CN107840820A - A kind of preparation technology of 4 (base of 5 bromine, 3 fluorine pyridine 2) morpholines - Google Patents
A kind of preparation technology of 4 (base of 5 bromine, 3 fluorine pyridine 2) morpholines Download PDFInfo
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- CN107840820A CN107840820A CN201711140717.6A CN201711140717A CN107840820A CN 107840820 A CN107840820 A CN 107840820A CN 201711140717 A CN201711140717 A CN 201711140717A CN 107840820 A CN107840820 A CN 107840820A
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- Prior art keywords
- morpholine
- bases
- pyridine
- reaction
- fluorine pyridine
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- 0 *NC=C(C=C)Br Chemical compound *NC=C(C=C)Br 0.000 description 1
- TWDWREWBZKBHGX-LDTZZKCISA-N C/C=C\C=C(/C(N1CCOCC1)=C)\[N+]([O-])=O Chemical compound C/C=C\C=C(/C(N1CCOCC1)=C)\[N+]([O-])=O TWDWREWBZKBHGX-LDTZZKCISA-N 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N C1NCCOC1 Chemical compound C1NCCOC1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- YLJPDCIIELIANF-UHFFFAOYSA-N CC(NN1N2CCOCC2)=CC=C1F Chemical compound CC(NN1N2CCOCC2)=CC=C1F YLJPDCIIELIANF-UHFFFAOYSA-N 0.000 description 1
- DHYQHRDXKCKJAN-UHFFFAOYSA-N Nc1c(N2CCOCC2)nccc1 Chemical compound Nc1c(N2CCOCC2)nccc1 DHYQHRDXKCKJAN-UHFFFAOYSA-N 0.000 description 1
- IFPPOIAPLDXATK-UHFFFAOYSA-N O=Nc1cccnc1Cl Chemical compound O=Nc1cccnc1Cl IFPPOIAPLDXATK-UHFFFAOYSA-N 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
Abstract
The invention discloses a kind of preparation technology of 4 (base of 5 bromine, 3 fluorine pyridine 2) morpholines.Comprise the steps of：(1) using the nitropyridine of 2 chlorine 3 as raw material, reaction 4 (base of 3 nitropyridine 2) morpholines of generation are substituted；(2) 4 (base of 3 nitropyridine 2) morpholines generate the amine of 2 morpholino pyridine 3 through reduction reaction；The amine of (3) 2 morpholino pyridine 3 generates 4 (base of 3 fluorine pyridine 2) morpholines through diazotising and substitution reaction；(4) 4 (base of 3 fluorine pyridine 2) morpholines are substituted reaction and obtain target compound 4 (base of 5 bromine, 3 fluorine pyridine 2) morpholine.This route raw material is cheap and easy to get, and operating condition is gently easily-controllable, and product is advantageous to practical application compared with easy purification.
Description
Technical field
The present invention relates to a kind of preparation technology of new 4- (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine.Belong to organic synthesis,
Fine chemistry industry, medicine intermediate field.
Background technology
Compound containing pyridine ring and the compound of the ring containing morpholine are the important source materials of chemical industry, are widely used in curing
Medicine intermediate, pharmaceutical products, agricultural chemicals, pesticide intermediate, feed and feedstuff and other multiple fields.4- (the bromo- 3- fluorine pyrroles of 5-
Pyridine -2- bases) contain pyridine ring and morpholine ring in morpholine molecule, while can also pass through coupling containing the halogen atom easily to react
Reaction etc. chemically reacts into target molecule while introduces pyridine ring and morpholine ring, thus is widely used in GPR40 receptor activations
The building-up process of the medicines such as agent, LSD1 inhibitor, Syk inhibitor.
The synthetic route on 4- (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine has following several at present：
WO2010143733 report using the fluoro- 5- bromopyridines of the chloro- 3- of 2- as raw material, with morpholine under 210 DEG C of high temperature microwave
Reaction generation 4- (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine.This route is raw materials used more expensive, also needs to use microwave reactor, and grasp
It is higher to make temperature, is unfavorable for commercial Application.
The route of WO2016007731 reports, with bromo- 2, the 3- difluoro pyridines of 5- for raw material, reacts 12 at room temperature with morpholine
Individual hour generates 4- (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine.This route is raw materials used costly, the difficult separation of accessory substance, is unfavorable for
Commercial Application.
The content of the invention
The technical problem to be solved in the present invention is：A kind of system of new 4- (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine is provided
Standby technique.Solves in the prior art the problem of cost of material is higher, and operating condition requirement is higher.
Technical scheme：A kind of preparation method of 4- (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine, including：(1) with
The chloro- 3- nitropyridines of 2- are raw material, are substituted reaction generation 4- (3- nitropyridine -2- bases) morpholine；(2) 4- (3- nitro pyrroles
Pyridine -2- bases) morpholine through reduction reaction generate 2- morpholino pyridine -3- amine；(3) 2- morpholinoes pyridine -3- amine through diazotising and takes
Generation reaction generation 4- (3- fluorine pyridine -2- bases) morpholine；(4) 4- (3- fluorine pyridine -2- bases) morpholine is substituted reaction and obtains targeted
Compound 4- (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine.
(1) the step reaction solvent for use is：DMF or DMSO；Acid binding agent is：Potassium carbonate, sodium carbonate, sodium acid carbonate or
Triethylamine；Substitution reagent be：Morpholine；Reaction temperature is： 85℃；Reaction time is：6~8h；Acid binding agent and the chloro- 3- nitros of 2-
The molar ratio of pyridine is：1:1~3:1；Substitution reagent and the chloro- 3- nitropyridines of 2- molar ratio be：1:1~2:1.
(2) the step reaction solvent for use is：Methanol, ethanol or acetone；Catalyst is：Palladium carbon；Reducing agent is：Hydrogen
Gas；Reaction temperature is：Room temperature；Reaction time is：10~16h；The matter that feeds intake of catalyst and 4- (3- nitropyridine -2- bases) morpholine
Measuring ratio is：1:100~1:10.
(3) step reaction is that 1eq 2- morpholino pyridine -3- amine is dissolved in into 1~5eq hydrogen fluoride pyrrole at 0 DEG C
In pyridine, 1~2eq natrium nitrosum, insulation reaction 0.5-1h, then 50 DEG C of 1~3h of back flow reaction are added.
(4) the step reaction solvent for use is：DMF or acetonitrile；Substitution reagent be：NBS；Reaction temperature is：50~80
℃；Reaction time is：1~2h；Substitution reagent and 4- (3- fluorine pyridine -2- bases) morpholine molar ratio be：1:1~1:2.
Beneficial effects of the present invention：The present invention synthesizes target using the chloro- 3- nitropyridines of 2- as initiation material, through four-step reaction
Compound.This route raw material is cheap and easy to get, and operating condition is gently easily-controllable, and product is advantageous to practical application compared with easy purification.
Embodiment
Embodiment 1
A.4- the preparation of (3- nitropyridine -2- bases) morpholine
The chloro- 3- nitropyridines (20.0g, 126.2mmol) of 2- are dissolved in DMF (160mL), addition potassium carbonate (52.3g,
378.5mmol), morpholine (13.2g, 151.4 mmol), 85 DEG C of reaction 7h are slowly added to.Reaction finishes, and is cooled to room temperature, adds
200mL pure water, ethyl acetate (200mL × 2) extraction, collects organic phase, anhydrous sodium sulfate drying, filters out solid, evaporated under reduced pressure
Solvent, residue cross silicagel column (mobile phase PE:EA=10:1) 4- (3- nitropyridine -2- bases) morpholine yellow solid, is obtained
21.2g, yield 80.3%.
B.2- the preparation of morpholino pyridine -3- amine
4- (3- nitropyridine -2- bases) morpholine (11.0g, 52.6mmol) is dissolved in methanol (100mL), adds 10%
Palladium carbon (1.1g, 1.1mmol), be passed through hydrogen, react at room temperature 14h.Reaction finishes, and removes solvent, residue water under reduced pressure
(100mL) dissolves, ethyl acetate (100 mL × 3) extraction, collects organic phase, and anhydrous sodium sulfate drying filters out solid, and decompression is steamed
Dry solvent, residue cross silicagel column (mobile phase PE:EA=10:1) 2- morpholino pyridine -3- amine gray solid 8.3g, are obtained, are received
Rate is 88.0%.
C.4- the preparation of (3- fluorine pyridine -2- bases) morpholine
Below 0 DEG C, 2- morpholino pyridine -3- amine (7.0g, 39.1mmol) is dissolved in hydrogen fluoride pyridine (35mL),
Natrium nitrosum (2.7g, 39.1mmol), insulation reaction 30min are slowly added to, then 50 DEG C of back flow reaction 1h, reaction finishes, and falls
Enter in ice, it is anhydrous to alkalescence, ethyl acetate (100mL × 3) extraction, collection organic phase to adjust pH value with saturated sodium carbonate solution
Sodium sulphate is dried, and filters out solid, evaporated under reduced pressure solvent, residue crosses silicagel column (mobile phase PE:EA=10:1) 4- (3- fluorine, is obtained
Pyridine -2- bases) morpholine yellow liquid 4.6g, yield 65.2%.
D.4- the preparation of (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine
4- (3- fluorine pyridine -2- bases) morpholine (3.0g, 16.5mmol) is dissolved in DMF (30mL), is slowly added to NBS
(2.9g, 16.5mmol), 80 DEG C of reaction 1h.Reaction finishes, and adds 50mL pure water, ethyl acetate (50mL × 3) extraction, and collection has
Machine phase, anhydrous sodium sulfate drying filter out solid, evaporated under reduced pressure solvent, and residue crosses silicagel column (mobile phase PE:EA=10:1),
Obtain 4- (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine yellow solid 3.9g, yield 90.7%.
1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.37-7.41(d,1H),3.81 -3.84(m,4H),3.45-
3.47(m,4H)。
Embodiment 2
A.4- the preparation of (3- nitropyridine -2- bases) morpholine
The chloro- 3- nitropyridines (20.0g, 126.2mmol) of 2- are dissolved in DMSO (160mL), add potassium carbonate
(34.9g, 252.3mmol), it is slowly added to morpholine (13.2g, 151.4 mmol), 85 DEG C of reaction 7h.Reaction finishes, and is cooled to room
Temperature, 200mL pure water is added, ethyl acetate (200mL × 2) extraction, organic phase is collected, anhydrous sodium sulfate drying, filters out solid, subtract
Solvent evaporated is pressed, residue crosses silicagel column (mobile phase PE:EA=10:1) 4- (3- nitropyridine -2- bases) morpholine yellow, is obtained to consolidate
Body 21.0g, yield 79.4%.
B.2- the preparation of morpholino pyridine -3- amine
4- (3- nitropyridine -2- bases) morpholine (10.0g, 47.8mmol) is dissolved in methanol (100mL), adds 10%
Palladium carbon (1.0g, 1.0mmol), be passed through hydrogen, react at room temperature 14h.Reaction finishes, and removes solvent, residue water under reduced pressure
(100mL) dissolves, ethyl acetate (100 mL × 3) extraction, collects organic phase, and anhydrous sodium sulfate drying filters out solid, and decompression is steamed
Dry solvent, residue cross silicagel column (mobile phase PE:EA=10:1) 2- morpholino pyridine -3- amine gray solid 7.5g, are obtained, are received
Rate is 87.4%.
C.4- the preparation of (3- fluorine pyridine -2- bases) morpholine
Below 0 DEG C, 2- morpholino pyridine -3- amine (7.0g, 39.1mmol) is dissolved in hydrogen fluoride pyridine (18mL),
Natrium nitrosum (2.7g, 39.1mmol), insulation reaction 30min are slowly added to, then 50 DEG C of back flow reaction 3h, reaction finishes, and falls
Enter in ice, it is anhydrous to alkalescence, ethyl acetate (100mL × 3) extraction, collection organic phase to adjust pH value with saturated sodium carbonate solution
Sodium sulphate is dried, and filters out solid, evaporated under reduced pressure solvent, residue crosses silicagel column (mobile phase PE:EA=10:1) 4- (3- fluorine, is obtained
Pyridine -2- bases) morpholine yellow liquid 4.5g, yield 63.4%.
D.4- the preparation of (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine
4- (3- fluorine pyridine -2- bases) morpholine (4.0g, 22.0mmol) is dissolved in DMF (40mL), is slowly added to NBS
(3.9g, 22.0mmol), 80 DEG C of reaction 1h.Reaction finishes, and adds 50mL pure water, ethyl acetate (50mL × 3) extraction, and collection has
Machine phase, anhydrous sodium sulfate drying filter out solid, evaporated under reduced pressure solvent, and residue crosses silicagel column (mobile phase PE:EA=10:1),
Obtain 4- (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine yellow solid 5.2g, yield 90.1%.
1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.37-7.41(d,1H),3.81 -3.84(m,4H),3.45-
3.47(m,4H)。
Embodiment 3
A.4- the preparation of (3- nitropyridine -2- bases) morpholine
The chloro- 3- nitropyridines (20.0g, 126.2mmol) of 2- are dissolved in DMF (160mL), addition sodium carbonate (40.1g,
378.5mmol), morpholine (16.5g, 189.2 mmol), 85 DEG C of reaction 6h are slowly added to.Reaction finishes, and is cooled to room temperature, adds
200mL pure water, ethyl acetate (200mL × 2) extraction, collects organic phase, anhydrous sodium sulfate drying, filters out solid, evaporated under reduced pressure
Solvent, residue cross silicagel column (mobile phase PE:EA=10:1) 4- (3- nitropyridine -2- bases) morpholine yellow solid, is obtained
21.7g, yield 82.1%.
B.2- the preparation of morpholino pyridine -3- amine
4- (3- nitropyridine -2- bases) morpholine (10.0g, 47.8mmol) is dissolved in ethanol (100mL), adds 10%
Palladium carbon (1.0g, 1.0mmol), be passed through hydrogen, react at room temperature 14h.Reaction finishes, and removes solvent, residue water under reduced pressure
(100mL) dissolves, ethyl acetate (100 mL × 3) extraction, collects organic phase, and anhydrous sodium sulfate drying filters out solid, and decompression is steamed
Dry solvent, residue cross silicagel column (mobile phase PE:EA=10:1) 2- morpholino pyridine -3- amine gray solid 7.6g, are obtained, are received
Rate is 88.6%.
C.4- the preparation of (3- fluorine pyridine -2- bases) morpholine
Below 0 DEG C, 2- morpholino pyridine -3- amine (7.0g, 39.1mmol) is dissolved in hydrogen fluoride pyridine (53mL),
Natrium nitrosum (2.7g, 39.1mmol), insulation reaction 30min are slowly added to, then 50 DEG C of back flow reaction 2h, reaction finishes, and falls
Enter in ice, it is anhydrous to alkalescence, ethyl acetate (100mL × 3) extraction, collection organic phase to adjust pH value with saturated sodium carbonate solution
Sodium sulphate is dried, and filters out solid, evaporated under reduced pressure solvent, residue crosses silicagel column (mobile phase PE:EA=10:1) 4- (3- fluorine, is obtained
Pyridine -2- bases) morpholine yellow liquid 4.8g, yield 67.7%.
D.4- the preparation of (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine
4- (3- fluorine pyridine -2- bases) morpholine (4.0g, 22.0mmol) is dissolved in DMF (40mL), is slowly added to NBS
(3.9g, 22.0mmol), 80 DEG C of reaction 1h.Reaction finishes, and adds 50mL pure water, ethyl acetate (50mL × 3) extraction, and collection has
Machine phase, anhydrous sodium sulfate drying filter out solid, evaporated under reduced pressure solvent, and residue crosses silicagel column (mobile phase PE:EA=10:1),
Obtain 4- (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine yellow solid 5.3g, yield 91.5%.
1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.37-7.41(d,1H),3.81 -3.84(m,4H),3.45-
3.47(m,4H)。
Embodiment 4
A.4- the preparation of (3- nitropyridine -2- bases) morpholine
The chloro- 3- nitropyridines (20.0g, 126.2mmol) of 2- are dissolved in DMF (160mL), add sodium acid carbonate
(31.8g, 378.5mmol), it is slowly added to morpholine (13.2g, 151.4mmol), 85 DEG C of reaction 8h.Reaction finishes, and is cooled to room
Temperature, 200mL pure water is added, ethyl acetate (200mL × 2) extraction, organic phase is collected, anhydrous sodium sulfate drying, filters out solid, subtract
Solvent evaporated is pressed, residue crosses silicagel column (mobile phase PE:EA=10:1) 4- (3- nitropyridine -2- bases) morpholine yellow, is obtained to consolidate
Body 20.5g, yield 77.6%.
B.2- the preparation of morpholino pyridine -3- amine
4- (3- nitropyridine -2- bases) morpholine (10.0g, 47.8mmol) is dissolved in acetone (100mL), adds 10%
Palladium carbon (1.0g, 1.0mmol), be passed through hydrogen, react at room temperature 14h.Reaction finishes, and removes solvent, residue water under reduced pressure
(100mL) dissolves, ethyl acetate (100 mL × 3) extraction, collects organic phase, and anhydrous sodium sulfate drying filters out solid, and decompression is steamed
Dry solvent, residue cross silicagel column (mobile phase PE:EA=10:1) 2- morpholino pyridine -3- amine gray solid 7.4g, are obtained, are received
Rate is 86.7%.
C.4- the preparation of (3- fluorine pyridine -2- bases) morpholine
Below 0 DEG C, 2- morpholino pyridine -3- amine (7.0g, 39.1mmol) is dissolved in hydrogen fluoride pyridine (53mL),
Natrium nitrosum (5.4g, 78.1mmol), insulation reaction 30min are slowly added to, then 50 DEG C of back flow reaction 1h, reaction finishes, and falls
Enter in ice, it is anhydrous to alkalescence, ethyl acetate (100mL × 3) extraction, collection organic phase to adjust pH value with saturated sodium carbonate solution
Sodium sulphate is dried, and filters out solid, evaporated under reduced pressure solvent, residue crosses silicagel column (mobile phase PE:EA=10:1) 4- (3- fluorine, is obtained
Pyridine -2- bases) morpholine yellow liquid 4.8g, yield 67.1%.
D.4- the preparation of (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine
4- (3- fluorine pyridine -2- bases) morpholine (3.0g, 16.5mmol) is dissolved in DMF (30mL), is slowly added to NBS
(4.4g, 24.7mmol), 70 DEG C of reaction 1h.Reaction finishes, and adds 50mL pure water, ethyl acetate (50mL × 3) extraction, and collection has
Machine phase, anhydrous sodium sulfate drying filter out solid, evaporated under reduced pressure solvent, and residue crosses silicagel column (mobile phase PE:EA=10:1),
Obtain 4- (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine yellow solid 3.8g, yield 89.1%.
1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.37-7.41(d,1H),3.81 -3.84(m,4H),3.45-
3.47(m,4H)。
Embodiment 5
A.4- the preparation of (3- nitropyridine -2- bases) morpholine
The chloro- 3- nitropyridines (20.0g, 126.2mmol) of 2- are dissolved in DMF (160mL), addition triethylamine (38.3g,
378.5mmol), morpholine (13.2g, 151.4 mmol), 85 DEG C of reaction 8h are slowly added to.Reaction finishes, and is cooled to room temperature, adds
200mL pure water, ethyl acetate (200mL × 2) extraction, collects organic phase, anhydrous sodium sulfate drying, filters out solid, evaporated under reduced pressure
Solvent, residue cross silicagel column (mobile phase PE:EA=10:1) 4- (3- nitropyridine -2- bases) morpholine yellow solid, is obtained
20.2g, yield 76.6%.
B.2- the preparation of morpholino pyridine -3- amine
4- (3- nitropyridine -2- bases) morpholine (10.0g, 47.8mmol) is dissolved in methanol (100mL), adds 10%
Palladium carbon (0.5g, 0.5mmol), be passed through hydrogen, react at room temperature 16h.Reaction finishes, and removes solvent, residue water under reduced pressure
(100mL) dissolves, ethyl acetate (100 mL × 3) extraction, collects organic phase, and anhydrous sodium sulfate drying filters out solid, and decompression is steamed
Dry solvent, residue cross silicagel column (mobile phase PE:EA=10:1) 2- morpholino pyridine -3- amine gray solid 7.4g, are obtained, are received
Rate is 86.0%.
C.4- the preparation of (3- fluorine pyridine -2- bases) morpholine
Below 0 DEG C, 2- morpholino pyridine -3- amine (7.0g, 39.1mmol) is dissolved in hydrogen fluoride pyridine (35mL),
Natrium nitrosum (4.0g, 58.6mmol), insulation reaction 30min are slowly added to, then 50 DEG C of back flow reaction 1h, reaction finishes, and falls
Enter in ice, it is anhydrous to alkalescence, ethyl acetate (100mL × 3) extraction, collection organic phase to adjust pH value with saturated sodium carbonate solution
Sodium sulphate is dried, and filters out solid, evaporated under reduced pressure solvent, residue crosses silicagel column (mobile phase PE:EA=10:1) 4- (3- fluorine, is obtained
Pyridine -2- bases) morpholine yellow liquid 4.7g, yield 65.8%.
D.4- the preparation of (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine
4- (3- fluorine pyridine -2- bases) morpholine (3.0g, 16.5mmol) is dissolved in DMF (30mL), is slowly added to NBS
(3.8g, 21.4mmol), 80 DEG C of reaction 1h.Reaction finishes, and adds 50mL pure water, ethyl acetate (50mL × 3) extraction, and collection has
Machine phase, anhydrous sodium sulfate drying filter out solid, evaporated under reduced pressure solvent, and residue crosses silicagel column (mobile phase PE:EA=10:1),
Obtain 4- (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine yellow solid 4.0g, yield 91.9%.
1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.37-7.41(d,1H),3.81 -3.84(m,4H),3.45-
3.47(m,4H)。
Embodiment 6
A.4- the preparation of (3- nitropyridine -2- bases) morpholine
The chloro- 3- nitropyridines (20.0g, 126.2mmol) of 2- are dissolved in DMF (160mL), addition potassium carbonate (17.4g,
126.2mmol), morpholine (11.0g, 126.2 mmol), 85 DEG C of reaction 8h are slowly added to.Reaction finishes, and is cooled to room temperature, adds
200mL pure water, ethyl acetate (200mL × 2) extraction, collects organic phase, anhydrous sodium sulfate drying, filters out solid, evaporated under reduced pressure
Solvent, residue cross silicagel column (mobile phase PE:EA=10:1) 4- (3- nitropyridine -2- bases) morpholine yellow solid, is obtained
20.7g, yield 78.3%.
B.2- the preparation of morpholino pyridine -3- amine
4- (3- nitropyridine -2- bases) morpholine (11.0g, 52.6mmol) is dissolved in methanol (100mL), adds 10%
Palladium carbon (5.6g, 5.3mmol), be passed through hydrogen, react at room temperature 10h.Reaction finishes, and removes solvent, residue water under reduced pressure
(100mL) dissolves, ethyl acetate (100 mL × 3) extraction, collects organic phase, and anhydrous sodium sulfate drying filters out solid, and decompression is steamed
Dry solvent, residue cross silicagel column (mobile phase PE:EA=10:1) 2- morpholino pyridine -3- amine gray solid 8.5g, are obtained, are received
Rate is 90.1%.
C.4- the preparation of (3- fluorine pyridine -2- bases) morpholine
Below 0 DEG C, 2- morpholino pyridine -3- amine (7.0g, 39.1mmol) is dissolved in hydrogen fluoride pyridine (35mL),
Natrium nitrosum (3.2g, 46.9mmol), insulation reaction 30min are slowly added to, then 50 DEG C of back flow reaction 1h, reaction finishes, and falls
Enter in ice, it is anhydrous to alkalescence, ethyl acetate (100mL × 3) extraction, collection organic phase to adjust pH value with saturated sodium carbonate solution
Sodium sulphate is dried, and filters out solid, evaporated under reduced pressure solvent, residue crosses silicagel column (mobile phase PE:EA=10:1) 4- (3- fluorine, is obtained
Pyridine -2- bases) morpholine yellow liquid 4.7g, yield 66.6%.
D.4- the preparation of (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine
4- (3- fluorine pyridine -2- bases) morpholine (3.0g, 16.5mmol) is dissolved in DMF (30mL), is slowly added to NBS
(2.9g, 16.5mmol), 65 DEG C of reaction 2h.Reaction finishes, and adds 50mL pure water, ethyl acetate (50mL × 3) extraction, and collection has
Machine phase, anhydrous sodium sulfate drying filter out solid, evaporated under reduced pressure solvent, and residue crosses silicagel column (mobile phase PE:EA=10:1),
Obtain 4- (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine yellow solid 3.8g, yield 87.1%.
1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.37-7.41(d,1H),3.81 -3.84(m,4H),3.45-
3.47(m,4H)。
Embodiment 7
A.4- the preparation of (3- nitropyridine -2- bases) morpholine
The chloro- 3- nitropyridines (20.0g, 126.2mmol) of 2- are dissolved in DMF (160mL), addition potassium carbonate (34.9g,
252.3mmol), morpholine (16.5g, 189.2 mmol), 85 DEG C of reaction 7h are slowly added to.Reaction finishes, and is cooled to room temperature, adds
200mL pure water, ethyl acetate (200mL × 2) extraction, collects organic phase, anhydrous sodium sulfate drying, filters out solid, evaporated under reduced pressure
Solvent, residue cross silicagel column (mobile phase PE:EA=10:1) 4- (3- nitropyridine -2- bases) morpholine yellow solid, is obtained
21.4g, yield 81.1%.
B.2- the preparation of morpholino pyridine -3- amine
4- (3- nitropyridine -2- bases) morpholine (11.0g, 52.6mmol) is dissolved in methanol (100mL), adds 10%
Palladium carbon (2.8g, 2.6mmol), be passed through hydrogen, react at room temperature 12h.Reaction finishes, and removes solvent, residue water under reduced pressure
(100mL) dissolves, ethyl acetate (100 mL × 3) extraction, collects organic phase, and anhydrous sodium sulfate drying filters out solid, and decompression is steamed
Dry solvent, residue cross silicagel column (mobile phase PE:EA=10:1) 2- morpholino pyridine -3- amine gray solid 8.5g, are obtained, are received
Rate is 89.7%.
C.4- the preparation of (3- fluorine pyridine -2- bases) morpholine
Below 0 DEG C, 2- morpholino pyridine -3- amine (7.0g, 39.1mmol) is dissolved in hydrogen fluoride pyridine (35mL),
Natrium nitrosum (3.5g, 50.8mmol), insulation reaction 30min are slowly added to, then 50 DEG C of back flow reaction 1h, reaction finishes, and falls
Enter in ice, it is anhydrous to alkalescence, ethyl acetate (100mL × 3) extraction, collection organic phase to adjust pH value with saturated sodium carbonate solution
Sodium sulphate is dried, and filters out solid, evaporated under reduced pressure solvent, residue crosses silicagel column (mobile phase PE:EA=10:1) 4- (3- fluorine, is obtained
Pyridine -2- bases) morpholine yellow liquid 4.7g, yield 66.1%.
D.4- the preparation of (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine
4- (3- fluorine pyridine -2- bases) morpholine (3.0g, 16.5mmol) is dissolved in DMF (30mL), is slowly added to NBS
(5.9g, 32.9mmol), 80 DEG C of reaction 1h.Reaction finishes, and adds 50mL pure water, ethyl acetate (50mL × 3) extraction, and collection has
Machine phase, anhydrous sodium sulfate drying filter out solid, evaporated under reduced pressure solvent, and residue crosses silicagel column (mobile phase PE:EA=10:1),
Obtain 4- (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine yellow solid 4.0g, yield 93.1%.
1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.37-7.41(d,1H),3.81 -3.84(m,4H),3.45-
3.47(m,4H)。
Embodiment 8
A.4- the preparation of (3- nitropyridine -2- bases) morpholine
The chloro- 3- nitropyridines (20.0g, 126.2mmol) of 2- are dissolved in DMF (160mL), addition potassium carbonate (52.3g,
378.5mmol), morpholine (22.0g, 252.3 mmol), 85 DEG C of reaction 6h are slowly added to.Reaction finishes, and is cooled to room temperature, adds
200mL pure water, ethyl acetate (200mL × 2) extraction, collects organic phase, anhydrous sodium sulfate drying, filters out solid, evaporated under reduced pressure
Solvent, residue cross silicagel column (mobile phase PE:EA=10:1) 4- (3- nitropyridine -2- bases) morpholine yellow solid, is obtained
21.7g, yield 82.2%.
B.2- the preparation of morpholino pyridine -3- amine
4- (3- nitropyridine -2- bases) morpholine (11.0g, 52.6mmol) is dissolved in methanol (100mL), adds 10%
Palladium carbon (1.7g, 1.6mmol), be passed through hydrogen, react at room temperature 14h.Reaction finishes, and removes solvent, residue water under reduced pressure
(100mL) dissolves, ethyl acetate (100 mL × 3) extraction, collects organic phase, and anhydrous sodium sulfate drying filters out solid, and decompression is steamed
Dry solvent, residue cross silicagel column (mobile phase PE:EA=10:1) 2- morpholino pyridine -3- amine gray solid 8.4g, are obtained, are received
Rate is 89.6%.
C.4- the preparation of (3- fluorine pyridine -2- bases) morpholine
Below 0 DEG C, 2- morpholino pyridine -3- amine (7.0g, 39.1mmol) is dissolved in hydrogen fluoride pyridine (35mL),
Natrium nitrosum (2.7g, 39.1mmol), insulation reaction 30min are slowly added to, then 50 DEG C of back flow reaction 3h, reaction finishes, and falls
Enter in ice, it is anhydrous to alkalescence, ethyl acetate (100mL × 3) extraction, collection organic phase to adjust pH value with saturated sodium carbonate solution
Sodium sulphate is dried, and filters out solid, evaporated under reduced pressure solvent, residue crosses silicagel column (mobile phase PE:EA=10:1) 4- (3- fluorine, is obtained
Pyridine -2- bases) morpholine yellow liquid 4.7g, yield 65.8%.
D.4- the preparation of (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine
4- (3- fluorine pyridine -2- bases) morpholine (3.0g, 16.5mmol) is dissolved in DMF (30mL), is slowly added to NBS
(4.4g, 24.7mmol), 50 DEG C of reaction 2h.Reaction finishes, and adds 50mL pure water, ethyl acetate (50mL × 3) extraction, and collection has
Machine phase, anhydrous sodium sulfate drying filter out solid, evaporated under reduced pressure solvent, and residue crosses silicagel column (mobile phase PE:EA=10:1),
Obtain 4- (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine yellow solid 3.7g, yield 86.9%.
1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.37-7.41(d,1H),3.81 -3.84(m,4H),3.45-
3.47(m,4H)。
Claims (6)
- A kind of 1. preparation technology of 4- (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine, it is characterised in that：Comprise the steps of：(1) with The chloro- 3- nitropyridines of 2- are raw material, are substituted reaction generation 4- (3- nitropyridine -2- bases) morpholine；(2) 4- (3- nitropyridines- 2- yls) morpholine through reduction reaction generate 2- morpholino pyridine -3- amine；(3) 2- morpholinoes pyridine -3- amine is anti-through diazotising and substitution 4- (3- fluorine pyridine -2- bases) morpholine should be generated；(4) 4- (3- fluorine pyridine -2- bases) morpholine is substituted reaction and obtains target compound 4- (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine.
- A kind of 2. preparation technology of 4- (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine according to claim 1, it is characterised in that: Intermediate is 4- (3- nitropyridine -2- bases) morpholine, 2- morpholinoes pyridine -3- amine and 4- (3- fluorine pyridine -2- bases) morpholine.
- A kind of 3. preparation technology of 4- (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine according to claim 1, it is characterised in that： (1) the step reaction solvent for use is：DMF or DMSO；Acid binding agent is：Potassium carbonate, sodium carbonate, sodium acid carbonate or triethylamine； Substitution reagent be：Morpholine；Reaction temperature is：85℃；Reaction time is：6~8h；The throwing of acid binding agent and the chloro- 3- nitropyridines of 2- Expect that mol ratio is：1:1~3:1；Substitution reagent and the chloro- 3- nitropyridines of 2- molar ratio be：1:1~2:1.
- A kind of 4. preparation technology of 4- (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine according to claim 1, it is characterised in that： (2) the step reaction solvent for use is：Methanol, ethanol or acetone；Catalyst is：Palladium carbon；Reducing agent is：Hydrogen；Reaction temperature Spend and be：Room temperature；Reaction time is：10~16h；The mass ratio that feeds intake of catalyst and 4- (3- nitropyridine -2- bases) morpholine is：1: 100~1:10.
- A kind of 5. preparation technology of 4- (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine according to claim 1, it is characterised in that： (3) step reaction is that 1eq 2- morpholino pyridine -3- amine is dissolved in 1~5eq hydrogen fluoride pyridine below 0 DEG C, adds 1 ~2eq natrium nitrosum, insulation reaction 0.5-1h, then 50 DEG C of back flow reactions.
- A kind of 6. preparation technology of 4- (the bromo- 3- fluorine pyridine -2- bases of 5-) morpholine according to claim 1, it is characterised in that： (4) step reaction solvent for use is：DMF or acetonitrile；Substitution reagent be：NBS；Reaction temperature is：50~80 DEG C；Substitute reagent with The molar ratio of 4- (3- fluorine pyridine -2- bases) morpholine is：1:1~1:2.
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| CN111777549A (en) * | 2020-07-07 | 2020-10-16 | 中瀚(齐河县)生物医药科技有限公司 | Synthesis process of 2-methoxy-3-bromo-5-fluoropyridine |
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| CN103214481A (en) * | 2012-01-21 | 2013-07-24 | 中国科学院上海药物研究所 | Novel imidazo[1,2-a]pyridines compound, preparation method, pharmaceutical composition containing imidazo[1,2-a]pyridines compound and application |
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| CN103214481A (en) * | 2012-01-21 | 2013-07-24 | 中国科学院上海药物研究所 | Novel imidazo[1,2-a]pyridines compound, preparation method, pharmaceutical composition containing imidazo[1,2-a]pyridines compound and application |
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| DAVID A. CLARK等: "Synthesis of insecticidal fluorinated anthranilic diamides", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
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| CN111777549A (en) * | 2020-07-07 | 2020-10-16 | 中瀚(齐河县)生物医药科技有限公司 | Synthesis process of 2-methoxy-3-bromo-5-fluoropyridine |
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