CN106478376A - A kind of preparation technology of 4 fluoronaphthalene 1 alcohol - Google Patents
A kind of preparation technology of 4 fluoronaphthalene 1 alcohol Download PDFInfo
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- CN106478376A CN106478376A CN201610874371.1A CN201610874371A CN106478376A CN 106478376 A CN106478376 A CN 106478376A CN 201610874371 A CN201610874371 A CN 201610874371A CN 106478376 A CN106478376 A CN 106478376A
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- fluoronaphthalene
- alcohol
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- bromo
- boric acid
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- CWLKTJOTWITYSI-UHFFFAOYSA-N 1-fluoronaphthalene Chemical compound C1=CC=C2C(F)=CC=CC2=C1 CWLKTJOTWITYSI-UHFFFAOYSA-N 0.000 title claims abstract description 74
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 238000005516 engineering process Methods 0.000 title claims abstract description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 title abstract 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 53
- 238000000034 method Methods 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 9
- 238000005885 boration reaction Methods 0.000 claims abstract description 8
- 230000007062 hydrolysis Effects 0.000 claims abstract description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 6
- 239000004327 boric acid Substances 0.000 claims description 33
- VAUJZKBFENPOCH-UHFFFAOYSA-N 1-bromo-4-fluoronaphthalene Chemical compound C1=CC=C2C(F)=CC=C(Br)C2=C1 VAUJZKBFENPOCH-UHFFFAOYSA-N 0.000 claims description 24
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 11
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical group [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 11
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 11
- -1 triisopropyl borate ester Chemical class 0.000 claims description 7
- MLSKXPOBNQFGHW-UHFFFAOYSA-N methoxy(dioxido)borane Chemical group COB([O-])[O-] MLSKXPOBNQFGHW-UHFFFAOYSA-N 0.000 claims description 6
- LGQXXHMEBUOXRP-UHFFFAOYSA-N tributyl borate Chemical group CCCCOB(OCCCC)OCCCC LGQXXHMEBUOXRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 229910052796 boron Inorganic materials 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- 125000005843 halogen group Chemical group 0.000 claims 2
- QPKFVRWIISEVCW-UHFFFAOYSA-N 1-butane boronic acid Chemical compound CCCCB(O)O QPKFVRWIISEVCW-UHFFFAOYSA-N 0.000 claims 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims 1
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- 238000012805 post-processing Methods 0.000 abstract description 5
- 238000011084 recovery Methods 0.000 abstract description 4
- 125000001475 halogen functional group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 32
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 23
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 20
- 238000001914 filtration Methods 0.000 description 17
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 238000001035 drying Methods 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 16
- 238000005406 washing Methods 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 208000035126 Facies Diseases 0.000 description 10
- 229960002163 hydrogen peroxide Drugs 0.000 description 10
- 235000011121 sodium hydroxide Nutrition 0.000 description 9
- 235000019270 ammonium chloride Nutrition 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 239000012467 final product Substances 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 238000001556 precipitation Methods 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 239000003513 alkali Substances 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 230000002140 halogenating effect Effects 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- GAMOBQXCYKWQLT-UHFFFAOYSA-N 1-(4-fluoronaphthalen-1-yl)ethanone Chemical compound C1=CC=C2C(C(=O)C)=CC=C(F)C2=C1 GAMOBQXCYKWQLT-UHFFFAOYSA-N 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- HKYGSMOFSFOEIP-UHFFFAOYSA-N dichloro(dichloromethoxy)methane Chemical compound ClC(Cl)OC(Cl)Cl HKYGSMOFSFOEIP-UHFFFAOYSA-N 0.000 description 1
- XIMIGUBYDJDCKI-UHFFFAOYSA-N diselenium Chemical compound [Se]=[Se] XIMIGUBYDJDCKI-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 150000002790 naphthalenes Chemical class 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
- C07C17/12—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms in the ring of aromatic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
The invention discloses a kind of preparation technology of 4 fluoronaphthalene 1 alcohol.With 1 fluoronaphthalene as raw material, can get 4 fluoronaphthalene 1 alcohol through halo, boration and hydrolysis three-step reaction, total recovery is up to 60%.This process route raw material is cheap and easy to get, and post processing is simple and easy to do, yield high it is easy to industrial applications.
Description
Technical field
The present invention relates to a kind of preparation technology of 4- fluoronaphthalene -1- alcohol.
Background technology
Hydroxyl activity in 4- fluoronaphthalene -1- alcohol structure is larger can be with many functional group reactionses, the ortho para position positioning of hydroxyl
Effect makes naphthalene nucleus activate, and can introduce other functional groups, be important pharmaceutical-chemical intermediate on the ortho position of hydroxyl.
The synthetic route reported at present mainly has following two：
The route of WO2009126333 report, with 1- fluoronaphthalene as raw material, needs to use 1,1- dichlormethyl ether in process route, former
Material is expensive, and reaction yield is relatively low, and production cost is higher.Furthermore, it is necessary to just purer product can be obtained through post separation, after
Processing procedure is loaded down with trivial details, and total recovery is only 29.7%
The route of EP1676834 report is with expensive 4- fluoro- 1- acetonaphthone as raw material, and uses no commercially available prod
Diselenide, with high costs.Meanwhile, product must be through column chromatography purification, and post processing bothers, and total recovery is only 30.5%
In sum, there is the problems such as cost of material is high, and post processing trouble, yield are relatively low in existing synthetic route, is unfavorable for
Industrialized production.
Content of the invention
The technical problem to be solved in the present invention is：There is provided a kind of synthesis technique of 4- fluoronaphthalene -1- alcohol, to solve existing process
Preparing that the expensive raw material price existing for 4- fluoronaphthalene -1- alcohol, post processing be complicated, yield high the problems such as.
Technical scheme：A kind of preparation method of 4- fluoronaphthalene -1- alcohol, including：Comprise the steps of：With 1- fluoronaphthalene
For raw material, obtain 1- bromo- 4- fluoronaphthalene through halogenating reaction；1- bromo- 4- fluoronaphthalene obtains 4- fluoronaphthalene -1- boric acid through boration reaction；4-
Fluoronaphthalene -1- boric acid obtains target product 4- fluoronaphthalene -1- alcohol through hydrolysis, and the intermediate in process route is 4- fluoronaphthalene -1- boron
Acid；
The reagent that described (1) step halogenating reaction uses is：Bromine；Reaction temperature is：Backflow；Response time is：1～
3h.
In described (1) step halogenating reaction, 1- fluoronaphthalene with the mol ratio of bromine is：1:0.5～0.6.
Described (2) step boration reaction reagent used is：Methyl borate., tri-n-butyl borate, boric acid three are different
Propyl ester；Catalyst is：N-BuLi；Reaction temperature is：-78℃；Response time is：0.5～1h.
1- bromo- 4- fluoronaphthalene and methyl borate., tri-n-butyl borate, boric acid three in described (2) step boration reaction
The mol ratio of isopropyl ester is：1:1～1.3.
In described (2) step boration reaction, 1- bromo- 4- fluoronaphthalene with the mol ratio of n-BuLi is：1:1.05～1.3.
The reagent that described (3) step hydrolysis use is：Hydrogen peroxide；Alkali is：Potassium hydroxide, sodium hydroxide；Alkali
Liquid concentration is：10%～30%；Reaction temperature is：Room temperature；Response time is：6～12h.
In described (3) step hydrolysis, 4- fluoronaphthalene -1- boric acid and the mol ratio of alkali are：1:2～2.5.
In described (3) step hydrolysis, 4- fluoronaphthalene -1- boric acid and the mol ratio of hydrogen peroxide are：1:2～5.
Beneficial effects of the present invention：By the present invention in that being that raw material obtains mesh through three-step reaction with 1- fluoronaphthalene cheap and easy to get
Mark product 4- fluoronaphthalene -1- alcohol, total recovery is up to 60%.This process route raw material is cheap and easily-available, intermediate and product through extraction,
The steps such as reduction vaporization, making beating, sucking filtration just can be with purification, and whole piece route post processing is not using the inconvenient industrialized side such as column chromatography
Method, simple and easy to do.
Specific embodiment
Embodiment 1
A. the preparation of 1- bromo- 4- fluoronaphthalene
In 500mL single port bottle, add 1- fluoronaphthalene (20.0g, 0.137mol) and carbon tetrachloride (120.0mL), Deca bromine
Plain (10.9g, 0.068mol), back flow reaction 2h.Reaction finishes, concentrating under reduced pressure, and concentrated solution pours low temperature in methanol (80.0mL) into
Stand overnight i.e. precipitation solid, sucking filtration obtains 1- bromo- 4- fluoronaphthalene 28.0g, yield is 90.9%.
B. the preparation of 4- fluoronaphthalene -1- boric acid
In 500mL there-necked flask, bromo- for 1- 4- fluoronaphthalene (28.0g, 0.124mol) is dissolved in anhydrous tetrahydro furan
(200.0mL), add triisopropyl borate ester (24.6g, 0.131mol), be cooled to -78 DEG C, Deca n-BuLi (9.2g,
0.143mol), after -78 DEG C of reaction 0.5h, recover to room temperature, add saturated aqueous ammonium chloride that reaction is quenched, adjust pH to
Highly acid, is extracted with ethyl acetate (200.0mL × 3), merges organic faciess, saturated common salt water washing, anhydrous sodium sulfate drying, subtracts
Pressure is evaporated off solvent, and residue is pulled an oar with normal hexane, and sucking filtration obtains final product 4- fluoronaphthalene -1- boric acid solid 21.0g, and yield is 89.0%.
1H NMR(CDCl3):2.0 (s, 2H), 7.31 (d, 1H), 7.58 (d, 1H), 7.55 (m, 2H), 8.08 (m, 2H).
C. the preparation of 4- fluoronaphthalene -1- alcohol
In 500mL single port bottle, add 4- fluoronaphthalene -1- boric acid (21.0g, 0.111mol), 15% potassium hydroxide aqueous solution
(13.0g containing KOH, 0.232mol) and 30% hydrogenperoxide steam generator are (containing H2O216.9g, 0.498mol), room temperature reaction 8h.Instead
Should finish, be carried with ether miscellaneous, aqueous phase adjusts pH to 1 with 1M hydrochloric acid, be extracted with ethyl acetate (150.0mL × 2), merge organic faciess,
Saturated common salt water washing, anhydrous sodium sulfate drying, remove solvent under reduced pressure, obtain 4- fluoronaphthalene -1- alcohol solid 12.9g, yield is
72.1%.
1H NMR(CDCl3):5.35 (s, 1H), 6.63 (d, 1H), 6.88 (d, 1H), 7.58 (t, 1H), 7.61 (t, 1H),
8.09 (d, 1H), 8.22 (d, 1H).
Embodiment 2
A. the preparation of 1- bromo- 4- fluoronaphthalene
In 500mL single port bottle, add 1- fluoronaphthalene (20.0g, 0.137mol) and carbon tetrachloride (120.0mL), Deca bromine
Plain (10.9g, 0.068mol), back flow reaction 2h.Reaction finishes, concentrating under reduced pressure, and concentrated solution pours low temperature in methanol (80.0mL) into
Stand overnight i.e. precipitation solid, sucking filtration obtains 1- bromo- 4- fluoronaphthalene 28.2g, yield is 91.5%.
B. the preparation of 4- fluoronaphthalene -1- boric acid
In 500mL there-necked flask, bromo- for 1- 4- fluoronaphthalene (28.2g, 0.125mol) is dissolved in anhydrous tetrahydro furan
(200.0mL), add tri-n-butyl borate (37.5g, 0.163mol), be cooled to -78 DEG C, Deca n-BuLi (10.4g,
0.163mol), after -78 DEG C of reaction 0.5h, recover to room temperature, add saturated aqueous ammonium chloride that reaction is quenched, adjust pH to
Highly acid, is extracted with ethyl acetate (200.0mL × 3), merges organic faciess, saturated common salt water washing, anhydrous sodium sulfate drying, subtracts
Pressure is evaporated off solvent, and residue is pulled an oar with normal hexane, and sucking filtration obtains final product 4- fluoronaphthalene -1- boric acid solid 21.3g, and yield is 89.5%.
1H NMR(CDCl3):2.0 (s, 2H), 7.31 (d, 1H), 7.58 (d, 1H), 7.55 (m, 2H), 8.08 (m, 2H).
C. the preparation of 4- fluoronaphthalene -1- alcohol
In 500mL single port bottle, add 4- fluoronaphthalene -1- boric acid (21.3g, 0.112mol), 25% potassium hydroxide aqueous solution
(15.7g containing KOH, 0.280mol) and 30% hydrogenperoxide steam generator are (containing H2O219.1g, 0.560mol), room temperature reaction 6h.Instead
Should finish, be carried with ether miscellaneous, aqueous phase 1M hydrochloric acid is adjusted after pH to 1, is extracted with ethyl acetate (150.0mL × 2), merges organic
Phase, saturated common salt water washing, anhydrous sodium sulfate drying, remove solvent under reduced pressure, obtain 4- fluoronaphthalene -1- alcohol solid 13.2g, yield is
72.6%.
1H NMR(CDCl3):5.35 (s, 1H), 6.63 (d, 1H), 6.88 (d, 1H), 7.58 (t, 1H), 7.61 (t, 1H),
8.09 (d, 1H), 8.22 (d, 1H).
Embodiment 3
A. the preparation of 1- bromo- 4- fluoronaphthalene
In 500mL single port bottle, add 1- fluoronaphthalene (20.0g, 0.137mol) and carbon tetrachloride (120.0mL), Deca bromine
Plain (10.9g, 0.075mol), back flow reaction 1.5h.Reaction finishes, concentrating under reduced pressure, and concentrated solution is poured into low in methanol (80.0mL)
Temperature stands overnight i.e. precipitation solid, and sucking filtration obtains 1- bromo- 4- fluoronaphthalene 26.2g, and yield is 85.0%.
B. the preparation of 4- fluoronaphthalene -1- boric acid
In 500mL there-necked flask, bromo- for 1- 4- fluoronaphthalene (26.2g, 0.116mol) is dissolved in anhydrous tetrahydro furan
(200.0mL), add methyl borate. (12.1g, 0.116mol), be cooled to -78 DEG C, Deca n-BuLi (7.8g,
0.122mol), after -78 DEG C of reaction 1h, recover to room temperature, add saturated aqueous ammonium chloride that reaction is quenched, adjust pH to strong
Acidity, is extracted with ethyl acetate (200.0mL × 3), merges organic faciess, saturated common salt water washing, anhydrous sodium sulfate drying, decompression
Solvent is evaporated off, residue is pulled an oar with normal hexane, sucking filtration obtains final product 4- fluoronaphthalene -1- boric acid solid 19.6g, yield is 88.5%.
1H NMR(CDCl3):2.0 (s, 2H), 7.31 (d, 1H), 7.58 (d, 1H), 7.55 (m, 2H), 8.08 (m, 2H).
C. the preparation of 4- fluoronaphthalene -1- alcohol
In 500mL single port bottle, add 4- fluoronaphthalene -1- boric acid (19.6g, 0.103mol), 25% potassium hydroxide aqueous solution
(12.1g containing KOH, 0.216mol) and 30% hydrogenperoxide steam generator are (containing H2O210.5g, 0.309mol), room temperature reaction 7h.Reaction
Finish, carried with ether miscellaneous, aqueous phase 1M hydrochloric acid is adjusted after pH to 1, is extracted with ethyl acetate (150.0mL × 2), merges organic faciess,
Saturated common salt water washing, anhydrous sodium sulfate drying, remove solvent under reduced pressure, obtain 4- fluoronaphthalene -1- alcohol solid 12.0g, yield is
72.1%.
1H NMR(CDCl3):5.35 (s, 1H), 6.63 (d, 1H), 6.88 (d, 1H), 7.58 (t, 1H), 7.61 (t, 1H),
8.09 (d, 1H), 8.22 (d, 1H).
Embodiment 4
A. the preparation of 1- bromo- 4- fluoronaphthalene
In 500mL single port bottle, add 1- fluoronaphthalene (20.0g, 0.137mol) and carbon tetrachloride (120.0mL), Deca bromine
Plain (10.9g, 0.068mol), back flow reaction 2h.Reaction finishes, concentrating under reduced pressure, and concentrated solution pours low temperature in methanol (80.0mL) into
Stand overnight i.e. precipitation solid, sucking filtration obtains 1- bromo- 4- fluoronaphthalene 27.9g, yield is 90.5%.
B. the preparation of 4- fluoronaphthalene -1- boric acid
In 500mL there-necked flask, bromo- for 1- 4- fluoronaphthalene (27.9g, 0.124mol) is dissolved in anhydrous tetrahydro furan
(200.0mL), add triisopropyl borate ester (25.6g, 0.136mol), be cooled to -78 DEG C, Deca n-BuLi (9.5g,
0.149mol), after -78 DEG C of reaction 0.5h, recover to room temperature, add saturated aqueous ammonium chloride that reaction is quenched, adjust pH to
Highly acid, is extracted with ethyl acetate (200.0mL × 3), merges organic faciess, saturated common salt water washing, anhydrous sodium sulfate drying, subtracts
Pressure is evaporated off solvent, and residue is pulled an oar with normal hexane, and sucking filtration obtains final product 4- fluoronaphthalene -1- boric acid solid 21.1g, and yield is 89.7%.
1H NMR(CDCl3):2.0 (s, 2H), 7.31 (d, 1H), 7.58 (d, 1H), 7.55 (m, 2H), 8.08 (m, 2H).
C. the preparation of 4- fluoronaphthalene -1- alcohol
In 500mL single port bottle, add 4- fluoronaphthalene -1- boric acid (21.1g, 0.111mol), 20% potassium hydroxide aqueous solution
(13.1g containing KOH, 0.233mol) and 30% hydrogenperoxide steam generator are (containing H2O218.9g, 0.555mol), room temperature reaction 8h.Instead
Should finish, be carried with ether miscellaneous, aqueous phase 1M hydrochloric acid is adjusted after pH to 1, is extracted with ethyl acetate (150.0mL × 2), merges organic
Phase, saturated common salt water washing, anhydrous sodium sulfate drying, remove solvent under reduced pressure, obtain 4- fluoronaphthalene -1- alcohol solid 13.3g, yield is
74.0%.
1H NMR(CDCl3):5.35 (s, 1H), 6.63 (d, 1H), 6.88 (d, 1H), 7.58 (t, 1H), 7.61 (t, 1H),
8.09 (d, 1H), 8.22 (d, 1H).
Embodiment 5
A. the preparation of 1- bromo- 4- fluoronaphthalene
In 500mL single port bottle, add 1- fluoronaphthalene (20.0g, 0.137mol) and carbon tetrachloride (120.0mL), Deca bromine
Plain (10.9g, 0.068mol), back flow reaction 2h.Reaction finishes, concentrating under reduced pressure, and concentrated solution pours low temperature in methanol (80.0mL) into
Stand overnight i.e. precipitation solid, sucking filtration obtains 1- bromo- 4- fluoronaphthalene 28.1g, yield is 91.2%.
B. the preparation of 4- fluoronaphthalene -1- boric acid
In 500mL there-necked flask, bromo- for 1- 4- fluoronaphthalene (28.1g, 0.125mol) is dissolved in anhydrous tetrahydro furan
(200.0mL), add tri-n-butyl borate (35.9g, 0.156mol), be cooled to -78 DEG C, Deca n-BuLi (10.4g,
0.162mol), after -78 DEG C of reaction 0.5h, recover to room temperature, add saturated aqueous ammonium chloride that reaction is quenched, adjust pH to
Highly acid, is extracted with ethyl acetate (200.0mL × 3), merges organic faciess, saturated common salt water washing, anhydrous sodium sulfate drying, subtracts
Pressure is evaporated off solvent, and residue is pulled an oar with normal hexane, and sucking filtration obtains final product 4- fluoronaphthalene -1- boric acid solid 21.3g, and yield is 90.0%.
1H NMR(CDCl3):2.0 (s, 2H), 7.31 (d, 1H), 7.58 (d, 1H), 7.55 (m, 2H), 8.08 (m, 2H).
C. the preparation of 4- fluoronaphthalene -1- alcohol
In 500mL single port bottle, add 4- fluoronaphthalene -1- boric acid (21.3g, 0.112mol), 20% sodium hydrate aqueous solution
(9.43g containing NaOH, 0.236mol) and 30% hydrogenperoxide steam generator are (containing H2O211.5g, 0.337mol), room temperature reaction 10h.
Reaction finishes, and is carried miscellaneous with ether, and aqueous phase 1M hydrochloric acid is adjusted after pH to 1, is extracted with ethyl acetate (150.0mL × 2), merges organic
Phase, saturated common salt water washing, anhydrous sodium sulfate drying, remove solvent under reduced pressure, obtain 4- fluoronaphthalene -1- alcohol solid 13.0g, yield is
71.5%.
1H NMR(CDCl3):5.35 (s, 1H), 6.63 (d, 1H), 6.88 (d, 1H), 7.58 (t, 1H), 7.61 (t, 1H),
8.09 (d, 1H), 8.22 (d, 1H).
Embodiment 6
A. the preparation of 1- bromo- 4- fluoronaphthalene
In 500mL single port bottle, add 1- fluoronaphthalene (20.0g, 0.137mol) and carbon tetrachloride (120.0mL), Deca bromine
Plain (13.1g, 0.082mol), back flow reaction 1.5h.Reaction finishes, concentrating under reduced pressure, and concentrated solution is poured into low in methanol (80.0mL)
Temperature stands overnight i.e. precipitation solid, and sucking filtration obtains 1- bromo- 4- fluoronaphthalene 24.6g, and yield is 80.0%.
B. the preparation of 4- fluoronaphthalene -1- boric acid
In 500mL there-necked flask, bromo- for 1- 4- fluoronaphthalene (24.6g, 0.109mol) is dissolved in anhydrous tetrahydro furan
(200.0mL), add methyl borate. (12.5g, 0.120mol), be cooled to -78 DEG C, Deca n-BuLi (7.7g,
0.120mol), after -78 DEG C of reaction 1h, recover to room temperature, add saturated aqueous ammonium chloride that reaction is quenched, adjust pH to strong
Acidity, is extracted with ethyl acetate (200.0mL × 3), merges organic faciess, saturated common salt water washing, anhydrous sodium sulfate drying, decompression
Solvent is evaporated off, residue is pulled an oar with normal hexane, sucking filtration obtains final product 4- fluoronaphthalene -1- boric acid solid 18.4g, yield is 88.6%.
1H NMR(CDCl3):2.0 (s, 2H), 7.31 (d, 1H), 7.58 (d, 1H), 7.55 (m, 2H), 8.08 (m, 2H).
C. the preparation of 4- fluoronaphthalene -1- alcohol
In 500mL single port bottle, add 4- fluoronaphthalene -1- boric acid (18.4g, 0.097mol), 25% sodium hydrate aqueous solution
(8.2g containing NaOH, 0.204mol) and 30% hydrogenperoxide steam generator are (containing H2O26.6g, 0.194mol), room temperature reaction 12h.Instead
Should finish, be carried with ether miscellaneous, aqueous phase 1M hydrochloric acid is adjusted after pH to 1, is extracted with ethyl acetate (150.0mL × 2), merges organic
Phase, saturated common salt water washing, anhydrous sodium sulfate drying, remove solvent under reduced pressure, obtain 4- fluoronaphthalene -1- alcohol solid 11.0g, yield is
70%.
1H NMR(CDCl3):5.35 (s, 1H), 6.63 (d, 1H), 6.88 (d, 1H), 7.58 (t, 1H), 7.61 (t, 1H),
8.09 (d, 1H), 8.22 (d, 1H).
Embodiment 7
A. the preparation of 1- bromo- 4- fluoronaphthalene
In 500mL single port bottle, add 1- fluoronaphthalene (20.0g, 0.137mol) and carbon tetrachloride (120.0mL), Deca bromine
Plain (10.9g, 0.068mol), back flow reaction 2h.Reaction finishes, concentrating under reduced pressure, and concentrated solution pours low temperature in methanol (80.0mL) into
Stand overnight i.e. precipitation solid, sucking filtration obtains 1- bromo- 4- fluoronaphthalene 27.9g, yield is 90.5%.
B. the preparation of 4- fluoronaphthalene -1- boric acid
In 500mL there-necked flask, bromo- for 1- 4- fluoronaphthalene (27.9g, 0.124mol) is dissolved in anhydrous tetrahydro furan
(200.0mL), add triisopropyl borate ester (26.8g, 0.142mol), be cooled to -78 DEG C, Deca n-BuLi (9.5g,
0.149mol), after -78 DEG C of reaction 0.5h, recover to room temperature, add saturated aqueous ammonium chloride that reaction is quenched, adjust pH to
Highly acid, is extracted with ethyl acetate (200.0mL × 3), merges organic faciess, saturated common salt water washing, anhydrous sodium sulfate drying, subtracts
Pressure is evaporated off solvent, and residue is pulled an oar with normal hexane, and sucking filtration obtains final product 4- fluoronaphthalene -1- boric acid solid 21.2g, and yield is 90.2%.
1H NMR(CDCl3):2.0 (s, 2H), 7.31 (d, 1H), 7.58 (d, 1H), 7.55 (m, 2H), 8.08 (m, 2H).
C. the preparation of 4- fluoronaphthalene -1- alcohol
In 500mL single port bottle, add 4- fluoronaphthalene -1- boric acid (21.2g, 0.112mol), 15% sodium hydrate aqueous solution
(9.4g containing NaOH, 0.235mol) and 30% hydrogenperoxide steam generator are (containing H2O215.2g, 0.447mol), room temperature reaction 11h.Instead
Should finish, be carried with ether miscellaneous, aqueous phase 1M hydrochloric acid is adjusted after pH to 1, is extracted with ethyl acetate (150.0mL × 2), merges organic
Phase, saturated common salt water washing, anhydrous sodium sulfate drying, remove solvent under reduced pressure, obtain 4- fluoronaphthalene -1- alcohol solid 13.2g, yield is
73.0%.
1H NMR(CDCl3):5.35 (s, 1H), 6.63 (d, 1H), 6.88 (d, 1H), 7.58 (t, 1H), 7.61 (t, 1H),
8.09 (d, 1H), 8.22 (d, 1H).
Embodiment 8
A. the preparation of 1- bromo- 4- fluoronaphthalene
In 500mL single port bottle, add 1- fluoronaphthalene (20.0g, 0.137mol) and carbon tetrachloride (120.0mL), Deca bromine
Plain (10.9g, 0.068mol), back flow reaction 2h.Reaction finishes, concentrating under reduced pressure, and concentrated solution pours low temperature in methanol (80.0mL) into
Stand overnight i.e. precipitation solid, sucking filtration obtains 1- bromo- 4- fluoronaphthalene 27.8g, yield is 90.4%.
B. the preparation of 4- fluoronaphthalene -1- boric acid
In 500mL there-necked flask, bromo- for 1- 4- fluoronaphthalene (27.8g, 0.124mol) is dissolved in anhydrous tetrahydro furan
(200.0mL), add triisopropyl borate ester (24.4g, 0.130mol), be cooled to -78 DEG C, Deca n-BuLi (8.7g,
0.136mol), after -78 DEG C of reaction 1h, recover to room temperature, add saturated aqueous ammonium chloride that reaction is quenched, adjust pH to strong
Acidity, is extracted with ethyl acetate (200.0mL × 3), merges organic faciess, saturated common salt water washing, anhydrous sodium sulfate drying, decompression
Solvent is evaporated off, residue is pulled an oar with normal hexane, sucking filtration obtains final product 4- fluoronaphthalene -1- boric acid solid 20.9g, yield is 88.5%.
1H NMR(CDCl3):2.0 (s, 2H), 7.31 (d, 1H), 7.58 (d, 1H), 7.55 (m, 2H), 8.08 (m, 2H).
C. the preparation of 4- fluoronaphthalene -1- alcohol
In 500mL single port bottle, add 4- fluoronaphthalene -1- boric acid (20.9g, 0.110mol), 20% sodium hydrate aqueous solution
(8.8g containing NaOH, 0.220mol) and 30% hydrogenperoxide steam generator are (containing H2O211.2g, 0.330mol), room temperature reaction 11h.Instead
Should finish, with ether extraction, aqueous phase 1M hydrochloric acid is adjusted after pH to 1, is extracted with ethyl acetate (150.0mL × 2), merges organic
Phase, saturated common salt water washing, anhydrous sodium sulfate drying, remove solvent under reduced pressure, obtain 4- fluoronaphthalene -1- alcohol solid 12.9g, yield is
72.3%.
1H NMR(CDCl3):5.35 (s, 1H), 6.63 (d, 1H), 6.88 (d, 1H), 7.58 (t, 1H), 7.61 (t, 1H),
8.09 (d, 1H), 8.22 (d, 1H).
Claims (4)
1. a kind of preparation technology of 4- fluoronaphthalene -1- alcohol it is characterised in that：Comprise the steps of：With 1- fluoronaphthalene as raw material, through halo
Reaction obtains 1- bromo- 4- fluoronaphthalene；1- bromo- 4- fluoronaphthalene obtains 4- fluoronaphthalene -1- boric acid through boration reaction；4- fluoronaphthalene -1- boric acid warp
Hydrolysis obtain target product 4- fluoronaphthalene -1- alcohol, and the intermediate in process route is 4- fluoronaphthalene -1- boric acid；
2. according to claim 1,4- fluoronaphthalene -1- alcohol preparation technology it is characterised in that：Described (1) step halo is anti-
The reagent that should use is bromine；1- fluoronaphthalene with the mol ratio of bromine or NBS is：1:0.5～0.6.
3. according to claim 1,4- fluoronaphthalene -1- alcohol preparation technology it is characterised in that：Described (2) step boration
Reaction agents useful for same is methyl borate., n-butyl boronate or triisopropyl borate ester；1- bromo- 4- fluoronaphthalene and methyl borate., boron
The mol ratio of sour tri-n-butyl or triisopropyl borate ester is：1:1～1.3.
4. according to claim 1,4- fluoronaphthalene -1- alcohol preparation technology it is characterised in that：Described (2) step boration
Reaction agents useful for same is n-BuLi；1- bromo- 4- fluoronaphthalene with the mol ratio of n-BuLi is：1:1.05～1.3.
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| CN116354928A (en) * | 2023-04-03 | 2023-06-30 | 南京优氟医药科技有限公司 | Preparation method of 4-bromo-2- (2, 6-dioxopiperidine-3-yl) 7-fluoroisoindoline-1, 3-dione |
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