CN109111355A - A kind of chemical synthesis process of (R) -2- phenoxy propionic acid - Google Patents
A kind of chemical synthesis process of (R) -2- phenoxy propionic acid Download PDFInfo
- Publication number
- CN109111355A CN109111355A CN201811009516.7A CN201811009516A CN109111355A CN 109111355 A CN109111355 A CN 109111355A CN 201811009516 A CN201811009516 A CN 201811009516A CN 109111355 A CN109111355 A CN 109111355A
- Authority
- CN
- China
- Prior art keywords
- sodium
- acid
- alanine
- amount
- propionic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of chemical synthesis process of (R) -2- phenoxy propionic acid, using l-Alanine as starting material, (S) -2- chloropropionic acid is obtained through diazotising, chlorination, etherified reaction again obtains (R) -2- phenoxy propionic acid ((R)-PPA).The present invention relates to one kind using l-Alanine as starting material, (S) -2- chloropropionic acid is obtained through diazotising, chlorination, the molar yield of etherified reaction again, the method for obtaining (R)-PPA, (R) -2- phenoxy propionic acid is up to 92.45%.Present invention firstly provides the chemical synthesis process of (R)-PPA, have many advantages, such as that raw material cheap and easy to get, simple process and product purity are higher.
Description
Technical field
The present invention relates to one kind using l-Alanine as starting material, obtains (S) -2- chloropropionic acid through diazotising, chlorination, then pass through
Etherification reaction, the method for obtaining (R) -2- phenoxy propionic acid ((R)-PPA), belongs to chemosynthesis technical field.
Background technique
(R)-PPA is bioanalysis synthesis virtue phenoxy phenoxy propionic acid herbicide key intermediate (R) -2- (4- hydroxyphenoxy)
The important substrate of propionic acid ((R)-HPPA).Fragrant phenoxy phenoxy propionic acid herbicide is a kind of new herbicides with optically active,
It is to be had gradually developed on the basis of the compound diclofop-methyl of research and development by Hoechst company the 1960s,
It is main to pass through the inhibition intracorporal acetyl-CoA carboxylase of gramineae plant (Acetyl-CoA Carboxylase, ACCase, EC
6.4.1.2 activity), and then inhibit the synthesis of fatty acid, make the synthesis of oleic acid, linoleic acid, linolenic acid, wax coat and cuticula
Process is obstructed, and the membrane structure of plant is caused to be destroyed rapidly, and permeability enhancing eventually leads to the death of plant.Such herbicide is because of it
Have the characteristics that efficient, less toxic, broad weed-killing spectrum, application phase are long, be readily biodegradable and safe to succession crop, in recent years not
Disconnected to obtain development and application, the market sales revenue grows steadily.And (R)-HPPA is the phenoxy propionic acid class for synthesizing enantiomer-pure
The key intermediate of herbicide (such as galloping horse, haloxyfop-r-methyl, fluazifop-p-butyl, Quizalotop-ethyl, clodinafop-propargyl).
Currently, the intermediate is mainly synthesized by chemical method, using Pfansteihl and l-Alanine as starting material and to hexichol
Phenol occurs etherified reaction and is made.Due to easily being aoxidized to biphenol and the activity of two hydroxyls is identical, it is easy to bis ether occur
Change, reaction process is difficult to control, and there are energy consumptions it is high, by-product is mostly big with environmental pollution the disadvantages of.Bioanalysis synthesizes (R)-
HPPA has many advantages, such as that reaction condition is mild, stereoselectivity is high and the easily separated extraction of product, therefore gradually attracts attention.Biology
The main method of method synthesis (R)-HPPA is to utilize the hydroxylation in the extracellular microbials such as beauveria bassiana, aspergillus niger and Sclerotium rolfsii
Substrate (R)-PPA single step reaction is converted (R)-HPPA by enzyme.Therefore, the sufficient supply of substrate (R)-PPA is raw for bioanalysis
The industrialization for producing (R)-HPPA plays an important role.
In addition, (R)-PPA applies also for the preparation of carboxyl benzene oxycarboxylic acid compound.Carboxyl benzene oxycarboxylic acid is that one kind has both
The bridge ligand of multibody system characteristic may be used as secondary construction unit to prepare novel supermolecule metal organic framework cooperation
Object, these complexs often have novel topological structure, and hand in light, electricity, magnetic, catalysis, molecular recognition, absorption, ion
It changes, gas stores and the fields such as bioactivity show potential application prospect.Therefore the foundation of (R)-PPA synthetic method is to virtue
The development and application of phenoxy phenoxy propionic acid herbicide and supermolecule metal organic framework complex has great importance.
Summary of the invention
It is an object of the present invention to provide the synthesis of a kind of application value, low cost and efficient (R)-PPA with higher
Method, synthetic route such as Fig. 1.
The technical solution adopted by the present invention is that:
The present invention provides a kind of chemical synthesis process of (R) -2- phenoxy propionic acid, and the method carries out as follows:
(1) using l-Alanine as raw material, using sodium nitrite as diazo reagent, in the work of hydrochloric acid, potassium chloride and sodium carbonate
Diazotising and chlorination reaction are carried out under, after reaction, reaction solution isolates and purifies, and obtains (S) -2- chloropropionic acid sodium；
(2) (S) -2- chloropropionic acid sodium is under phenol, sodium hydroxide and catalyst action, in 45-125 DEG C, pH value 12-13
Under the conditions of carry out etherification reaction, after fully reacting, reaction solution post-processing, obtain (R) -2- phenoxy propionic acid；The catalyst is
Dehydrated alcohol or potassium iodide.
Further, step (1) diazotising and chlorination reaction method are as follows: l-Alanine, hydrochloric acid, potassium chloride are mixed,
After stirring is cooled to 0 DEG C, sodium nitrite in aqueous solution is added dropwise dropwise, after completion of dropwise addition, continues to stir to react fully (preferably to react
0.5~2.5h, more preferable 1h), it is then warmed to room temperature (25-30 DEG C), sodium carbonate is added, reaction, which is stirred at room temperature, to be terminated (preferably instead
Answer 1~3h, more preferable 2h) after, reaction solution isolates and purifies, and obtains (S) -2- chloropropionic acid sodium.The hydrochloric acid is water-soluble with 8.0mol/L
The form of liquid is added, and the ratio between amount of hydrochloric acid and l-Alanine substance is 2-3:1 (preferably 2.5:1), institute in the aqueous hydrochloric acid solution
The ratio between amount of potassium chloride and l-Alanine substance is stated as 0.5~0.9:1 (preferably 0.7:1)；The sodium nitrite is with the Asia 8mol/L
Sodium nitrate aqueous solution form is added, and the ratio between amount of sodium nitrite and l-Alanine substance is 1.0- in the sodium nitrite in aqueous solution
1.5:1 (preferably 1.2:1)；The ratio between amount of the sodium carbonate and l-Alanine substance is 0.5~1.0:1 (preferably 0.5:1), carbonic acid
Sodium, without influence, only serves the effect for the gas discharge for promoting the reaction to generate to reaction itself, so, the dosage of sodium carbonate is not done
It is strict with.
Further, step (1) reaction solution isolation and purification method are as follows: after reaction, reaction solution is extracted with isopropyl ether, is merged
300g/L sodium hydrate aqueous solution is added in organic phase, and (the S) -2- chloropropionic acid generated is made to become (S) -2- chloropropionic acid sodium, stands and divides
Layer removes organic phase, retains water phase, obtains (S) -2- chloropropionic acid sodium；The sodium hydrate aqueous solution volumetric usage is with l-Alanine
The amount of substance is calculated as 60.0~100.0ml/mol, and the amount of sodium hydroxide does not influence the conversion ratio of (S) -2- chloropropionic acid, it is therefore an objective to make
It is converted to salt, is transferred in water phase from organic phase, so, dosage does not do specific investigation, appropriate excess.
Further, step (2) etherification method are as follows: in room temperature (25-30 DEG C) anaerobic after mixing phenol, sodium hydroxide
Under the conditions of stirring (preferably 500rpm) so that phenol is converted into sodium phenate, (being preferably slowly added dropwise with constant pressure separatory funnel) is slowly added dropwise
(S) -2- chloropropionic acid sodium of step (1) preparation, adds catalyst, 45-125 DEG C, pH value be 12-13 (preferably 100~125 DEG C,
More preferable 125 DEG C) after fully reacting (preferably reaction 0.5~3.0h, more preferable 1.5h), reaction solution post-processing obtain (R) -2-
Phenoxy propionic acid.The sodium hydroxide is added in the form of 300g/L sodium hydrate aqueous solution, the sodium hydroxide and phenol object
The ratio between amount of matter is 1.2-2.0:1 (preferably 1.25:1), the ratio between amount of (the S) -2- chloropropionic acid sodium and phenol substance 0.9~
The ratio between amount of 1.3:1 (preferably 1.2:1), the catalyst and phenol substance is 0.1~0.5:1 (preferably 0.25:1).
Further, the method for step (2) reaction solution post-processing are as follows: after fully reacting, reaction solution tune pH=4.0 (is preferably used
Mass concentration 8.0mol/L hydrochloric acid is adjusted), pH≤2.0 (preferably being adjusted with 8.0mol/L hydrochloric acid) is mutually adjusted in stratification, water intaking, takes out
Filter, filter cake drying, obtains (R) -2- phenoxy propionic acid.
Further, the synthetic method of (R) -2- phenoxy propionic acid of the present invention carries out as follows: (1) the third ammonia of L-
Sour diazotising, chlorination synthesize (S) -2- chloropropionic acid sodium: l-Alanine, hydrochloric acid, potassium chloride being mixed, stirring (preferably 500rpm) drop
To 8mol/L sodium nitrite in aqueous solution after 0 DEG C, is added dropwise dropwise, (time for adding is about 3h to temperature, and solution turned yellow during dropwise addition has gas
Body is emerged), after completion of dropwise addition, continues stirring and react fully (preferably reaction 0.5~2.5h, more preferable 1h), then heat to
Room temperature；Sodium carbonate is added portionwise again, sodium carbonate, which reacts the carbon dioxide gas generated with acid excessive in reaction system, to be broken
The nitrogen oxides in reaction system is discharged in the combination of bad nitrogen oxides and product, and after reaction, reaction solution is extracted with isopropyl ether
It takes, merges organic phase, 300g/L sodium hydrate aqueous solution is added, so that the chloropropionic acid generated is become chloropropionic acid sodium, stratification is gone
Fall organic phase, retain water phase, obtains (S) -2- chloropropionic acid sodium；The hydrochloric acid is added in the form of 8.0mol/L aqueous hydrochloric acid solution,
The ratio between amount of the hydrochloric acid and l-Alanine substance is 2-3:1 (preferably 2.5:1), the amount of the potassium chloride and l-Alanine substance
The ratio between be 0.5~0.9:1 (preferably 0.7:1)；The sodium nitrite is added in the form of 8mol/L sodium nitrite in aqueous solution, the Asia
The ratio between amount of sodium nitrate and l-Alanine substance is 1.0-1.5:1 (preferably 1.2:1)；The sodium carbonate and l-Alanine substance
The ratio between amount is 0.5~1.0:1 (preferably 0.5:1)；The sodium hydrate aqueous solution volumetric usage is with the meter of l-Alanine substance
For 60.0~100.0ml/mol；
(2) (S) -2- chloropropionic acid etherificate synthesis (R) -2- phenoxy propionic acid: by phenol, sodium hydroxide mix after room temperature without
(preferably 500rpm) is stirred under the conditions of oxygen makes phenol be converted into sodium phenate, and (being preferably slowly added dropwise with constant pressure separatory funnel) slowly drips
(the S) -2- chloropropionic acid sodium for adding step (1) to prepare, adds catalyst, and 45-125 DEG C, after pH value is 12-13 fully reacting, instead
Liquid tune pH=4.0, stratification are answered, pH≤2.0 are mutually adjusted in water intaking, are filtered, and filter cake drying obtains (R) -2- phenoxy propionic acid；It is described
Sodium hydroxide is added in the form of 300g/L sodium hydrate aqueous solution, and the ratio between amount of the sodium hydroxide and phenol substance is 1.2-
The ratio between the amount of 2.0:1 (preferably 1.25:1), (the S) -2- chloropropionic acid sodium and phenol substance 0.9~1.3:1 (preferably 1.2:1),
The ratio between amount of the catalyst and phenol substance is 0.1~0.5:1 (preferably 0.25:1), and the catalyst is dehydrated alcohol or iodine
Change potassium.
The present invention synthesizes (R)-PPA reaction mechanism: 2. nitrous acid generates nitrous acyl cation through reversible reaction, sub-
Nitryl cation and the nitrous acid of protonation as the lone pair electrons on the amino N atom in diazo reagent and l-Alanine into
Row, which combines, generates N- nitroso reactive intermediate, then by 4. 5. 6. 7. waiting series of proton transfer, generates 2- azido third
Acid, the Cl in reaction system-Unimolecular nucleophilic substitution (SN1) is carried out to α-C in 2- azido propionic acid, ultimately generates (S) -2- chlorine
Propionic acid.(S) α-C shows positive electricity in -2- chloropropionic acid, bimolecular nucleophilic substitution (SN2) can be carried out by benzene negative oxygen ion, due to phenyl ring
Steric hindrance it is larger, nucleophilic attack is from Cl-The back side carries out, after benzene negative oxygen ion is combined with α-C in (S) -2- chloropropionic acid, Cl-
It leaves away, completes substitution reaction, replace process at configuration reversal occurs, finally obtain (R) -2- phenoxy propionic acid (such as Fig. 2).
Compared with prior art, the method for the present invention beneficial effect is mainly reflected in:
The present invention relates to one kind using l-Alanine as starting material, obtains (S) -2- chloropropionic acid through diazotising, chlorination, then pass through
The molar yield of etherification reaction, the method for obtaining (R)-PPA, (R) -2- phenoxy propionic acid is up to 92.45%.The present invention is for the first time
The chemical synthesis process of (R)-PPA is proposed, has many advantages, such as that raw material cheap and easy to get, simple process and product purity are higher.
Furthermore the foundation of this method is to bioanalysis preparation virtue phenoxy phenoxy propionic acid herbicide intermediate (R)-HPPA industrialization
It plays an important role and the development and application of supermolecule metal organic framework complex has great importance.
Detailed description of the invention
Fig. 1 is (R)-PPA synthetic route.
Fig. 2 is (R)-PPA synthetic reaction mechanism.
Fig. 3 is the influence that different l-Alanine synthesize (S) -2- chloropropionic acid with hydrochloric acid molar ratio.
Fig. 4 is the influence that different l-Alanine synthesize (S) -2- chloropropionic acid with nitrous acid molar ratio.
Fig. 5 is the influence that different l-Alanine synthesize (S) -2- chloropropionic acid with potassium chloride molar ratio.
Fig. 6 is influence of the different temperatures to synthesis (R)-PPA.
Fig. 7 is influence of the different catalysts to (R)-PPA molar yield.
Fig. 8 is the influence that different phenol synthesize (R)-PPA with potassium iodide molar ratio.
Fig. 9 is the influence that different phenol synthesize (R)-PPA with (S) -2- chloropropionic acid sodium molar ratio.
Figure 10 is embodiment 1 (S) -2- chloropropionic acid gas chromatographic detection standard curve.
Figure 11 is embodiment 1 (R)-PPA high performance liquid chromatography detection standard curve.
Figure 12 is the 1H NMR spectra of (the R)-PPA standard items (a) of embodiment 1 and synthetic product (b).
Figure 13 is the 13C NMR spectra of (the R)-PPA standard items (a) of embodiment 1 and synthetic product (b).
Figure 14 is the FTIR spectrum figure of (the R)-PPA standard items (a) of embodiment 1 and synthetic product (b).
The high-efficient liquid phase chromatogram of 1 synthetic product (a) of Figure 15 embodiment and (R)-PPA standard items.
Specific embodiment
The present invention is described further combined with specific embodiments below, but protection scope of the present invention is not limited in
This:
Embodiment 1
1, reagent and instrument
Instrument: 2695 type high performance liquid chromatograph of Waters；Autopol IV-T polarimeter；Bruker AVANCE
III500MHz type nuclear magnetic resonance spectrometer；6700 Fourier transformation infrared spectrometer of Nicolet.
Reagent: l-Alanine (AR), uncommon love (Shanghai) the chemical conversion industry Development Co., Ltd of ladder；Phenol (AR), Chinese medicines group
Chemical reagent Co., Ltd；Sodium carbonate (AR), granary Mei Da reagent Co., Ltd；Potassium chloride (AR), Chinese medicines group chemical reagent
Co., Ltd；Potassium iodide (AR), Sinopharm Chemical Reagent Co., Ltd.；Hydrochloric acid (36-38%, AR), western Gansu Province science share have
Limit company；Sodium nitrite (AR), Guangdong Guanghua Science and Technology Co., Ltd.；Sodium hydroxide (AR), the western limited public affairs of Gansu Province science share
Department.
2, the drafting of (S) -2- chloropropionic acid gas chromatographic detection standard curve
Gas chromatographic column: capillary column (30m × 0.25mm)；Detector: FID；N2Flow velocity: 30mL/min；H2Flow velocity:
40mL/min；O2Flow velocity: 400mL/min: column temperature: 100 DEG C；Temperature of vaporization chamber: 220 DEG C；Detector temperature: 250 DEG C；Sample introduction
Amount: temperature programming: 5 μ L are warming up to 200 DEG C in 100 DEG C of holding 4min, then with the speed of 20 DEG C/min.
(the S) -2- chloropropionic acid standard ethyl acetate solution for preparing 0.2,0.4,0.6,0.8 and 1.0g/L, passes through gas phase color
Spectrometer detection, drafting (S) -2- chloropropionic acid peak area are X-axis, and (S) -2- chloropropionic acid concentration is the X-Y standard curve of Y-axis, are such as schemed
10。
3, the drafting of (R)-PPA high performance liquid chromatography detection standard curve
HPLC testing conditions: C18 chromatographic column: 250mm × 4.6mm；Mobile phase: phosphate aqueous solution (phosphate aqueous solution pH=
2): acetonitrile=6:4；Flow velocity, 1mL/min；Detector DAD；Detection wavelength: 220nm；Sample volume, 5 μ L；Column temperature: 30 DEG C.
(the R)-PPA standard aqueous solution for preparing 0.2,0.4,0.6,0.8 and 1.0g/L, is detected by HPLC, is drawn (R)-
PPA peak area is X-axis, and (R)-PPA concentration is the X-Y standard curve of Y-axis, such as Figure 11.
4, (R)-PPA is synthesized
(1) l-Alanine diazotising, chlorination synthesize (S) -2- chloropropionic acid
Addition 53.46g (0.6mol) l-Alanine in the three-necked flask of 1000mL, 187.5mL hydrochloric acid (8.0mol/L),
8mol/L sodium nitrite in aqueous solution is slowly added dropwise after 500rpm stirring is cooled to 0 DEG C in 44.76g (0.7mol) potassium chloride dropwise
90.0mL, time for adding are about 3h, and solution turned yellow during dropwise addition has gas to emerge；After completion of dropwise addition, in order to fill reaction
Point, continuation stirs 2h under the conditions of 0 DEG C；Then room temperature (25-30 DEG C, similarly hereinafter) is warmed naturally to, should be stirred continuously in the process, when
Between at least 6h；63.6g (0.6mol) sodium carbonate solid is added portionwise, stirs 1h, is extracted, be associated with isopropyl ether after reaction
60mL 300g/L sodium hydrate aqueous solution is added in machine phase 130ml, is stirred to react 1h, and stratification separates water phase, obtains (S)-
(hydrochloric acid acidification is added in sampling to 2- chloropropionic acid sodium, ethyl acetate solution is made into, through vapor detection, in conjunction with (S) -2- chloropropionic acid gas phase
Chromatography examination criteria curve, total amount 46.98g), for reacting in next step.
(2) (S) -2- chloropropionic acid etherificate synthesis (R)-PPA
28.23g phenol (0.3mol) is added in the three-necked flask of 1000mL, 50mL 300g/L sodium hydrate aqueous solution,
500rpm is stirred to react 1h under room temperature oxygen free condition, is slowly added dropwise with constant pressure separatory funnel into 0.36mol step (1) preparation
(S) 0.075mol potassium iodide is added in -2- chloropropionic acid sodium, and 125 DEG C of back flow reaction 1.5h, in reflux course, pH value of reaction system is
12-13, reaction solution is acidified to pH=4.0 with hydrochloric acid after reaction, there is yellow oil precipitation, separates water phase, water phase while hot
PH≤2.0 are acidified to hydrochloric acid, a large amount of white powdery solids are precipitated, filter while hot, is dried, is obtained (R)-PPA 23.52g, rub
That yield 42.61%.
(3) characterization of synthetic product
1) synthetic product and (R)-PPA standard items1H NMR analysis
From1H NMR spectra (Figure 12), which can be seen that, 6 proton in compound, proton ratio 3:1:2:1:2:1, always
Proton number be 10.There is obvious CH between chemical shift δ=1-5ppm3The peak shape of-CH-, chemical shift δ=1.5ppm are
CH3Methyl peak in-CH-, 3 protons, one methyl are split into double peak by adjacent tertiary base；Chemical shift δ=4.8ppm is
CH3Tertiary base peak in-CH-, 1 proton, one tertiary base, may connect oxygen atom, so resonating compared with low field, while be abutted
Methyl is split into quartet.There is obvious phenyl ring peak shape between chemical shift chemical shift δ=6-9ppm, there is 3 proton, and proton
Number is 5, illustrates there is a substituent group on phenyl ring, has double peak at chemical shift δ=6.8ppm, illustrate on coupled carbon
Only 1 proton, and the proton number at this is 2, i.e. proton at chemical shift δ=6.8ppm is the ortho position matter on phenyl ring
Son；There is triplet at chemical shift δ=6.9ppm, illustrates on coupled carbon there are two identical proton, and the matter at this
Subnumber is 1, i.e. proton at chemical shift δ=6.9ppm is the para proton on phenyl ring；Have at chemical shift δ=7.2ppm
Quartet illustrates that there are two different protons on coupled carbon, and the proton number at this is 2, i.e. chemical shift δ=
Proton at 7.2ppm is the meta position proton on phenyl ring.There is the peak shape of obvious-COOH at chemical shift δ=13ppm, and is a weight
Peak illustrates do not have proton in carboxyl carbon.Through analyzing, there are methyl proton, tertiary matrix, carboxylic protons and phenyl ring matter on the compound
Son, with standard sample1The comparison of H NMR spectra, which is 2- phenoxy propionic acid.
2) synthetic product and (R)-PPA standard items13C NMR analysis
From13C NMR spectra (Figure 13) is as can be seen that share 8 groups of peaks, wherein 7 weights at chemical shift δ=39-41ppm
Peak is the characteristic peak of carbon in solvent deuterated dimethyl sulfoxide；Other 7 groups of peaks illustrate containing there are 7 kinds of varying environments in compound
Carbon-based group.Peak at chemical shift δ=173.149ppm is the characteristic peak of carboxyl carbon；At chemical shift δ=157.477ppm
Peak is the characteristic peak that carbon is substituted on phenyl ring, and chemical shift δ=129.515,120.946, the peak at 114.749ppm are all benzene
The characteristic peak of unsubstituted carbon on ring, and phenyl ring is total13The spectral line number of C is 4, less than the C number in Benzene Molecule formula, illustrates benzene
There are the identical carbon-containing groups of two groups of environment on ring, i.e. phenyl ring is monosubstituted；Peak at chemical shift δ=71.416ppm is C-O
The characteristic peak of middle carbon；Peak at chemical shift δ=18.340ppm is the characteristic peak of methyl carbon.Through analyzing, on the compound in total
There are 9 carbon atoms, has methyl carbon, tertiary base carbon, carboxyl carbon and phenyl ring carbon, in conjunction with the compound1H NMR spectra, and and standard
Sample13The comparison of C NMR spectra, which is 2- phenoxy propionic acid.
3) FTIR spectrum of synthetic product and (R)-PPA standard items is analyzed
From FTIR spectrogram (Figure 14) as can be seen that in 3064.1cm-1And 1600-1450cm-1(1674.7cm-1、1589cm-1、1487.3cm-1And 1453cm-1) at the absorption peak that generates be aromatic ring characteristic absorption peak, wherein 3064.1cm-1It is flexible for C-H
The characteristic absorption peak of vibration, 1600-1450cm-1For the characteristic absorption peak of C=C skeletal vibration, illustrate exist in gained compound
Benzene ring structure；In 1227cm-1And 1043.7cm-1The absorption peak that place generates is that the feature of two C-O stretching vibrations in aromatic ether is inhaled
Peak is received, wherein 1227cm-1For Ar-O stretching absorbance peak, 1043.7cm-1For R-O stretching absorbance peak, this can illustrate that reaction generates
Fragrant ether structure；1713cm-1、1291.4cm-1And 915cm-1The absorption peak that place generates is the characteristic absorption peak of carboxyl, wherein
1713cm-1For C=O stretching absorbance peak, 1291.4cm-1For C-O stretching absorbance peak, 915cm-1It is absorbed for the bending vibration of O-H key
Peak illustrates that there are carboxyl functional groups in compound；2939.6cm-1The absorption peak that place generates is that saturation C-H stretching vibration feature is inhaled
Peak is received, illustrates that there are methyl in compound；691cm-1Locate appearance, show as monosubstituted, illustrates that only one H is taken on phenyl ring
Generation.In conjunction with the compound1H NMR spectra and13C NMR spectra, and compared and analyzed with the FTIR spectrogram of standard specimen, Ke Yichu
Step determination has synthesized 2- phenoxy propionic acid, the optical value measured in conjunction with polarimeter(C=1, CH3OH；Standard specimen
Value) R configuration can be determined as, i.e., gained synthetic is (R)-PPA.
4) efficient liquid phase chromatographic analysis of synthetic product and (R) -2- phenoxy propionic acid standard items
Product (dries to constant weight) after 65 DEG C of baking ovens are dried after hydrochloric acid is acidified and is precipitated and filters, and takes appropriate amount of sample with ultrapure
Water is configured to the solution that concentration is less than 1.0g/L, and liquid phase detection is carried out after 0.22 μm of filtering with microporous membrane.Under similarity condition with
(R) -2- phenoxy propionic acid standard items are control.
(such as Figure 15) is detected, after being calculated by (R) -2- phenoxy propionic acid standard curve as a result, determining preliminary extract
The purity of product is 95.24%.
Embodiment 2 (S) -2- chloropropionic acid optimum conditions
1, l-Alanine and the molar ratio of hydrochloric acid optimize
Experimental implementation is changed to 1:2,1:2.5 with embodiment 1, by the molar ratio of 1 step of embodiment (1) l-Alanine and hydrochloric acid
And 1:3, after sodium nitrite is added dropwise, 2.5h is reacted respectively, is sampled every 0.5h, the conversion through vapor detection l-Alanine
Rate investigates the influence that l-Alanine synthesizes (S) -2- chloropropionic acid with the molar ratio of hydrochloric acid, as a result such as Fig. 3, to select best
Hydrochloric acid dosage.
From the figure 3, it may be seen that increasing the amount of hydrochloric acid, is conducive to the synthesis of (S) -2- chloropropionic acid, works as l-Alanine: hydrochloric acid 1:
When 2.5 (mol/mol), the molar yield highest of (S) -2- chloropropionic acid is 60.50%, as the amount for further increasing hydrochloric acid, L-
Alanine: when hydrochloric acid is 1:3.0 (mol/mol), it is unfavorable for the synthesis of (S) -2- chloropropionic acid, product molar conversion ratio reduces.It can
It can be because excessive hydrochloric acid makes l-Alanine generate ammonium salt, ammonium salt hydrolysis generates unhindered amina, and nitrous acid is in acidic environment
It easily ionizes, is unfavorable for the progress of diazo-reaction.So the best material ratio of this experiment is l-Alanine: hydrochloric acid 1:
2.5(mol/mol)。
2, l-Alanine and the molar ratio of nitrous acid optimize
Experimental implementation with embodiment 1, by the molar ratio of 1 step of embodiment (1) l-Alanine and nitrous acid be changed to 1:1.0,
1:1.2 and 1:1.5 after sodium nitrite is added dropwise, reacts 2.5h respectively, samples every 0.5h, through vapor detection l-Alanine
Conversion ratio, investigate the influence that synthesize with the molar ratio of sodium nitrite to (S) -2- chloropropionic acid of l-Alanine, as a result such as Fig. 4, from
And select best sodium nitrite dosage.
As shown in Figure 4, the amount for increasing nitrous acid is conducive to the synthesis of (S) -2- chloropropionic acid, works as l-Alanine: sodium nitrite
When for 1:1.2 (mol/mol), the molar yield highest of (S) -2- chloropropionic acid is 65.10%, when further increasing nitrous acid
Amount, l-Alanine: when nitrous acid is 1:1.5 (mol/mol), being unfavorable for the synthesis of (S) -2- chloropropionic acid, product molar conversion
Rate reduces.It may be to be unfavorable for weight because excessive sodium nitrite can make coupling component nitrosation, oxidation or other reactions occur
The progress of nitridation reaction.So the best material ratio of this experiment is l-Alanine: nitrous acid is 1:1.2 (mol/mol).
3, l-Alanine and the molar ratio of potassium chloride optimize
Experimental implementation with embodiment 1, by the molar ratio of 1 step of embodiment (1) l-Alanine and potassium chloride be changed to 1:0.5,
1:0.7 and 1:0.9 after sodium nitrite is added dropwise, reacts 2.5h respectively, samples every 0.5h, through vapor detection l-Alanine
Conversion ratio, investigate the influence that synthesize with the molar ratio of potassium chloride to (S) -2- chloropropionic acid of l-Alanine, as a result such as Fig. 5, thus
Select best sodium nitrite dosage.
As shown in Figure 5, the amount for increasing potassium chloride, is conducive to the synthesis of (S) -2- chloropropionic acid, works as l-Alanine: potassium chloride is
When 1:0.7 (mol/mol), the molar yield highest of (S) -2- chloropropionic acid is 65.10%, when further increasing nitrous acid
L-Alanine: amount when potassium chloride is 1:0.9 (mol/mol), is unfavorable for the synthesis of (S) -2- chloropropionic acid, product molar conversion ratio
It reduces.It may be that it is anti-to be unfavorable for diazotising because of the excessively high solubility that can reduce other reagents of potassium chloride concentration in reaction system
The progress answered.So the best material ratio of this experiment is l-Alanine: potassium chloride is 1:0.7 (mol/mol).
Embodiment 3 (R)-PPA optimum conditions
1, the optimization of etherification reaction temperature
Experimental implementation is changed to 25,45,65,85 and 125 with embodiment 1, by the etherification reaction temperature of 1 step of embodiment (2)
DEG C, 3h is reacted respectively, and interval 0.5h sampling investigates etherification reaction temperature to (R) -2- benzene oxygen through HPLC detection substrate conversion ratio
The influence of base propionic acid synthesis, as a result such as Fig. 6, to select optimal reaction temperature.
It will be appreciated from fig. 6 that temperature increases the synthesis for being conducive to (R) -2- phenoxy propionic acid, it is different when reaching 125 DEG C of reflux
(R) -2- phenoxy propionic acid molar yield in reaction time is above other temperature.This may be because reflux on the one hand can be with
Anakmetomeres number is improved, mixing well for each reactant in reaction system is on the other hand facilitated, reaction can be made to carry out more
Sufficiently.When being heated to reflux 1.5h for 125 DEG C, (R) -2- phenoxy propionic acid molar yield reaches 92.45% (in terms of phenol).It returns
After flowing 2.5h, with the increase of return time, (R) -2- phenoxy propionic acid molar yield is gradually decreased.Experimental selection is most preferably warm
Degree is 125 DEG C, return time 1.5h.
2, the optimization of etherification reaction catalyst
Experimental implementation is changed to 0.075mol ethylene glycol with embodiment 1, by 1 step of embodiment (2) catalyst potassium iodide, simultaneously
Not add catalyst as control, influence of the catalyst to etherification reaction is investigated, as a result such as Fig. 7, to select optimal catalysis
Agent.
As seen from Figure 7, two kinds of catalyst of ethylene glycol and potassium iodide have apparent facilitation to etherification reaction, (R)-
PPA molar yield is improved.Under 125 DEG C of counterflow conditions, catalyst be ethylene glycol when, (R)-PPA molar yield by
The 70.21% of control is increased to 83.40% (in terms of phenol)；When using potassium iodide as catalyst, (R)-PPA molar yield is by right
According to 70.21% be increased to 92.45% (in terms of phenol).So selecting catalyst of the potassium iodide as etherification reaction.
3, the optimization of phenol and potassium iodide molar ratio
Experimental implementation is changed to 1:0.1,1 with embodiment 1, by the molar ratio of 1 step of embodiment (2) phenol and potassium iodide:
0.25 and 1:0.5, maintenance initial reaction system pH are 12-13, react 1.5h respectively, investigate different phenol and potassium iodide
The influence that molar ratio synthesizes (R) -2- phenoxy propionic acid, as a result such as Fig. 8.
As shown in Figure 8, the amount for increasing potassium iodide, is conducive to the synthesis of (R) -2- phenoxy propionic acid, works as phenol: potassium iodide is
When 1:0.25 (mol/mol), the molar yield highest of (R) -2- phenoxy propionic acid is 92.45%, when further increasing iodate
The amount of potassium, phenol: when potassium iodide is 1:0.5 (mol/mol), product molar conversion ratio is not significantly improved.Illustrate to work as phenol: iodine
When change potassium is 1:0.25 (mol/mol), the amount of potassium iodide is enough.So the best material ratio of this experiment is phenol: iodate
Potassium=1:0.25 (mol/mol).
4, the optimization of phenol and (S) -2- chloropropionic acid molar ratio
Experimental implementation is changed to 1 with embodiment 1, by the molar ratio of 1 step of embodiment (2) phenol and (S) -2- chloropropionic acid:
0.9,1:1.0,1:1.1,1:1.2 and 1:1.3, maintenance initial reaction system pH are 12-13, react 1.5h respectively, investigate not
The influence that same phenol synthesizes (R) -2- phenoxy propionic acid with the molar ratio of (S) -2- chloropropionic acid, as a result such as Fig. 9.
As shown in Figure 8, the amount for increasing (S) -2- chloropropionic acid, is conducive to the synthesis of (R) -2- phenoxy propionic acid, works as phenol:
(S) when -2- chloropropionic acid is 1:1.2 (mol/mol), the molar yield highest of (R) -2- phenoxy propionic acid is 92.45%, when
The amount of (S) -2- chloropropionic acid is further increased, phenol: when (S) -2- chloropropionic acid is 1:1.3 (mol/mol), being unfavorable for (R) -2- benzene
The synthesis of oxygroup propionic acid, product molar conversion ratio reduce.It may be because excessive (S) -2- chloropropionic acid is easy in alkaline environment
Hydrolysis occurs, generates lactic acid, reduces the pH value of reaction system, is unfavorable for phenol and carries out nucleophilic substitution.So this reality
The best material ratio tested is phenol: (S) -2- chloropropionic acid=1:1.2 (mol/mol).
4 propionic acid of embodiment is Material synthesis (S) -2- chloropropionic acid
First 148g propionic acid (2mol) and 3.7g red phosphorus (0.12mol, co-catalyst) are heated in 1000ml reaction kettle
120-122 DEG C, then lead to people 42.24gSO2And 184.34gCl2, after reacting and carrying out completely, rectification under vacuum mixed liquor collects 84
DEG C/fraction of 1.6kPa is 2- chloropropionic acid, total amount 183.83g.Reaction condition are as follows: propionic acid: SO2:Cl2(mole)=1:0.33:
1.3,120-122 DEG C of reaction temperature, gas boot speed: SO2For 0.16g/min, Cl2For 0.7g/min.During chloro
(S) -2- chloropropionic acid and two kinds of isomers of (R) -2- chloropropionic acid are generated, and are difficult to split out pure (S) -2- chloropropionic acid, gained produces
Object 2- chloropropionic acid is not suitable as the raw material of synthesis (R)-PPA.
5 lactic acid of embodiment is Material synthesis (R)-PPA
28.23g phenol (0.3mol) is added in the three-necked flask of 1000mL, 50.0mL 300g/L sodium hydroxide is water-soluble
Liquid, 500rpm is stirred to react 1h under room temperature oxygen free condition, is slowly added dropwise with constant pressure separatory funnel into 0.36mol lactic acid, is added
0.075mol potassium iodide, 125 DEG C of back flow reaction 3h, every 0.5 sampling.It detects through liquid phase, is produced without (R)-PPA.
Claims (10)
1. a kind of chemical synthesis process of (R) -2- phenoxy propionic acid, it is characterised in that the method carries out as follows:
(1) using l-Alanine as raw material, using sodium nitrite as diazo reagent, under the action of hydrochloric acid, potassium chloride and sodium carbonate
Diazotising and chlorination reaction are carried out, after reaction, reaction solution isolates and purifies, and obtains (S) -2- chloropropionic acid sodium；
(2) (S) -2- chloropropionic acid sodium is 12-13 condition in 45-125 DEG C, pH value under phenol, sodium hydroxide and catalyst action
Lower carry out etherification reaction, after fully reacting, reaction solution post-processing obtains (R) -2- phenoxy propionic acid；The catalyst is anhydrous
Ethyl alcohol or potassium iodide.
2. the chemical synthesis process of (R) -2- phenoxy propionic acid as described in claim 1, it is characterised in that step (1) described diazonium
Change and chlorination reaction method are as follows: l-Alanine, hydrochloric acid, potassium chloride are mixed, after stirring is cooled to 0 DEG C, nitrous acid is added dropwise dropwise
Sodium after completion of dropwise addition, continues stirring and reacts fully, be then warmed to room temperature, sodium carbonate is added, is stirred at room temperature after reaction,
Reaction solution isolates and purifies, and obtains (S) -2- chloropropionic acid sodium.
3. the chemical synthesis process of (R) -2- phenoxy propionic acid as claimed in claim 2, it is characterised in that step (1) described hydrochloric acid
Be added in the form of 8.0mol/L aqueous solution, the ratio between amount of the hydrochloric acid and l-Alanine substance is 2-3:1, the potassium chloride with
The ratio between amount of l-Alanine substance is 0.5~0.9:1；The sodium nitrite is added in the form of 8mol/L sodium nitrite in aqueous solution,
The ratio between amount of the sodium nitrite and l-Alanine substance is 1.0-1.5:1；The amount of the sodium carbonate and l-Alanine substance it
Than for 0.5~1.0:1.
4. the chemical synthesis process of (R) -2- phenoxy propionic acid as claimed in claim 2, it is characterised in that step (1) reaction solution point
From purification process are as follows: after reaction, reaction solution is extracted with isopropyl ether, merges organic phase, and sodium hydrate aqueous solution is added, makes to give birth to
At (S) -2- chloropropionic acid become (S) -2- chloropropionic acid sodium, stratification removes organic phase, retains water phase, obtains (S) -2- chlorine third
Sour sodium.
5. the chemical synthesis process of (R) -2- phenoxy propionic acid as described in claim 1, it is characterised in that step (2) etherification reaction
Method are as follows: stirring makes phenol be converted into sodium phenate under room temperature oxygen free condition after mixing phenol, sodium hydroxide, and step is slowly added dropwise
Suddenly (S) -2- chloropropionic acid sodium of (1) preparation, adds catalyst, under being 12-13 in 45-125 DEG C, pH value after fully reacting, instead
It answers liquid to post-process, obtains (R) -2- phenoxy propionic acid.
6. the chemical synthesis process of (R) -2- phenoxy propionic acid as claimed in claim 5, it is characterised in that step (2) described hydrogen-oxygen
Change sodium to be added in the form of 300g/L sodium hydrate aqueous solution, the ratio between amount of the sodium hydroxide and phenol substance is 1.2-2.0:
1,0.9~1.3:1 of the ratio between (the S) -2- chloropropionic acid sodium and the amount of phenol substance, the ratio between the amount of the catalyst and phenol substance
For 0.1~0.5:1.
7. the chemical synthesis process of (R) -2- phenoxy propionic acid as claimed in claim 6, it is characterised in that described in step (2) (S) -
The ratio between amount of 2- chloropropionic acid and phenol substance is 1.2:1.
8. the chemical synthesis process of (R) -2- phenoxy propionic acid as claimed in claim 6, it is characterised in that step (2) described catalysis
The ratio between amount of agent and phenol substance is 0.25:1.
9. the chemical synthesis process of (R) -2- phenoxy propionic acid as claimed in claim 5, it is characterised in that after step (2) reaction solution
The method of processing are as follows: after fully reacting, reaction solution tune pH=4.0, stratification fetches water and mutually adjusts pH≤2.0 pH, filters, filter cake
Drying, obtains (R) -2- phenoxy propionic acid.
10. the chemical synthesis process of (R) -2- phenoxy propionic acid as described in claim 1, it is characterised in that the method is by as follows
Step carries out: (1) l-Alanine diazotising, chlorination synthesize (S) -2- chloropropionic acid sodium: l-Alanine, 8mol/L hydrochloric acid is water-soluble
8mol/L sodium nitrite in aqueous solution is added dropwise after 500rpm stirring is cooled to 0 DEG C in liquid, potassium chloride mixing dropwise, after completion of dropwise addition,
Continue stirring to react fully, then heats to room temperature；Sodium carbonate is added portionwise again, after reaction, reaction solution isopropyl ether
Extraction merges organic phase, and 300g/L sodium hydrate aqueous solution is added, and the chloropropionic acid generated is made to become chloropropionic acid sodium, stratification
Remove organic phase, retain water phase, obtains (S) -2- chloropropionic acid sodium；The amount of hydrochloric acid and l-Alanine substance in the aqueous hydrochloric acid solution
The ratio between meter is 2.5:1, and the ratio between the potassium chloride and the amount of l-Alanine substance are 0.7:1；The sodium nitrite in aqueous solution Central Asia
The ratio between amount of sodium nitrate and l-Alanine substance is 1.2:1, and the ratio between the sodium carbonate and the amount of l-Alanine substance are 0.5:1；
The sodium hydrate aqueous solution volumetric usage is calculated as 60.0~100.0ml/mol with the amount of l-Alanine substance；
(2) (S) -2- chloropropionic acid sodium etherificate synthesis (R) -2- phenoxy propionic acid:
500rpm stirring makes phenol be converted into benzene under room temperature oxygen free condition after phenol, 300g/L sodium hydrate aqueous solution are mixed
Phenol sodium is slowly added dropwise (S) -2- chloropropionic acid sodium of step (1) preparation, adds catalyst, 45-125 DEG C, pH value be that 12-13 is anti-
After answering completely, reaction solution tune pH=4.0, stratification, mutually tune pH≤2.0, suction filtration, filter cake are dried for water intaking, obtain (R) -2- benzene oxygen
Base propionic acid；The ratio between amount of sodium hydroxide and phenol substance is 1.25:1, (the S) -2- chlorine third in the sodium hydrate aqueous solution
The ratio between amount of sour sodium and phenol substance is 1.2:1, and the catalyst is dehydrated alcohol or potassium iodide, the catalyst and phenol object
The ratio between amount of matter is 0.25:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811009516.7A CN109111355A (en) | 2018-08-31 | 2018-08-31 | A kind of chemical synthesis process of (R) -2- phenoxy propionic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811009516.7A CN109111355A (en) | 2018-08-31 | 2018-08-31 | A kind of chemical synthesis process of (R) -2- phenoxy propionic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109111355A true CN109111355A (en) | 2019-01-01 |
Family
ID=64860320
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811009516.7A Pending CN109111355A (en) | 2018-08-31 | 2018-08-31 | A kind of chemical synthesis process of (R) -2- phenoxy propionic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109111355A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH10279521A (en) * | 1997-04-07 | 1998-10-20 | Daito Kagaku Kk | Production of optically active 2-aryloxypropionic acid |
| CN103922923A (en) * | 2014-03-24 | 2014-07-16 | 广东广益科技实业有限公司 | Industrial production method of 2-(4-methoxyphenoxy)sodium propionate |
| CN105732358A (en) * | 2016-04-06 | 2016-07-06 | 衢州信步化工科技有限公司 | Synthesizing method of L-2-sodium chloropropionate |
| KR20170142035A (en) * | 2016-06-16 | 2017-12-27 | (주) 에프엔지리서치 | Novel method for preparing hexamethyl propyleneamine oxime and intermediate thereof |
| CN107827734A (en) * | 2017-11-23 | 2018-03-23 | 中山奕安泰医药科技有限公司 | A kind of synthesis technique of 2 phenoxy group propionyl chloride |
-
2018
- 2018-08-31 CN CN201811009516.7A patent/CN109111355A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH10279521A (en) * | 1997-04-07 | 1998-10-20 | Daito Kagaku Kk | Production of optically active 2-aryloxypropionic acid |
| CN103922923A (en) * | 2014-03-24 | 2014-07-16 | 广东广益科技实业有限公司 | Industrial production method of 2-(4-methoxyphenoxy)sodium propionate |
| CN105732358A (en) * | 2016-04-06 | 2016-07-06 | 衢州信步化工科技有限公司 | Synthesizing method of L-2-sodium chloropropionate |
| KR20170142035A (en) * | 2016-06-16 | 2017-12-27 | (주) 에프엔지리서치 | Novel method for preparing hexamethyl propyleneamine oxime and intermediate thereof |
| CN107827734A (en) * | 2017-11-23 | 2018-03-23 | 中山奕安泰医药科技有限公司 | A kind of synthesis technique of 2 phenoxy group propionyl chloride |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101817713B (en) | Preparation method of 2, 2'-biphenyl diphenol and derivatives thereof | |
| CN103145568A (en) | Cardanol cationoid quaternary ammonium salt and preparation method thereof | |
| CN109020889A (en) | A kind of pyrazole carboxylic acid copper complex and its preparation method and application | |
| CN110938077A (en) | Method for synthesizing Avapritinib | |
| CN101219399B (en) | Preparation method and application of N-heterocyclic carbine metal palladium catalyst | |
| CN106749259B (en) | A kind of synthetic method of cyclopenta pyrimido azoles | |
| CN101941947A (en) | Synthesis method of 2-chloro-6-chloroquinoxaline | |
| CN109111355A (en) | A kind of chemical synthesis process of (R) -2- phenoxy propionic acid | |
| CN113248437B (en) | Tetraphenyl vinyl poly-pyrazole nitrogen-containing heterocyclic compound and preparation method and application thereof | |
| CN100408544C (en) | Synthesis method of glycollate | |
| US20170131256A1 (en) | Carboxylate-bridged binuclear iron-sulfur clusters flourescent probe, preparation method and application thereof | |
| CN105732331A (en) | Synthesis method of 1-pyrenol and intermediates thereof | |
| CN102698768B (en) | Catalyst used in preparation of fluorine-containing low carbon alcohol and preparation method for catalyst | |
| CN102010378B (en) | Preparation method of quizalofop-p-ethyl | |
| CN109400555A (en) | A kind of α-acetyl group-gamma-butyrolacton sodium salt free hydrochloric acid ethanamidine technique | |
| CN108752205A (en) | The industrialized production modified technique of one kind (R) -2- (4- chloro-2-methyl benzene oxygen) octyl propionate root resistance agent | |
| CN105669413B (en) | A kind of method that microwave radiation prepares 2- methyl-1,4-naphthaquinone | |
| CN109942456B (en) | Method for synthesizing p-benzoquinone monoimine from p-aminophenol | |
| CN103922934B (en) | The alkylation of active methylene compound | |
| CN103073420A (en) | Method for catalytic esterification of -SO3H-containing metal-organic framework compound | |
| CN105622642A (en) | Voriconazole copper nitrate complex with bacteriostatic activity and preparation method thereof | |
| CN110483403A (en) | A kind of synthetic method of the bromo- 4- methoxyl group -1H- indazole of 5- | |
| CN110294768A (en) | A method of pinoxaden is synthesized by 2,6- diethyl -4- methylbenzene malonate | |
| CN102558196A (en) | Method for preparing (3,4)-1,4-dioxoethylidene thiophene-2'-methanol | |
| CN115448813B (en) | Method for preparing (S) -2, 6-dichloro-3-fluorophenylethanol |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190101 |
|
| RJ01 | Rejection of invention patent application after publication |