the zinc modification Pd catalyst of silicon carbide load according to claim 1, it is characterised in that: according to
Molar ratio calculates, ZnCl2:PdCl2=1:8。
5. a kind of purposes of the zinc modification Pd catalyst of silicon carbide load according to claim 1, it is characterised in that: described
The dosage of the zinc modification Pd catalyst of silicon carbide load is the 0.2-2.0%wt of paranitrophenylacetic acid weight.
6. a kind of purposes of the zinc modification Pd catalyst of silicon carbide load according to claim 1, it is characterised in that: described
The reaction temperature that catalysis paranitrophenylacetic acid reduction prepares equal amido phenenyl acid is 40-70 DEG C.
7. a kind of purposes of the zinc modification Pd catalyst of silicon carbide load according to claim 1, it is characterised in that: described
Hydrogen donor is ammonium formate, and the solvent is acetonitrile.
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| CN103214384B (en) * | 2013-04-10 | 2015-04-01 | 淮阴师范学院 | Preparation method of p-aminophenylacetic acid |
| CN104744287A (en) * | 2013-12-25 | 2015-07-01 | 储海燕 | Actarit production method |
| CN106810436B (en) * | 2015-11-30 | 2020-06-30 | 中国科学院大连化学物理研究所 | Method for preparing lactic acid by catalytic oxidation of glycerol |
| CN106083631B (en) * | 2016-06-02 | 2018-11-16 | 平光制药股份有限公司 | A kind of preparation method of equal amido phenenyl acid |
| CN106380413A (en) * | 2016-08-30 | 2017-02-08 | 枣阳市福星化工有限公司 | Preparation method of 4-aminophenylacetic acid medicine intermediate |
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