CN107857725A - A kind of synthetic method of the methanol of 2 aminopyridine 4 - Google Patents
A kind of synthetic method of the methanol of 2 aminopyridine 4 Download PDFInfo
- Publication number
- CN107857725A CN107857725A CN201711370476.4A CN201711370476A CN107857725A CN 107857725 A CN107857725 A CN 107857725A CN 201711370476 A CN201711370476 A CN 201711370476A CN 107857725 A CN107857725 A CN 107857725A
- Authority
- CN
- China
- Prior art keywords
- methanol
- synthetic method
- added dropwise
- mass concentration
- solution
- 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.)
- Withdrawn
Links
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 title claims abstract description 63
- 238000010189 synthetic method Methods 0.000 title claims abstract description 20
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 title abstract 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 48
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 45
- 239000000243 solution Substances 0.000 claims abstract description 30
- CRWJEUDFKNYSBX-UHFFFAOYSA-N sodium;hypobromite Chemical compound [Na+].Br[O-] CRWJEUDFKNYSBX-UHFFFAOYSA-N 0.000 claims abstract description 22
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229940125782 compound 2 Drugs 0.000 claims abstract description 18
- 230000002459 sustained effect Effects 0.000 claims abstract description 16
- 239000007864 aqueous solution Substances 0.000 claims abstract description 15
- 239000012074 organic phase Substances 0.000 claims abstract description 8
- 238000010792 warming Methods 0.000 claims abstract description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 32
- PTMBWNZJOQBTBK-UHFFFAOYSA-N pyridin-4-ylmethanol Chemical class OCC1=CC=NC=C1 PTMBWNZJOQBTBK-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 18
- -1 formyl amine Chemical class 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 238000001556 precipitation Methods 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 150000003222 pyridines Chemical class 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 11
- SHNUBALDGXWUJI-UHFFFAOYSA-N pyridin-2-ylmethanol Chemical class OCC1=CC=CC=N1 SHNUBALDGXWUJI-UHFFFAOYSA-N 0.000 abstract description 5
- 239000000376 reactant Substances 0.000 abstract 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 6
- QLSWIGRIBOSFMV-UHFFFAOYSA-N 1h-pyrrol-2-amine Chemical compound NC1=CC=CN1 QLSWIGRIBOSFMV-UHFFFAOYSA-N 0.000 description 5
- 101001031591 Mus musculus Heart- and neural crest derivatives-expressed protein 2 Proteins 0.000 description 5
- 150000003927 aminopyridines Chemical class 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 238000000034 method Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000003905 agrochemical Substances 0.000 description 2
- 150000001879 copper Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- UDDVPFLXGOBESH-UHFFFAOYSA-N (2-chloropyridin-4-yl)methanol Chemical compound OCC1=CC=NC(Cl)=C1 UDDVPFLXGOBESH-UHFFFAOYSA-N 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- 150000005759 2-chloropyridine Chemical class 0.000 description 1
- QXCOHSRHFCHCHN-UHFFFAOYSA-N 2-chloropyridine-4-carboxylic acid Chemical class OC(=O)C1=CC=NC(Cl)=C1 QXCOHSRHFCHCHN-UHFFFAOYSA-N 0.000 description 1
- FFNVQNRYTPFDDP-UHFFFAOYSA-N 2-cyanopyridine Chemical compound N#CC1=CC=CC=N1 FFNVQNRYTPFDDP-UHFFFAOYSA-N 0.000 description 1
- KCDNYRPDKSGQCM-UHFFFAOYSA-N 4-[4-(3-chlorophenyl)-4-(pyrrolidine-1-carbonyl)piperidin-1-yl]-1-(4-fluorophenyl)butan-1-one Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCC(C=2C=C(Cl)C=CC=2)(C(=O)N2CCCC2)CC1 KCDNYRPDKSGQCM-UHFFFAOYSA-N 0.000 description 1
- NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- IOOFPEBRBXNMKX-UHFFFAOYSA-N Cc(c(CO)c1)cnc1C(N)=O Chemical compound Cc(c(CO)c1)cnc1C(N)=O IOOFPEBRBXNMKX-UHFFFAOYSA-N 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- 239000005630 Diquat Substances 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 238000001949 anaesthesia Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- MXZACTZQSGYANA-UHFFFAOYSA-N chembl545463 Chemical compound Cl.C1=CC(OC)=CC=C1C(N=C1)=CN2C1=NC(C)=C2O MXZACTZQSGYANA-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 229960004979 fampridine Drugs 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 108091008039 hormone receptors Proteins 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 229940045997 vitamin a Drugs 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
- C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
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 kind of synthetic method of the methanol of 2 aminopyridine 4, comprise the following steps：Compound 2 is made in 4 pyridinemethanols and formamide reactant aqueous solution；Compound 2 and NaOH solution are mixed, it is placed in reactor, it is 5 10 DEG C to control temperature, and NaBrO solution is added dropwise thereto, after being added dropwise to complete, the 2h of sustained response 1 at such a temperature, after being warming up to 50 60 DEG C of sustained response 1h afterwards, it is down to room temperature, repeatedly extracted using ethyl acetate, merge organic phase, be evaporated under reduced pressure and remove ethyl acetate, the methanol of 2 aminopyridine 4 is made.The synthetic method of the application is simple to operate, and mild condition, accessory substance is less, and product purity is high, and product yield is higher.
Description
Technical field
The present invention relates to organic synthesis field, more particularly to a kind of synthetic method of PA -4- methanol.
Background technology
The noval chemical compound that phenyl ring is replaced by pyridine and is prepared has higher bioactivity and lower toxicity, Huo Zhegeng
High absorbability and selectivity, therefore pyridines intermediate has obtained news and developed fastly.Pyridine can be used for synthesizing medical industry
Sulfanilamide (SN), cortisone, close toxin, vitamin A and the medicine for treating blood vessel dilatation, reducing blood lipid and local anaesthesia；Also can be in agricultural chemicals
It is used to produce diquat dibromide, herbicide and agrochemical in industry.Wherein aminopyridines are that one kind has heterocycle knot
The ring ammoniacal substance of structure, equally also had a wide range of applications in many fields of organic chemical industry.PA -4- methanol is a variety of
Enzyme, polypeptide, the new inhibitor of hormone receptor, antagonist, the raw material of conditioning agent, have in medicine intermediate field quite important
Status.
The preparation method of existing research report aminopyridines has following several：1st, pyridine and Sodamide are direct
Aminating reaction is carried out, but this method reaction condition is more harsh, reaction reagent is difficult to obtain, and accessory substance is more, product
Yield is relatively low；2nd, ammonolysis reaction is carried out under the catalyst such as mantoquita or palladium carbon by haloperidid, this method uses catalyst
Cost is higher, and the requirement to equipment is more strict, operating difficulties；3rd, pyridine is nitrified through hydrogen peroxide oxidation, fuming nitric aicd
After nitrification pyridine is made, then through reducing obtained aminopyridine, this method step is more, and pollution is more serious, and composition is high, it is difficult to work
Industry metaplasia is produced；4th, using cyanopyridine as raw material, aminopyridine is made by catalyzing hydrolysis, Hofmann degradation, this method raw material is honest and clean
Valency is easy to get, and yield is higher, but its catalyst obtains complex, and is only capable of preparing 4-aminopyridine, use range by
Limitation.Therefore, a kind of operation of research and development is relatively simple, and the preparation methods of the higher aminopyridines of yield has important
Practical value.
Chinese patent CN201310680246.3 discloses a kind of preparation method of PA -4- methanol, wraps successively
Include following steps：Using 2- chloroisonicotinic acids as raw material, under thionyl chloride effect with small molecular alcohol carrying out esterification, to obtain 2- chlorine different
Nicotinate, 2- chloroisonicotinic acids ester are reduced into 2- chloropyridine -4- methanol under reducing agent effect, last 2- chloropyridines -4- methanol and
Ammoniacal liquor carries out aminating reaction under copper class catalyst and obtains PA -4- methanol.2- amino is prepared using the invention
Pyridine -4- methanol technics routes are short, avoid the generation of a large amount of waste liquids and waste residue, reduce the pollution to environment, and product
High income, copper class catalyst can be recycled in aminating reaction, reduce production cost, suitable industrialized production.
The content of the invention
It is an object of the invention to provide a kind of synthetic method of PA -4- methanol, the synthetic method is simple to operate,
Mild condition, accessory substance is less, and product purity is high, and product yield is higher.
To achieve the above object, the present invention uses following technical scheme：
A kind of synthetic method of PA -4- methanol, comprises the following steps：
(1) 4- pyridinemethanols are mixed in a kettle with tetrahydrofuran, adds the concentrated sulfuric acid, be heated to 70-80 DEG C, afterwards
After addition formyl amine aqueous solution is well mixed thereto, hydrogen peroxide, after being added dropwise to complete, keeping temperature back flow reaction 45- is added dropwise
60min, it is evaporated under reduced pressure afterwards, after the solid filtering of precipitation, is cleaned 3-5 times with water, compound 2 is made after drying；
(2) obtained compound 2 and NaOH solution are mixed, are placed in reactor, it is 5-10 DEG C to control temperature, thereto
NaBrO solution is added dropwise, after being added dropwise to complete, sustained response 1-2h, is warming up to 50-60 DEG C of sustained response 1h afterwards at such a temperature
Afterwards, room temperature is down to, is repeatedly extracted using ethyl acetate, merges organic phase, is evaporated under reduced pressure and removes ethyl acetate, is made described
PA -4- methanol；
Preferably, the mass concentration of the concentrated sulfuric acid is 80-85% in the step (1).
Preferably, the mass concentration of formyl amine aqueous solution is 75-82% in the step (1).
Preferably, the usage amount mol ratio of 4- pyridinemethanols and formamide is 4 in the step (1):5-7.
Preferably, the usage amount mol ratio of 4- pyridinemethanols and hydrogen peroxide is 1 in the step (1):1.2-1.5.
Preferably, the mass concentration of NaOH solution is that the mass concentration of 40%, NaBrO solution is 15- in the step (2)
25%.
Preferably, compound 2 and NaBrO usage amounts mol ratio are 1 in the step (2):1.2-1.5.
The invention has the advantages that hydrogen peroxide is used as initiator so that 4- pyridinemethanols enter with formamide
Row reaction, the course of reaction is selectively strong, and accessory substance is less, and reaction rate is fast, improves reaction efficiency.By further
Abjection carbonyl reaction, prepare target product, course of reaction condition is more gentle, simple to operate, and final product extract
Easily, the product obtained has higher purity and yield, is very suitable for large-scale industrial production.
Embodiment
In order to be better understood from the present invention, below by embodiment, the present invention is further described, and embodiment is served only for solving
The present invention is released, any restriction will not be formed to the present invention.
Embodiment 1
A kind of synthetic method of PA -4- methanol, comprises the following steps：
(1) 4- pyridinemethanols are mixed in a kettle with tetrahydrofuran, adds the concentrated sulfuric acid, be heated to 70 DEG C, it is backward
After wherein addition formyl amine aqueous solution is well mixed, hydrogen peroxide is added dropwise, after being added dropwise to complete, keeping temperature back flow reaction 45min,
It is evaporated under reduced pressure afterwards, after the solid filtering of precipitation, is cleaned 3 times with water, compound 2 is made after drying；
(2) obtained compound 2 and NaOH solution are mixed, are placed in reactor, it is 5 DEG C to control temperature, is dripped thereto
Add NaBrO solution, after being added dropwise to complete, sustained response 1h, after being warming up to 50 DEG C of sustained response 1h afterwards, is down to room at such a temperature
Temperature, repeatedly extracted using ethyl acetate, merge organic phase, be evaporated under reduced pressure and remove ethyl acetate, the 2- amino pyrrole is made
Pyridine -4- methanol；
The mass concentration of the concentrated sulfuric acid is 80-85% in the step (1)；The mass concentration of formyl amine aqueous solution is 75%；
The usage amount mol ratio of 4- pyridinemethanols and formamide is 4:5；The usage amount mol ratio of 4- pyridinemethanols and hydrogen peroxide is 1:
1.2。
The mass concentration of NaOH solution is that the mass concentration of 40%, NaBrO solution is 15% in the step (2), chemical combination
Thing 2 is 1 with NaBrO usage amounts mol ratio:1.2.
The purity of the PA -4- methanol of preparation is 99.5%, yield 94.6%.
Embodiment 2
A kind of synthetic method of PA -4- methanol, comprises the following steps：
(1) 4- pyridinemethanols are mixed in a kettle with tetrahydrofuran, adds the concentrated sulfuric acid, be heated to 80 DEG C, it is backward
After wherein addition formyl amine aqueous solution is well mixed, hydrogen peroxide is added dropwise, after being added dropwise to complete, keeping temperature back flow reaction 60min,
It is evaporated under reduced pressure afterwards, after the solid filtering of precipitation, is cleaned 5 times with water, compound 2 is made after drying；
(2) obtained compound 2 and NaOH solution are mixed, are placed in reactor, it is 10 DEG C to control temperature, is dripped thereto
Add NaBrO solution, after being added dropwise to complete, sustained response 2h, after being warming up to 60 DEG C of sustained response 1h afterwards, is down to room at such a temperature
Temperature, repeatedly extracted using ethyl acetate, merge organic phase, be evaporated under reduced pressure and remove ethyl acetate, the 2- amino pyrrole is made
Pyridine -4- methanol.
The mass concentration of the concentrated sulfuric acid is 85% in the step (1)；The mass concentration of formyl amine aqueous solution is 82%；4- pyrroles
The usage amount mol ratio of pyridine methanol and formamide is 4:7；The usage amount mol ratio of 4- pyridinemethanols and hydrogen peroxide is 1:1.5.
The mass concentration of NaOH solution is that the mass concentration of 40%, NaBrO solution is 25% in the step (2), chemical combination
Thing 2 is 1 with NaBrO usage amounts mol ratio:1.5.
The purity of the PA -4- methanol of preparation is 99.6%, yield 95.2%.
Embodiment 3
A kind of synthetic method of PA -4- methanol, comprises the following steps：
(1) 4- pyridinemethanols are mixed in a kettle with tetrahydrofuran, adds the concentrated sulfuric acid, be heated to 70 DEG C, it is backward
After wherein addition formyl amine aqueous solution is well mixed, hydrogen peroxide is added dropwise, after being added dropwise to complete, keeping temperature back flow reaction 60min,
It is evaporated under reduced pressure afterwards, after the solid filtering of precipitation, is cleaned 3 times with water, compound 2 is made after drying；
(2) obtained compound 2 and NaOH solution are mixed, are placed in reactor, it is 10 DEG C to control temperature, is dripped thereto
Add NaBrO solution, after being added dropwise to complete, sustained response 1h, after being warming up to 60 DEG C of sustained response 1h afterwards, is down to room at such a temperature
Temperature, repeatedly extracted using ethyl acetate, merge organic phase, be evaporated under reduced pressure and remove ethyl acetate, the 2- amino pyrrole is made
Pyridine -4- methanol.
The mass concentration of the concentrated sulfuric acid is 80% in the step (1)；The mass concentration of formyl amine aqueous solution is 82%；4- pyrroles
The usage amount mol ratio of pyridine methanol and formamide is 4:5；The usage amount mol ratio of 4- pyridinemethanols and hydrogen peroxide is 1:1.5.
The mass concentration of NaOH solution is that the mass concentration of 40%, NaBrO solution is 15% in the step (2), chemical combination
Thing 2 is 1 with NaBrO usage amounts mol ratio:1.5.
The purity of the PA -4- methanol of preparation is 99.5%, yield 95.9%.
Embodiment 4
A kind of synthetic method of PA -4- methanol, comprises the following steps：
(1) 4- pyridinemethanols are mixed in a kettle with tetrahydrofuran, adds the concentrated sulfuric acid, be heated to 80 DEG C, it is backward
After wherein addition formyl amine aqueous solution is well mixed, hydrogen peroxide is added dropwise, after being added dropwise to complete, keeping temperature back flow reaction 45min,
It is evaporated under reduced pressure afterwards, after the solid filtering of precipitation, is cleaned 5 times with water, compound 2 is made after drying；
(2) obtained compound 2 and NaOH solution are mixed, are placed in reactor, it is 5 DEG C to control temperature, is dripped thereto
Add NaBrO solution, after being added dropwise to complete, sustained response 2h, after being warming up to 50 DEG C of sustained response 1h afterwards, is down to room at such a temperature
Temperature, repeatedly extracted using ethyl acetate, merge organic phase, be evaporated under reduced pressure and remove ethyl acetate, the 2- amino pyrrole is made
Pyridine -4- methanol.
The mass concentration of the concentrated sulfuric acid is 85% in the step (1)；The mass concentration of formyl amine aqueous solution is 75%；4- pyrroles
The usage amount mol ratio of pyridine methanol and formamide is 4:7；The usage amount mol ratio of 4- pyridinemethanols and hydrogen peroxide is 1:1.2.
The mass concentration of NaOH solution is that the mass concentration of 40%, NaBrO solution is 25% in the step (2), chemical combination
Thing 2 is 1 with NaBrO usage amounts mol ratio:1.2.
The purity of the PA -4- methanol of preparation is 99.4%, yield 95.5%.
Embodiment 5
A kind of synthetic method of PA -4- methanol, comprises the following steps：
(1) 4- pyridinemethanols are mixed in a kettle with tetrahydrofuran, adds the concentrated sulfuric acid, be heated to 75 DEG C, it is backward
After wherein addition formyl amine aqueous solution is well mixed, hydrogen peroxide is added dropwise, after being added dropwise to complete, keeping temperature back flow reaction 50min,
It is evaporated under reduced pressure afterwards, after the solid filtering of precipitation, is cleaned 4 times with water, compound 2 is made after drying；
(2) obtained compound 2 and NaOH solution are mixed, are placed in reactor, it is 10 DEG C to control temperature, is dripped thereto
Add NaBrO solution, after being added dropwise to complete, sustained response 1h, after being warming up to 55 DEG C of sustained response 1h afterwards, is down to room at such a temperature
Temperature, repeatedly extracted using ethyl acetate, merge organic phase, be evaporated under reduced pressure and remove ethyl acetate, the 2- amino pyrrole is made
Pyridine -4- methanol.
The mass concentration of the concentrated sulfuric acid is 82% in the step (1)；The mass concentration of formyl amine aqueous solution is 80%；4- pyrroles
The usage amount mol ratio of pyridine methanol and formamide is 4:6；The usage amount mol ratio of 4- pyridinemethanols and hydrogen peroxide is 1:1.4.
The mass concentration of NaOH solution is that the mass concentration of 40%, NaBrO solution is 18% in the step (2), chemical combination
Thing 2 is 1 with NaBrO usage amounts mol ratio:1.3.
The purity of the PA -4- methanol of preparation is 99.6%, yield 94.9%.
Claims (7)
1. a kind of synthetic method of PA -4- methanol, it is characterised in that comprise the following steps：
(1) 4- pyridinemethanols are mixed in a kettle with tetrahydrofuran, add the concentrated sulfuric acid, be heated to 70-80 DEG C, it is backward its
After middle addition formyl amine aqueous solution is well mixed, hydrogen peroxide, after being added dropwise to complete, keeping temperature back flow reaction 45- is added dropwise
60min, it is evaporated under reduced pressure afterwards, after the solid filtering of precipitation, is cleaned 3-5 times with water, compound 2 is made after drying；
(2) obtained compound 2 and NaOH solution are mixed, are placed in reactor, it is 5-10 DEG C to control temperature, is added dropwise thereto
NaBrO solution, after being added dropwise to complete, sustained response 1-2h, after being warming up to 50-60 DEG C of sustained response 1h afterwards, drops at such a temperature
To room temperature, repeatedly extracted using ethyl acetate, merge organic phase, be evaporated under reduced pressure and remove ethyl acetate, the 2- ammonia is made
Yl pyridines -4- methanol；
2. the synthetic method of PA -4- methanol according to claim 1, it is characterised in that：In the step (1)
The mass concentration of the concentrated sulfuric acid is 80-85%.
3. the synthetic method of PA -4- methanol according to claim 1, it is characterised in that：In the step (1)
The mass concentration of formyl amine aqueous solution is 75-82%.
4. the synthetic method of PA -4- methanol according to claim 1, it is characterised in that：In the step (1)
The usage amount mol ratio of 4- pyridinemethanols and formamide is 4:5-7.
5. the synthetic method of PA -4- methanol according to claim 1, it is characterised in that：In the step (1)
The usage amount mol ratio of 4- pyridinemethanols and hydrogen peroxide is 1:1.2-1.5.
6. the synthetic method of PA -4- methanol according to claim 1, it is characterised in that：In the step (2)
The mass concentration of NaOH solution is that the mass concentration of 40%, NaBrO solution is 15-25%.
7. the synthetic method of PA -4- methanol according to claim 1, it is characterised in that：In the step (2)
Compound 2 is 1 with NaBrO usage amounts mol ratio:1.2-1.5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711370476.4A CN107857725A (en) | 2017-12-19 | 2017-12-19 | A kind of synthetic method of the methanol of 2 aminopyridine 4 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711370476.4A CN107857725A (en) | 2017-12-19 | 2017-12-19 | A kind of synthetic method of the methanol of 2 aminopyridine 4 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107857725A true CN107857725A (en) | 2018-03-30 |
Family
ID=61706433
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711370476.4A Withdrawn CN107857725A (en) | 2017-12-19 | 2017-12-19 | A kind of synthetic method of the methanol of 2 aminopyridine 4 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107857725A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1627874B1 (en) * | 2004-08-17 | 2008-04-02 | Lanxess Deutschland GmbH | Preparation of fluorinated 1,3-benzodioxanes |
| CN101302193A (en) * | 2008-05-27 | 2008-11-12 | 上海瑞恒生物技术有限公司 | A kind of preparation method of environmentally friendly Sorafenib intermediate |
| CN102459246A (en) * | 2009-04-07 | 2012-05-16 | 阿斯利康(瑞典)有限公司 | Isoxazol-3(2H)-one analogs as therapeutic agents |
-
2017
- 2017-12-19 CN CN201711370476.4A patent/CN107857725A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1627874B1 (en) * | 2004-08-17 | 2008-04-02 | Lanxess Deutschland GmbH | Preparation of fluorinated 1,3-benzodioxanes |
| CN101302193A (en) * | 2008-05-27 | 2008-11-12 | 上海瑞恒生物技术有限公司 | A kind of preparation method of environmentally friendly Sorafenib intermediate |
| CN102459246A (en) * | 2009-04-07 | 2012-05-16 | 阿斯利康(瑞典)有限公司 | Isoxazol-3(2H)-one analogs as therapeutic agents |
Non-Patent Citations (1)
| Title |
|---|
| 王清龙等: "Ｍｉｎｉｓｃｉ自由基取代反应最新研究进展", 《河南师范大学学报（自然科学版）》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104725303B (en) | The synthetic method of one kind 2 chlorine N (base of 4 ' chlordiphenyl 2) niacinamide | |
| CN105294653B (en) | The preparation technology of Vonoprazan fumarate | |
| CN105085388A (en) | Synthesis method for sorafenib intermediate | |
| CN104892599A (en) | Preparation method of imidazopyridine compound | |
| CN107857725A (en) | A kind of synthetic method of the methanol of 2 aminopyridine 4 | |
| CN113788765B (en) | A kind of preparation method of α, β-unsaturated amides | |
| CN102101841B (en) | Method for synthesis preparation of 2-chloro-4-aminopyridine | |
| CN103848783B (en) | The method of the synthetic 2-chlorine apellagrin of a kind of oxidation step | |
| CN107266361A (en) | The synthetic method of the picoline of 2 amino 5 | |
| CN105218437A (en) | The synthetic method of a kind of 3-chloro-5-bromo-2-pyridyl formic acid | |
| CN102358944A (en) | Preparation method of aminopyridine chloride | |
| CN102093288B (en) | Preparation method of trichlorohydrazinopyridine hydrate | |
| CN103028356A (en) | Device and method for performing aromatic heterocyclic lithium halide exchange reaction at room temperature | |
| CN115925707B (en) | A method for continuously preparing flaky diquat dichloride salt using a microfluidic reactor | |
| CN105646486B (en) | A kind of synthetic method of 5 azaindole | |
| CN102050754B (en) | Method for preparing alpha-amino-dialkyl substituted acetamide | |
| CN111423372B (en) | A method for preparing N-(5-hydroxyquinolin-8-yl)benzamide compounds by an electrochemical microchannel reaction device | |
| CN104387317B (en) | Preparation method and separation and purification method for 6-chloronicotinic acid | |
| CN105037239B (en) | A kind of preparation method of the acetic acid of 4 chloro-indole 3 | |
| CN107759515A (en) | A kind of synthetic method of the fluorine pyridine of 2 amino 4 | |
| CN109575036B (en) | Metal hematoporphyrin diester compound, catalyst and preparation method thereof, and method for catalytic oxidation of cyclohexane | |
| CN107868040A (en) | A kind of synthetic method of the methyl formate of 2 aminopyridine 4 | |
| CN106748689B (en) | A kind of method for preparing α-tetralone | |
| CN114213202B (en) | A preparation method of 2,4-substituted benzoic acid | |
| CN109134356A (en) | A kind of preparation method of intermediate 2-amino pyridine -4- methanol |
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 | ||
| WW01 | Invention patent application withdrawn after publication | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20180330 |