CN111995566A - Synthesis method of 2-hydroxyethyl pyridine - Google Patents
Synthesis method of 2-hydroxyethyl pyridine Download PDFInfo
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- CN111995566A CN111995566A CN201911317600.XA CN201911317600A CN111995566A CN 111995566 A CN111995566 A CN 111995566A CN 201911317600 A CN201911317600 A CN 201911317600A CN 111995566 A CN111995566 A CN 111995566A
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- methylpyridine
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- molar ratio
- formaldehyde
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- BXGYBSJAZFGIPX-UHFFFAOYSA-N 2-pyridin-2-ylethanol Chemical compound OCCC1=CC=CC=N1 BXGYBSJAZFGIPX-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 238000001308 synthesis method Methods 0.000 title description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 137
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims abstract description 132
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 97
- 239000002904 solvent Substances 0.000 claims abstract description 32
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical group C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 21
- 150000007530 organic bases Chemical class 0.000 claims abstract description 18
- 230000035484 reaction time Effects 0.000 claims abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 239000003513 alkali Substances 0.000 claims abstract description 4
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims abstract 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims abstract 2
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims abstract 2
- -1 hexamethylene diamine, tetramethyl Chemical group 0.000 claims abstract 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 20
- 229920002866 paraformaldehyde Polymers 0.000 claims description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- NAQMVNRVTILPCV-UHFFFAOYSA-N hexane-1,6-diamine Chemical compound NCCCCCCN NAQMVNRVTILPCV-UHFFFAOYSA-N 0.000 claims description 8
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 4
- FVKFHMNJTHKMRX-UHFFFAOYSA-N 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine Chemical compound C1CCN2CCCNC2=N1 FVKFHMNJTHKMRX-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 2
- 239000007789 gas Substances 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 claims 1
- 230000001476 alcoholic effect Effects 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 238000010189 synthetic method Methods 0.000 abstract description 2
- UURSXESKOOOTOV-UHFFFAOYSA-N dec-5-ene Chemical compound CCCCC=CCCCC UURSXESKOOOTOV-UHFFFAOYSA-N 0.000 abstract 1
- 239000012263 liquid product Substances 0.000 description 38
- 238000004128 high performance liquid chromatography Methods 0.000 description 25
- 229910001220 stainless steel Inorganic materials 0.000 description 15
- 239000010935 stainless steel Substances 0.000 description 15
- 238000004458 analytical method Methods 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 238000007664 blowing Methods 0.000 description 13
- 239000012295 chemical reaction liquid Substances 0.000 description 13
- 239000007810 chemical reaction solvent Substances 0.000 description 13
- 229910001873 dinitrogen Inorganic materials 0.000 description 13
- 238000005086 pumping Methods 0.000 description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 12
- 239000003054 catalyst Substances 0.000 description 12
- 239000001257 hydrogen Substances 0.000 description 12
- 229910052739 hydrogen Inorganic materials 0.000 description 12
- 238000001228 spectrum Methods 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000012973 diazabicyclooctane Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000002994 raw material Substances 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- MCMNRKCIXSYSNV-UHFFFAOYSA-N Zirconium dioxide Chemical compound O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000005711 Benzoic acid Substances 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000012847 fine chemical Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000003930 superacid Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- NRGGMCIBEHEAIL-UHFFFAOYSA-N 2-ethylpyridine Chemical compound CCC1=CC=CC=N1 NRGGMCIBEHEAIL-UHFFFAOYSA-N 0.000 description 1
- KGIGUEBEKRSTEW-UHFFFAOYSA-N 2-vinylpyridine Chemical compound C=CC1=CC=CC=N1 KGIGUEBEKRSTEW-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 229940106681 chloroacetic acid Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 229920006324 polyoxymethylene Polymers 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N titanium dioxide Inorganic materials O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthetic method of 2-hydroxyethyl pyridine. The preparation method comprises the following steps: reacting 2-methylpyridine with formaldehyde in a solvent under the pressure of 2-8MPa and the action of organic alkali; the organic base is triethylene diamine, hexamethylene diamine, tetramethyl guanidine, 1, 8-diazabicycloundecen-7-ene and 1,5, 7-triazabicyclo [ 4.4.0%]One or more of dec-5-ene. The method for preparing 2-hydroxyethyl pyridine obviously shortens the reaction time, has higher conversion per pass, and can save the production cost.
Description
Technical Field
The invention relates to a synthetic method of 2-hydroxyethyl pyridine.
Background
The 2-hydroxyethyl pyridine is a fine chemical product with wide application, can synthesize 2-vinylpyridine and other fine organic chemical intermediates, has wide application in the aspects of pesticides, medicines and the like, and has higher development value. At present, the 2-hydroxyethyl pyridine is mainly synthesized by taking polyformaldehyde or formaldehyde aqueous solution and 2-methylpyridine as raw materials.
In the patent application with the publication number of CN86103091A, 2-methylpyridine and formaldehyde aqueous solution are used as raw materials, the raw materials are reacted for 45-70 h at 105-128 ℃ under the catalysis of benzoic acid or acetic acid, the conversion per pass reaches 40-60%, then the 2-methylpyridine which is not completely reacted is recovered, new formaldehyde aqueous solution and 2-methylpyridine are added to be the initial proportion, and the reaction is carried out for multiple times until the yield of the target product reaches about 95% after eight times of reaction. Although the method is carried out at normal temperature and normal pressure, the single-pass conversion rate of the reaction is low, and the reaction needs a long time and is repeated for many times, so that the production efficiency is low, and the production cost is increased.
In patent application with publication number CN1580046A, 2-ethylpyridine is obtained by condensation reaction of 2-methylpyridine as raw material and paraformaldehyde at 100 ℃ for 30h in the presence of acetic acid, benzoic acid or chloroacetic acid as catalyst, wherein n (2-methylpyridine): n (paraformaldehyde): n (catalyst) ═ 1: 0.12: 0.012. the process method has the advantages that the consumption of the raw material 2-methylpyridine is too large, the amount of the obtained product 2-hydroxyethyl pyridine is less, the loss rate of the recovered 2-methylpyridine is high, and the production cost is obviously increased.
In patent application publication No. CN102731372A, an organic base (potassium methoxide, sodium methoxide, potassium ethoxide, sodium ethoxide, or lithium diisopropylamide) is used as a catalyst, and the molar ratio of the organic base to 2-methylpyridine is 1:1, reacting for 3-5 hours at-60 ℃ to obtain the product 2-hydroxyethyl pyridine. The method has very strict requirements on reaction operation due to the use of the organic base, and the organic base is expensive, difficult to recover and expensive, and difficult to industrialize.
An article of journal of fine chemical intermediate, vol 4, vol 42, 2012, explores the use of two catalysts, namely acid and alkali, and analyzes the catalytic effect in detail, finds that basic catalyst triethylamine is very beneficial to the addition reaction, and the author optimizes the conditions of the catalyst, the catalyst dosage, the reaction time, the reaction ratio and the like, wherein the specific feed ratio is n (2-methylpyridine): n (formaldehyde) ═ 5: 1, reacting for 40 hours under the action of catalyst triethylamine to obtain a product 2-hydroxyethyl pyridine. Although the reaction conditions are mild, the method has the disadvantages of long reaction time, low single-pass conversion rate and high cost, and is not favorable for industrial production.
In the patent publication No. CN102863375A, sodium hydroxide or potassium hydroxide is used as a catalyst, and the molar charge ratio of the formaldehyde solution to the 2-methylpyridine is 1:10, reacting for 1h in an autoclave at the pressure of 0.5MPa and the temperature of 160 ℃ to obtain the product 2-hydroxyethyl pyridine. The method has high requirements on process equipment, more reaction byproducts and low single-pass conversion rate of 2-methylpyridine.
In the publication CN104109114A, 2-methylpyridine and formaldehyde aqueous solution are used as raw materials, and 10% solid superacid based on 2-methylpyridine by mass is used as a catalyst (for example, WO 104109114A)3/ZrO2、SO2/ZrO2、WO3/TiQ2、SO2/TiO2Or SiO2Loaded benzoic acid) is reacted for 80min at 140 ℃ in an autoclave to obtain the 2-hydroxyethyl pyridine. Although the method has high synthesis efficiency, the method has more byproducts and tedious later separation, and has high requirements on equipment.
In the patent with publication number CN105237468A, paraformaldehyde and 2-methylpyridine are used as raw materials, oxalic acid as a catalyst and N, N-Dimethylformamide (DMF) as a solvent, and the reaction is performed at 110-120 ℃ for 30-40 h, and then the product 2-hydroxyethyl pyridine is obtained after rectification and post-treatment, and the 2-methylpyridine single-pass conversion rate is 35.15% by chromatography analysis, and the purity reaches 99.0%. Although the purity of the obtained product is high, the reaction time is long and the single-pass conversion rate is low.
Through the analysis, the processes reported in the literature and the patent mostly adopt the large molar charge ratio of the 2-methylpyridine and the formaldehyde, the reaction time is long, and the single-pass conversion rate of the 2-methylpyridine is low. When high-pressure reaction equipment is used, the equipment requirement is high, the number of byproducts is large, the purity is low, and the post-treatment is complicated. And solid super acid or organic base is used as a catalyst, so that the single-pass conversion rate of the reaction is low, the cost of raw materials is high, and the industrial production is not facilitated.
Disclosure of Invention
The invention aims to overcome the defects of long reaction time, low single-pass conversion rate, high production cost and the like of the existing preparation method of 2-hydroxyethyl pyridine and provides a synthesis method of 2-hydroxyethyl pyridine. The method for preparing 2-hydroxyethyl pyridine obviously shortens the reaction time, has higher conversion per pass, and can save the production cost.
The invention provides a preparation method of 2-hydroxyethyl pyridine, which comprises the following steps: reacting 2-methylpyridine with formaldehyde in a solvent under the pressure of 2-8MPa and in the presence of organic alkali; the organic base is one or more of triethylene Diamine (DABCO), hexamethylene diamine, tetramethylguanidine, 1, 8-diazabicycloundecen-7-ene (DBU) and 1,5, 7-triazabicyclo [4.4.0] dec-5-ene (TBD);
in the present invention, the organic base is preferably triethylenediamine, hexamethylenediamine, tetramethylguanidine or 1,5, 7-triazabicyclo [4.4.0] dec-5-ene, and more preferably triethylenediamine.
In the present invention, the solvent may be a solvent conventional in the art, preferably water and/or an alcohol solvent, more preferably water. The alcohol solvent is preferably one or more of ethanol, isopropanol and n-butanol.
In the present invention, the molar ratio of the solvent to the 2-methylpyridine may be a molar ratio conventionally used in the art, preferably 0.1:1 to 2.0:1, more preferably 0.3:1 to 1.2:1, such as 0.351:1, 0.702:1 or 1.056:1, and further preferably 0.3:1 to 1: 1.
In the present invention, the molar ratio of the formaldehyde to the 2-methylpyridine may be a molar ratio conventional in the art, preferably 1:2 to 1:20, more preferably 1:5 to 1:10, such as 1:5 or 1: 10.
In the present invention, the molar ratio of the organic base and the 2-methylpyridine may be a molar ratio as conventional in the art, preferably 1:5 to 1:500, more preferably 1:50 to 1:200, such as 1:50, 1:100 or 1: 200.
In the present invention, the temperature of the reaction is preferably 180-230 ℃, for example 180 ℃ or 200 ℃.
In the present invention, the reaction time is preferably 5 to 50min, more preferably 8 to 15min, for example 8min or 15 min.
In the present invention, the pressure is preferably 4 to 5MPa, for example 4MPa or 5 MPa.
In the present invention, the pressure is preferably an absolute pressure.
In certain preferred embodiments of the present invention, the molar ratio of said solvent to said 2-methylpyridine is from 0.3:1 to 1.2: 1; the molar ratio of the formaldehyde to the 2-methylpyridine is 1:5-1: 10; the molar ratio of the organic base to the 2-methylpyridine is 1:50-1: 200; the reaction temperature is 180-230 ℃; the reaction time is 8-15 min; the pressure is 4-5 MPa.
In certain preferred embodiments of the present invention, the molar ratio of said solvent to said 2-methylpyridine is from 0.3:1 to 1: 1; the molar ratio of the formaldehyde to the 2-methylpyridine is 1:5-1: 10; the molar ratio of the organic base to the 2-methylpyridine is 1:50-1: 200; the reaction temperature is 180-230 ℃; the reaction time is 8-15 min; the pressure is 4-5 MPa.
In certain preferred embodiments of the present invention, the reaction is preferably carried out in a continuous flow reactor.
In certain preferred embodiments of the present invention, the solvent, organic base, 2-methylpyridine and formaldehyde are continuously added by a pump. The flow rate of the addition is preferably 1-3ml/min, more preferably 1-2ml/min, e.g. 1ml/min or 2 ml/min. The pump may be used to regulate the flow rate.
In certain preferred embodiments of the present invention, the reaction is preferably carried out in a microreaction tube (e.g., a stainless steel microreaction tube). Preferably, the micro-reaction pipeline is rinsed and dried in advance. The rinsing solvent is preferably the same as the solvent for the above reaction, the flow rate of the rinsing solvent is preferably 1 to 3ml/min (e.g., 1ml/min), and the rinsing time is preferably 20 to 40min (e.g., 30 min). The drying gas is preferably nitrogen, and the drying time is preferably 20-40min (e.g. 30 min).
In certain preferred embodiments of the present invention, the reaction is performed in a micro-reaction tube (e.g., a stainless steel micro-reaction tube), the micro-reaction tube is connected to a constant flow pump, and is further connected to a back pressure valve, and the front end of the back pressure valve is connected to a pre-cooling tube. The advection pump can be used for adjusting the flow rate. The back pressure valve may be used to regulate pressure.
In certain preferred embodiments of the present invention, the formaldehyde is obtained by depolymerizing paraformaldehyde.
In certain preferred embodiments of the present invention, the reaction may further comprise the steps of: and (3) depolymerizing paraformaldehyde in a solvent to obtain the formaldehyde.
In certain preferred embodiments of the present invention, the solvent used in the depolymerization is as described above.
In certain preferred embodiments of the present invention, the temperature of the depolymerization may be a temperature conventional in the art, preferably 110-.
In some preferred embodiments of the present invention, the time for depolymerization is not particularly limited, and the time for depolymerization is preferably 15 to 30min, for example 20min, based on complete depolymerization of paraformaldehyde.
In the present invention, the reaction can be carried out in a flow reactor conventional in the art, which can be a pipe, a pipeline, or a microstructure integrated device.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the method for preparing 2-hydroxyethyl pyridine obviously shortens the reaction time, has higher conversion per pass, and can save the production cost.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
The selectivity in the following examples refers to the proportion of 2-hydroxypyridine in the reaction product, and the yield is the product of the conversion and the selectivity.
Example 1
2-methylpyridine (30g,322mmol), paraformaldehyde (2.04g,64.4mmol, 95%), water (4.08g,226mmol) and DABCO (0.36g,3.22mmol) were charged into a depolymerization flask to depolymerize at 120 ℃ for 20min, and this was used as a reaction solution to wait for feeding. Connecting a stainless steel micro-reaction pipeline with an advection pump, connecting a backpressure valve capable of adjusting pressure, controlling the pipeline reaction pressure to be 4MPa, and connecting a precooling pipeline with the length of 5m at the front end of the backpressure valve. A reaction tube having a length of 30m was sufficiently rinsed with reaction solvent water at a flow rate of 1ml/min for 30min, and then the reaction tube was sufficiently dried by blowing with nitrogen gas for 30 min. Controlling the temperature heater to reach 200 ℃, adjusting the flow rate of the pump to be 2ml/min, and pumping the reaction liquid to start reaction. After 8min, the light yellow liquid product begins to flow out, and the collected liquid product has high performance liquid chromatography analysis on the conversion rate (calculated by taking the amount of single-molecule formaldehyde as a reference) of the 2-methylpyridine of 81 percent, the selectivity of 96 percent and the yield of 78 percent. And distilling the collected liquid product under reduced pressure to obtain the 2-hydroxyethyl pyridine, wherein the purity of HPLC analysis is more than 99.9%.
The nuclear magnetic hydrogen spectrum data of the 2-hydroxyethyl pyridine are as follows:
1H NMR(400MHz,CDCl3)8.45(d,J＝4.4Hz,1H),7.58(dt,J＝7.7,1.8Hz,1H),7.14(d,J＝7.7Hz,1H),7.12(m,1H),4.51(s,1H),3.98(t,J＝5.7Hz,2H),2.99(t,J＝5.7Hz,2H).
example 2
2-methylpyridine (30g,322mmol), paraformaldehyde (2.04g,64.4mmol, 95%), water (4.08g,226mmol) and DABCO (0.36g,3.22mmol) were charged into a depolymerization flask to depolymerize at 120 ℃ for 20min, and this was used as a reaction solution to wait for feeding. Connecting a stainless steel micro-reaction pipeline with an advection pump, connecting a backpressure valve capable of adjusting pressure, controlling the pipeline reaction pressure to be 4MPa, and connecting a precooling pipeline with the length of 5m at the front end of the backpressure valve. A reaction tube having a length of 30m was sufficiently rinsed with reaction solvent water at a flow rate of 1ml/min for 30min, and then the reaction tube was sufficiently dried by blowing with nitrogen gas for 30 min. Controlling the temperature heater to reach 200 ℃, adjusting the flow rate of the pump to be 1ml/min, and pumping the reaction liquid to start reaction. After 15min, the light yellow liquid product began to flow out, and the high performance liquid chromatography analysis of the collected liquid product showed that the conversion rate (calculated by taking the amount of the monomolecular formaldehyde) of 2-methylpyridine was 82%, the selectivity was 94% and the yield was 77%. And distilling the collected liquid product under reduced pressure to obtain the 2-hydroxyethyl pyridine, wherein the purity of HPLC analysis is more than 99.9%. The hydrogen spectrum data are the same as in example 1.
Example 3
2-methylpyridine (30g,322mmol), paraformaldehyde (2.04g,64.4mmol, 95%), water (6.12g,340mmol) and DABCO (0.36g,3.22mmol) were charged into a depolymerization flask to depolymerize at 120 ℃ for 20min, and this was used as a reaction solution to wait for feeding. Connecting a stainless steel micro-reaction pipeline with an advection pump, connecting a backpressure valve capable of adjusting pressure, controlling the pipeline reaction pressure to be 4MPa, and connecting a precooling pipeline with the length of 5m at the front end of the backpressure valve. A reaction tube having a length of 30m was sufficiently rinsed with reaction solvent water at a flow rate of 2ml/min for 30min, and then the reaction tube was sufficiently dried by blowing with nitrogen gas for 30 min. Controlling the temperature heater to reach 200 ℃, adjusting the flow rate of the pump to be 2ml/min, and pumping the reaction liquid to start reaction. After 8min, the light yellow liquid product begins to flow out, and the collected liquid product has high performance liquid chromatography analysis on the conversion rate (calculated by taking the amount of single-molecule formaldehyde as a reference) of the 2-methylpyridine of 77 percent, the selectivity of 94 percent and the yield of 72 percent. And distilling the collected liquid product under reduced pressure to obtain the 2-hydroxyethyl pyridine, wherein the purity of HPLC analysis is more than 99.9%. The hydrogen spectrum data are the same as in example 1.
Example 4
2-methylpyridine (30g,322mmol), paraformaldehyde (2.04g,64.4mmol, 95%), water (4.08g,226mmol) and DABCO (0.36g,3.22mmol) were charged into a depolymerization flask to depolymerize at 120 ℃ for 20min, and this was used as a reaction solution to wait for feeding. Connecting a stainless steel micro-reaction pipeline with an advection pump, connecting a backpressure valve capable of adjusting pressure, controlling the pipeline reaction pressure to be 5MPa, and connecting a precooling pipeline with the length of 5m at the front end of the backpressure valve. A reaction tube having a length of 30m was sufficiently rinsed with reaction solvent water at a flow rate of 1ml/min for 30min, and then the reaction tube was sufficiently dried by blowing with nitrogen gas for 30 min. Controlling the temperature heater to reach 200 ℃, adjusting the flow rate of the pump to be 2ml/min, and pumping the reaction liquid to start reaction. After 8min, the light yellow liquid product begins to flow out, and the collected liquid product has high performance liquid chromatography analysis on the conversion rate (calculated by taking the amount of single-molecule formaldehyde as a reference) of the 2-methylpyridine of 86 percent, the selectivity of 86 percent and the yield of 74 percent. And distilling the collected liquid product under reduced pressure to obtain the 2-hydroxyethyl pyridine, wherein the purity of HPLC analysis is more than 99.9%. The hydrogen spectrum data are the same as in example 1.
Example 5
To a depolymerization flask were added 2-methylpyridine (30g,322mmol), paraformaldehyde (1.02g,32.2mmol, 95%), water (2.04g,113mmol), and DABCO (0.18g,1.61mmol) to depolymerize at 120 ℃ for 20min, and this was used as a reaction solution to wait for feeding. Connecting a stainless steel micro-reaction pipeline with an advection pump, connecting a backpressure valve capable of adjusting pressure, controlling the pipeline reaction pressure to be 4MPa, and connecting a precooling pipeline with the length of 5m at the front end of the backpressure valve. A reaction tube having a length of 30m was sufficiently rinsed with reaction solvent water at a flow rate of 1ml/min for 30min, and then the reaction tube was sufficiently dried by blowing with nitrogen gas for 30 min. Controlling the temperature heater to reach 200 ℃, adjusting the flow rate of the pump to be 2ml/min, and pumping the reaction liquid to start reaction. After 8min, the light yellow liquid product begins to flow out, and the collected liquid product has high performance liquid chromatography analysis on the conversion rate (calculated by taking the amount of single-molecule formaldehyde as a reference) of the 2-methylpyridine of 95 percent, selectivity of 94 percent and yield of 89 percent. And distilling the collected liquid product under reduced pressure to obtain the 2-hydroxyethyl pyridine, wherein the purity of HPLC analysis is more than 99.9%. The hydrogen spectrum data are the same as in example 1.
Comparative example 1
2-methylpyridine (30g,322mmol), paraformaldehyde (1.02g,32.2mmol, 95%), water (2.04g,113mmol) and triethylamine (0.18g,1.61mmol) were charged into a depolymerization flask to depolymerize at 120 ℃ for 20min, and the reaction solution was used as a reaction solution to wait for feeding. Connecting a stainless steel micro-reaction pipeline with an advection pump, connecting a backpressure valve capable of adjusting pressure, controlling the pipeline reaction pressure to be 4MPa, and connecting a precooling pipeline with the length of 5m at the front end of the backpressure valve. A reaction tube having a length of 30m was sufficiently rinsed with reaction solvent water at a flow rate of 1ml/min for 30min, and then the reaction tube was sufficiently dried by blowing with nitrogen gas for 30 min. Controlling the temperature heater to reach 200 ℃, adjusting the flow rate of the pump to be 2ml/min, and pumping the reaction liquid to start reaction. After 8min, the light yellow liquid product begins to flow out, and the collected liquid product has high performance liquid chromatography analysis on the conversion rate (calculated by taking the amount of single-molecule formaldehyde as a reference) of the 2-methylpyridine of 62 percent, the selectivity of 89 percent and the yield of 55 percent.
Example 6
2-methylpyridine (30g,322mmol), paraformaldehyde (2.04g,64.4mmol, 95%), water (4.08g,226mmol) and DABCO (0.72g,6.44mmol) were charged into a depolymerization flask to depolymerize at 120 ℃ for 20min, and this was used as a reaction solution to wait for feeding. Connecting a stainless steel micro-reaction pipeline with an advection pump, connecting a backpressure valve capable of adjusting pressure, controlling the pipeline reaction pressure to be 4MPa, and connecting a precooling pipeline with the length of 5m at the front end of the backpressure valve. A reaction tube having a length of 30m was sufficiently rinsed with reaction solvent water at a flow rate of 1ml/min for 30min, and then the reaction tube was sufficiently dried by blowing with nitrogen gas for 30 min. Controlling the temperature heater to reach 200 ℃, adjusting the flow rate of the pump to be 2ml/min, and pumping the reaction liquid to start reaction. After 8min, the light yellow liquid product begins to flow out, and the collected liquid product has high performance liquid chromatography analysis on the conversion rate (calculated by taking the amount of single-molecule formaldehyde as a reference) of the 2-methylpyridine of 83 percent, the selectivity of 97 percent and the yield of 81 percent. And distilling the collected liquid product under reduced pressure to obtain the 2-hydroxyethyl pyridine, wherein the purity of HPLC analysis is more than 99.9%. The hydrogen spectrum data are the same as in example 1.
Example 7
2-methylpyridine (300g,3220mmol), paraformaldehyde (20.4g,644mmol, 95%), water (40.8g,2260mmol) and DABCO (3.6g,32.2mmol) were charged to a depolymerization flask and depolymerized at 120 ℃ for 20min to serve as a reaction solution to wait for feeding. Connecting a stainless steel micro-reaction pipeline with an advection pump, connecting a backpressure valve capable of adjusting pressure, controlling the pipeline reaction pressure to be 4MPa, and connecting a precooling pipeline with the length of 5m at the front end of the backpressure valve. A reaction tube having a length of 30m was sufficiently rinsed with reaction solvent water at a flow rate of 2ml/min for 30min, and then the reaction tube was sufficiently dried by blowing with nitrogen gas for 30 min. Controlling the temperature heater to reach 200 ℃, adjusting the flow rate of the pump to be 2ml/min, and pumping the reaction liquid to start reaction. After 8min, the light yellow liquid product begins to flow out, and the collected liquid product has high performance liquid chromatography analysis on the conversion rate (calculated by taking the amount of single-molecule formaldehyde as a reference) of the 2-methylpyridine of 85 percent, the selectivity of 95 percent and the yield of 72 percent. And distilling the collected liquid product under reduced pressure to obtain the 2-hydroxyethyl pyridine, wherein the purity of HPLC analysis is more than 99.9%. The hydrogen spectrum data are the same as in example 1.
Example 8
2-methylpyridine (30g,322mmol), paraformaldehyde (2.04g,64.4mmol, 95%), water (4.08g,226mmol) and DBU (0.49g,3.22mmol) were charged into a depolymerization flask to depolymerize at 120 ℃ for 20min, and this was used as a reaction solution to wait for feeding. Connecting a stainless steel micro-reaction pipeline with an advection pump, connecting a backpressure valve capable of adjusting pressure, controlling the pipeline reaction pressure to be 4MPa, and connecting a precooling pipeline with the length of 5m at the front end of the backpressure valve. A reaction tube having a length of 30m was sufficiently rinsed with reaction solvent water at a flow rate of 1ml/min for 30min, and then the reaction tube was sufficiently dried by blowing with nitrogen gas for 30 min. Controlling the temperature heater to reach 200 ℃, adjusting the flow rate of the pump to be 1ml/min, and pumping the reaction liquid to start reaction. After 15min, the light yellow liquid product begins to flow out, and the collected liquid product has high performance liquid chromatography analysis of 2-methylpyridine, wherein the conversion rate (calculated by taking the amount of single-molecule formaldehyde as a reference) is 79%, the selectivity is 94% and the yield is 74%. And distilling the collected liquid product under reduced pressure to obtain the 2-hydroxyethyl pyridine, wherein the purity of HPLC analysis is more than 99.9%. The hydrogen spectrum data are the same as in example 1.
Example 9
2-methylpyridine (30g,322mmol), paraformaldehyde (2.04g,64.4mmol, 95%), water (4.08g,226mmol) and TBD (0.45g,3.22mmol) were charged into a depolymerization flask to depolymerize at 120 ℃ for 20min, and this was used as a reaction solution to wait for feeding. Connecting a stainless steel micro-reaction pipeline with an advection pump, connecting a backpressure valve capable of adjusting pressure, controlling the pipeline reaction pressure to be 4MPa, and connecting a precooling pipeline with the length of 5m at the front end of the backpressure valve. A reaction tube having a length of 30m was sufficiently rinsed with reaction solvent water at a flow rate of 1ml/min for 30min, and then the reaction tube was sufficiently dried by blowing with nitrogen gas for 30 min. Controlling the temperature heater to reach 200 ℃, adjusting the flow rate of the pump to be 1ml/min, and pumping the reaction liquid to start reaction. After 15min, the light yellow liquid product begins to flow out, and the collected liquid product has high performance liquid chromatography analysis on the conversion rate (calculated by taking the amount of single-molecule formaldehyde as a reference) of the 2-methylpyridine of 77 percent, the selectivity of 98 percent and the yield of 75 percent. And distilling the collected liquid product under reduced pressure to obtain the 2-hydroxyethyl pyridine, wherein the purity of HPLC analysis is more than 99.9%. The hydrogen spectrum data are the same as in example 1.
Example 10
A depolymerization flask was charged with 2-methylpyridine (30g,322mmol), paraformaldehyde (2.04g,64.4mmol, 95%), water (4.08g,226mmol) and tetramethylguanidine (0.49g,3.22mmol) and the reaction solution was allowed to depolymerize at 120 ℃ for 20min, and the reaction solution was allowed to stand by. Connecting a stainless steel micro-reaction pipeline with an advection pump, connecting a backpressure valve capable of adjusting pressure, controlling the pipeline reaction pressure to be 4MPa, and connecting a precooling pipeline with the length of 5m at the front end of the backpressure valve. A reaction tube having a length of 30m was sufficiently rinsed with reaction solvent water at a flow rate of 1ml/min for 30min, and then the reaction tube was sufficiently dried by blowing with nitrogen gas for 30 min. Controlling the temperature heater to reach 200 ℃, adjusting the flow rate of the pump to be 1ml/min, and pumping the reaction liquid to start reaction. After 15min, the light yellow liquid product begins to flow out, and the collected liquid product has high performance liquid chromatography analysis on the conversion rate (calculated by taking the amount of single-molecule formaldehyde as a reference) of the 2-methylpyridine of 86 percent, the selectivity of 92 percent and the yield of 79 percent. And distilling the collected liquid product under reduced pressure to obtain the 2-hydroxyethyl pyridine, wherein the purity of HPLC analysis is more than 99.9%. The hydrogen spectrum data are the same as in example 1.
Example 11
A depolymerization flask was charged with 2-methylpyridine (30g,322mmol), paraformaldehyde (2.04g,64.4mmol, 95%), water (4.08g,226mmol) and hexamethylenediamine (0.37g,3.22mmol) and the reaction mixture was fed to the flask to be depolymerized at 120 ℃ for 20 min. Connecting a stainless steel micro-reaction pipeline with an advection pump, connecting a backpressure valve capable of adjusting pressure, controlling the pipeline reaction pressure to be 4MPa, and connecting a precooling pipeline with the length of 5m at the front end of the backpressure valve. A reaction tube having a length of 30m was sufficiently rinsed with reaction solvent water at a flow rate of 1ml/min for 30min, and then the reaction tube was sufficiently dried by blowing with nitrogen gas for 30 min. Controlling the temperature heater to reach 200 ℃, adjusting the flow rate of the pump to be 1ml/min, and pumping the reaction liquid to start reaction. After 15min, the light yellow liquid product begins to flow out, and the collected liquid product has high performance liquid chromatography analysis on the conversion rate (calculated by taking the amount of single-molecule formaldehyde as a reference) of 89 percent, selectivity of 89 percent and yield of 79 percent. And distilling the collected liquid product under reduced pressure to obtain the 2-hydroxyethyl pyridine, wherein the purity of HPLC analysis is more than 99.9%. The hydrogen spectrum data are the same as in example 1.
Example 12
2-methylpyridine (30g,322mmol), paraformaldehyde (2.04g,64.4mmol, 95%), water (4.08g,226mmol) and DABCO (0.36g,3.22mmol) were charged into a depolymerization flask to depolymerize at 120 ℃ for 20min, and this was used as a reaction solution to wait for feeding. Connecting a stainless steel micro-reaction pipeline with an advection pump, connecting a backpressure valve capable of adjusting pressure, controlling the pipeline reaction pressure to be 4MPa, and connecting a precooling pipeline with the length of 5m at the front end of the backpressure valve. A reaction tube having a length of 30m was sufficiently rinsed with reaction solvent water at a flow rate of 1ml/min for 30min, and then the reaction tube was sufficiently dried by blowing with nitrogen gas for 30 min. Controlling the temperature heater to reach 180 ℃, adjusting the flow rate of the pump to be 1ml/min, and pumping the reaction liquid to start reaction. After 15min, the light yellow liquid product begins to flow out, and the collected liquid product has high performance liquid chromatography analysis on the conversion rate (calculated by taking the amount of single-molecule formaldehyde as a reference) of the 2-methylpyridine of 63 percent, the selectivity of 96 percent and the yield of 60 percent. And distilling the collected liquid product under reduced pressure to obtain the 2-hydroxyethyl pyridine, wherein the purity of HPLC analysis is more than 99.9%. The hydrogen spectrum data are the same as in example 1.
Claims (10)
1. A preparation method of 2-hydroxyethyl pyridine comprises the following steps: reacting 2-methylpyridine with formaldehyde in a solvent under the pressure of 2-8MPa and the action of organic alkali to obtain 2-hydroxyethyl pyridine; the organic base is one or more of triethylene diamine, hexamethylene diamine, tetramethyl guanidine, 1, 8-diazabicycloundec-7-ene and 1,5, 7-triazabicyclo [4.4.0] dec-5-ene;
2. the process according to claim 1, wherein the organic base is triethylenediamine, hexamethylenediamine, tetramethylguanidine or 1,5, 7-triazabicyclo [4.4.0] dec-5-ene, preferably triethylenediamine;
and/or, the solvent is water and/or alcohol solvent, preferably water; the alcohol solvent is preferably one or more of ethanol, isopropanol and n-butanol;
and/or the molar ratio of the solvent to the 2-methylpyridine is 0.1:1 to 2.0:1, preferably 0.3:1 to 1.2:1, more preferably 0.3:1 to 1: 1;
and/or the molar ratio of the formaldehyde to the 2-methylpyridine is 1:2-1:20, preferably 1:5-1: 10;
and/or the molar ratio of the organic base to the 2-methylpyridine is 1:5 to 1:500, preferably 1:50 to 1: 200;
and/or, the pressure is 4-5 MPa;
and/or the temperature of the reaction is 180-230 ℃;
and/or the reaction time is 5-50min, preferably 8-15 min.
3. The process of claim 1, wherein the molar ratio of the solvent to the 2-methylpyridine is from 0.3:1 to 1.2: 1; the molar ratio of the formaldehyde to the 2-methylpyridine is 1:5-1: 10; the molar ratio of the organic base to the 2-methylpyridine is 1:50-1: 200; the reaction temperature is 180-230 ℃; the reaction time is 8-15 min; the pressure is 4-5 MPa;
or,
the molar ratio of the solvent to the 2-methylpyridine is 0.3:1-1: 1; the molar ratio of the formaldehyde to the 2-methylpyridine is 1:5-1: 10; the molar ratio of the organic base to the 2-methylpyridine is 1:50-1: 200; the reaction temperature is 180-230 ℃; the reaction time is 8-15 min; the pressure is 4-5 MPa.
4. The method of claim 1, wherein the reaction is carried out in a continuous flow reactor.
5. The process according to claim 1, wherein the solvent, the organic base, 2-methylpyridine and formaldehyde are continuously fed by a pump; the flow rate of the addition is preferably 1 to 3ml/min, more preferably 1 to 2 ml/min.
6. The method of claim 1, wherein the reaction is carried out in a micro-reaction tube; preferably, the micro-reaction pipeline is rinsed and dried in advance.
7. The process according to claim 6, wherein the rinsing solvent is water and/or an alcohol solvent, preferably water; the alcohol solvent is preferably one or more of ethanol, isopropanol and n-butanol;
and/or the flow rate of the rinsing solvent is 1-3 ml/min;
and/or, the rinsing time is 20-40 min;
and/or the dry gas is nitrogen;
and/or the drying time is 20-40 min.
8. The preparation method of claim 6, wherein the micro-reaction pipeline is connected with a constant flow pump and then connected with a back pressure valve, and the front end of the back pressure valve is connected with a pre-cooling pipeline.
9. The method of claim 1, wherein the reacting further comprises the steps of: and (3) depolymerizing paraformaldehyde in a solvent to obtain the formaldehyde.
10. The process according to claim 9, wherein the depolymerizing solvent is water and/or an alcoholic solvent, preferably water; the alcohol solvent is preferably one or more of ethanol, isopropanol and n-butanol;
and/or the temperature of the depolymerization is 110-130 ℃;
and/or the time for depolymerization is 15-30 min.
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|---|---|---|---|---|
| GB901654A (en) * | 1958-08-07 | 1962-07-25 | Robert Sancier Aries | Preparation of pyridine alcohols and their homologues |
| CN102731372A (en) * | 2012-07-16 | 2012-10-17 | 山东天一化学股份有限公司 | Preparation method of 2-ethoxyl pyridina |
| CN104016905A (en) * | 2014-06-06 | 2014-09-03 | 江苏亚泰化工有限公司 | Method for preparing 2-vinylpyridine |
| CN104109114A (en) * | 2014-07-17 | 2014-10-22 | 东南大学 | High-efficiency environment-friendly preparation method of 2-hydroxyethylpyridine |
| CN107827813A (en) * | 2017-11-27 | 2018-03-23 | 陕西启源科技发展有限责任公司 | The preparation method of orthogonal optimization Betahistine Hydrochloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB901654A (en) * | 1958-08-07 | 1962-07-25 | Robert Sancier Aries | Preparation of pyridine alcohols and their homologues |
| CN102731372A (en) * | 2012-07-16 | 2012-10-17 | 山东天一化学股份有限公司 | Preparation method of 2-ethoxyl pyridina |
| CN104016905A (en) * | 2014-06-06 | 2014-09-03 | 江苏亚泰化工有限公司 | Method for preparing 2-vinylpyridine |
| CN104109114A (en) * | 2014-07-17 | 2014-10-22 | 东南大学 | High-efficiency environment-friendly preparation method of 2-hydroxyethylpyridine |
| CN107827813A (en) * | 2017-11-27 | 2018-03-23 | 陕西启源科技发展有限责任公司 | The preparation method of orthogonal optimization Betahistine Hydrochloride |
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