CN107827811A - A kind of method for preparing N and substituting 1,2,3,6 tetrahydropyridines - Google Patents
A kind of method for preparing N and substituting 1,2,3,6 tetrahydropyridines Download PDFInfo
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- CN107827811A CN107827811A CN201711133334.6A CN201711133334A CN107827811A CN 107827811 A CN107827811 A CN 107827811A CN 201711133334 A CN201711133334 A CN 201711133334A CN 107827811 A CN107827811 A CN 107827811A
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- 238000000034 method Methods 0.000 title claims abstract description 16
- 150000008083 1,2,3,6-tetrahydropyridines Chemical group 0.000 title abstract description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 238000006467 substitution reaction Methods 0.000 claims abstract description 14
- 239000002253 acid Substances 0.000 claims abstract description 10
- 150000005690 diesters Chemical class 0.000 claims abstract description 8
- -1 4 piperidine alcohols Chemical class 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims description 21
- 239000007787 solid Substances 0.000 claims description 19
- 239000000706 filtrate Substances 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 claims description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000005292 vacuum distillation Methods 0.000 claims description 2
- 125000005604 azodicarboxylate group Chemical group 0.000 claims 1
- 125000004494 ethyl ester group Chemical group 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 3
- 239000012675 alcoholic extract Substances 0.000 abstract description 2
- 125000003342 alkenyl group Chemical group 0.000 abstract description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 2
- 231100000614 poison Toxicity 0.000 abstract description 2
- 230000007096 poisonous effect Effects 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- YWKYQRWNOXUYJK-UHFFFAOYSA-N benzyl 3,6-dihydro-2h-pyridine-1-carboxylate Chemical class C1CC=CCN1C(=O)OCC1=CC=CC=C1 YWKYQRWNOXUYJK-UHFFFAOYSA-N 0.000 description 6
- 239000003921 oil Substances 0.000 description 5
- SHHHRQFHCPINIB-UHFFFAOYSA-N tert-butyl 3,6-dihydro-2h-pyridine-1-carboxylate Chemical class CC(C)(C)OC(=O)N1CCC=CC1 SHHHRQFHCPINIB-UHFFFAOYSA-N 0.000 description 5
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Chemical group CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- SIRJFTFGHZXRRZ-UHFFFAOYSA-N 1-benzyl-3,6-dihydro-2h-pyridine Chemical class C=1C=CC=CC=1CN1CCC=CC1 SIRJFTFGHZXRRZ-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 230000000536 complexating effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical compound C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 0 CC(C)(*)OC(N(CC1)CCC1O)=O Chemical compound CC(C)(*)OC(N(CC1)CCC1O)=O 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- OOMGJVYAAJCVCH-UHFFFAOYSA-N amino(carboxy)carbamic acid Chemical compound OC(=O)N(N)C(O)=O OOMGJVYAAJCVCH-UHFFFAOYSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses the method that one kind prepares N 1,2,3,6 tetrahydropyridines of substitution, belong to technical field of organic chemistry.4 piperidine alcohols are substituted as raw material using N, alcoholic extract hydroxyl group is transformed into alkenyl with triphenylphosphine and the reaction of azoformic acid diester obtains N and substitute 1,2,3,6 tetrahydropyridines.This method raw material is easy to get, easy to operate, and product purity is high, and avoiding previous methods needs the use of hot conditions and severe poisonous chemicals, has potential route advantage.
Description
Technical field：
The present invention relates to the method that one kind prepares N- -1,2,3,6- tetrahydropyridines of substitution, belong to technical field of organic synthesis.
Background technology：
Many piperidine derivatives have antibacterial, antitumor, treatment a variety of pharmacological activity such as senile dementia and anesthesia, while
One of important drugs for the treatment of virus infection (including AIDS) and diabetes.N- substitution -1,2,3,6- tetrahydropyridines or its derivative
Thing is one of which important intermediate, is widely used in the synthesis of the pharmaceutical intermediates such as synthesis kinase inhibitor, develops suitable work
The synthetic method of industry metaplasia production is significant.
The synthetic method of the compound mainly includes following two at present：1) 1,2,3,6- tetrahydropyridines and protection group are direct
Reaction obtain N- substitution-1,2,3,6- tetrahydropyridines (Tetrahedron, 2014,70,3893-3900；J.Org.Chem.,
1991,56,3133–3137；Synth.Commun., 2015,45,2259-2265), this method is although easy to operate, only
Single step reaction, but the tetrahydropyridine source of raw material 1,2,3,6- is limited, and is not easy to obtain.
Second, N- substitutions -4- piperidines sulphonic acid ester and highly basic DUB or potassium tert-butoxide are heated to 75- in high boiling solvent
150 DEG C or so occur elimination and obtain -1,2,3,6- tetrahydropyridine (WO201371697, WO2010/16005 of N- substitutions；
Tetrahedron Lett., 2010,51,5191-5194), for this method reaction temperature close to 150 DEG C, power consumption is serious；Original used
Material N- substitution -4- piperidines sulphonic acid esters need to substitute -4- piperidine alcohols to be made with mesyl chloride or paratoluensulfonyl chloride reaction through N-, first
Sulfonic acid chloride or paratoluensulfonyl chloride have penetrating odor and severe corrosive, while mesyl chloride belongs to severe poisonous chemicals, purchase
It is unfriendly to environment by a definite limitation, constrain the amplification synthesis of such compound.
The content of the invention：
To overcome disadvantage mentioned above, it is an object of the present invention to provide a kind of N- substitute -1,2,3,6- tetrahydropyridines preparation method,
- 4- piperidine alcohols are substituted as raw material using N-, alcoholic extract hydroxyl group is transformed into alkenyl and obtained with triphenylphosphine and the reaction of azoformic acid diester
N- substitution -1,2,3,6- tetrahydropyridines.
One kind prepares the method that N- substitutes -1,2,3,6- tetrahydropyridines, is obtained after single step reaction, the technical side of use
Case is as follows：
N- substitution -4- piperidine alcohols and triphenylphosphine dissolved are added dropwise azoformic acid diester, are stirred at room temperature in organic solvent
Reaction；After completion of the reaction, cooling separates out solid, filtering, filtrate solvent distillation, after then adding alkane solvent stirring, mistake again
Solid is filtered, filtrate is spin-dried for, and vacuum distillation obtains N- and substitutes -1,2,3,6- tetrahydropyridines.
Further, the N- substitutions -4- piperidine alcohols, the upper substituents of N are selected from Boc, Cbz or benzyl；Azoformic acid two
Ester is selected from diethyl azodiformate or diisopropyl azodiformate.
Further, the organic solvent is selected from tetrahydrofuran, glycol dimethyl ether or dichloromethane.
Further, the mol ratio of the N- substitutions -4- piperidine alcohols, triphenylphosphine and azoformic acid diester is 1：1-2：
1-2.Triphenylphosphine is 1 with azoformic acid diester mol ratio：1.In post processing, chance on, triphenylphosphine and azo two
The accessory substance triphenylphosphine oxide and hydrazine dicarboxylate generated after the reaction of formic acid diester:PPh3O/ (NHCO2R) 2 can form good
Good crystalline complex, (less than -20 DEG C) crystallization precipitations at low temperature, after filtering can a clearance up to 85-93%, mistake
Filter obtained solid and confirm as both complex compounds by GC-MS.
Further, the alkane solvent is selected from normal heptane or n-hexane.
Invention beneficial effect
(1) this method raw material is easy to get, easy to operate, has saved production cost, while the time greatly shortens；
(2) reaction condition is gentle, avoids the pyroreaction of previous methods needs, saves the energy；(3) product purity is high,
Reaction has implicit costs and route advantage, environment-friendly, is more suitable for industrialized production, is advantageous to improve the market of such product
Competitiveness.
Embodiment
Embodiment 1
The synthesis of N- benzyl -1,2,3,6- tetrahydropyridines
In 500mL there-necked flasks, by N- benzyl -4- piperidine alcohols (38.3g, 0.2mol) and triphenylphosphine (78.7g,
0.3mol) it is dissolved in 400mL dichloromethane, diisopropyl azodiformate (60.7g, 0.3mol), drop is added dropwise at -5~0 DEG C
Finish, be stirred at room temperature 4 hours, after reaction terminates, be cooled to less than -20 DEG C, stirring separates out solid, filtering, filters out PPh3O/
(NHCO2i-Pr) 2 complex compound 89.7g, filtrate distilling off solvent, normal heptane is added, is stirred 1 hour at 0 DEG C, filters out solid network
Compound 4.8g, filtrate are evaporated under reduced pressure to colorless oil N- benzyls -1,2,3,6- tetrahydropyridine 28.8g (95- after concentrating out solvent
98 DEG C/5mmHg), yield 83.5%, GC：98.7%,1HNMR(400MHz,CDCl3)：δ2.15-2.22(2H,m),2.58(t,
), J=5.6,2H 2.97-3.01 (2H, m), 3.60 (2H, s), 5.65-5.71 (1H, m), 5.74-5.81 (1H, m), 7.24-
7.40(5H,m)。
Embodiment 2
The synthesis of N- benzyl -1,2,3,6- tetrahydropyridines
In 500mL there-necked flasks, by N- benzyl -4- piperidine alcohols (38.3g, 0.2mol) and triphenylphosphine (63.0g,
0.24mol) it is dissolved in 400mL tetrahydrofurans, diethyl azodiformate (41.8g, 0.24mol), drop is added dropwise at -5~0 DEG C
Finish, be stirred at room temperature 4 hours, after reaction terminates, be cooled to less than -20 DEG C, stirring separates out solid, filtering, filters out PPh3O/
(NHCO2Et) 2 complex compound 80.5g, filtrate distilling off solvent, n-hexane is added, is stirred 1 hour at 0 DEG C, filter out solid complexing
Thing 6.1g, filtrate are evaporated under reduced pressure to colorless oil N- benzyls -1,2,3,6- tetrahydropyridine 28.5g (95-98 after concentrating out solvent
DEG C/5mmHg), yield 82.3%, GC：98.8%.
Embodiment 3
The synthesis of N-Boc-1,2,3,6- tetrahydropyridines
In 500mL there-necked flasks, by N-Boc-4- piperidine alcohols (40.3g, 0.2mol) and triphenylphosphine (104.9g,
0.4mol) it is dissolved in 400mL tetrahydrofurans, diisopropyl azodiformate (80.9g, 0.4mol), drop is added dropwise at -5~0 DEG C
Finish, be stirred at room temperature 4 hours, after reaction terminates, be cooled to less than -20 DEG C, stirring separates out solid, filtering, filters out PPh3O/
(NHCO2i-Pr) 2 complex compound 80.0g, filtrate distilling off solvent, normal heptane is added, is stirred 1 hour at 0 DEG C, filters out solid network
Compound 6.9g, filtrate are evaporated under reduced pressure give light yellow oil N-Boc-1,2,3,6- tetrahydropyridine 31.2g after concentrating out solvent
(55-57 DEG C/3mmHg), yield 85.1%, GC detections：Purity 98.5%,1H-NMR(400MHz,CDCl3)：δ5.83–5.74
(m,1H),5.67–5.57(m,1H),3.84(2H),3.45(2H),2.09(m,2H),1.44(s,9H)。
Embodiment 4
The synthesis of N-Boc-1,2,3,6- tetrahydropyridines
In 500mL there-necked flasks, by N-Boc-4- piperidine alcohols (40.3g, 0.2mol) and triphenylphosphine (78.7g,
0.3mol) it is dissolved in 400mL glycol dimethyl ethers, diethyl azodiformate (52.2g, 0.3mol), drop is added dropwise at -5~0 DEG C
Finish, be stirred at room temperature 4 hours, after reaction terminates, be cooled to less than -20 DEG C, stirring separates out solid, filtering, filters out PPh3O/
(NHCO2Et) 2 complex compound 78.2g, filtrate distilling off solvent, n-hexane is added, is stirred 1 hour at 0 DEG C, filter out solid complexing
Thing 9.1g, filtrate are evaporated under reduced pressure give light yellow oil N-Boc-1,2,3,6- tetrahydropyridine 30.7g (55- after concentrating out solvent
57 DEG C/3mmHg), yield 83.8%, GC detections：Purity 98.6%.
Embodiment 5
The synthesis of N-Cbz-1,2,3,6- tetrahydropyridines
In 500mL there-necked flasks, by N-Cbz-4- piperidine alcohols (47.0g, 0.2mol) and triphenylphosphine (52.5g,
0.2mol) it is dissolved in 400mL glycol dimethyl ethers, diethyl azodiformate (34.8g, 0.2mol), drop is added dropwise at -5~0 DEG C
Finish, be stirred at room temperature 4 hours, after reaction terminates, after reaction terminates, be cooled to less than -20 DEG C, stirring separates out solid, filtering, filters out
The complex compound 77.3g of PPh3O/ (NHCO2Et) 2, filtrate distilling off solvent, n-hexane is added, is stirred 1 hour at 0 DEG C, filtered out solid
Body complex compound 9.8g, filtrate are evaporated under reduced pressure give light yellow oil N-Cbz-1,2,3,6- tetrahydropyridines after concentrating out solvent
35.7g (63-66 DEG C/3mmHg), yield 82.2%, GC：98.8%,1H-NMR(400MHz,CDCl3)：δ7.43–7.27(m,
5H),5.82(m,1H),5.74–5.54(m,1H),5.16(2H),3.96(m,2H),3.57(m,2H),2.14(m,2H)。
Embodiment 6
The synthesis of N-Cbz-1,2,3,6- tetrahydropyridines
In 500mL there-necked flasks, by N-Cbz-4- piperidine alcohols (47.0g, 0.2mol) and triphenylphosphine (104.9g,
0.4mol) it is dissolved in 400mL dichloromethane, diisopropyl azodiformate (80.9g, 0.4mol), drop is added dropwise at -5~0 DEG C
Finish, be stirred at room temperature 4 hours, after reaction terminates, after reaction terminates, be cooled to less than -20 DEG C, stirring separates out solid, filtering, filters out
The complex compound 88.7g of PPh3O/ (NHCO2i-Pr) 2, filtrate distilling off solvent, normal heptane is added, stirs 1 hour, filters out at 0 DEG C
Solid complex 4.9g, filtrate are evaporated under reduced pressure give light yellow oil N-Cbz-1,2,3,6- tetrahydropyridines after concentrating out solvent
37.2g (63-66 DEG C/3mmHg), yield 85.6%, GC：98.5%.
Embodiment 7
The synthesis of N-Cbz-1,2,3,6- tetrahydropyridines
In 5L reactors, N-Cbz-4- piperidine alcohols (472g, 2mol) and triphenylphosphine (1049g, 4mol) are dissolved in 4L
In dichloromethane, diisopropyl azodiformate (809g, 4mol) is added dropwise at -5~0 DEG C, drop finishes, is stirred at room temperature 4 hours, reacts
After end, after reaction terminates, less than -20 DEG C are cooled to, stirring separates out solid, filtering, filters out the networks of PPh3O/ (NHCO2i-Pr) 2
Compound 895g, filtrate distilling off solvent, normal heptane is added, is stirred 1 hour at 0 DEG C, filters out solid complex 52g, filtrate is dense
Contract and give light yellow oil N-Cbz-1,2,3,6- tetrahydropyridine 370g (63-66 DEG C/3mmHg) are evaporated under reduced pressure after solvent, receive
Rate 85.3%, GC：98.6%.
The general principle and principal character and advantages of the present invention of the present invention has been shown and described above.The technology of the industry
Personnel are it should be appreciated that the present invention is not limited to the above embodiments, and the simply explanation described in above-described embodiment and specification is originally
The principle of invention, without departing from the spirit and scope of the present invention, various changes and modifications of the present invention are possible, these changes
Change and improvement all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and its
Equivalent thereof.
Claims (5)
1. one kind prepares the method that N- substitutes -1,2,3,6- tetrahydropyridines, it is characterised in that comprises the following steps：N- substitutions -4-
Piperidine alcohols and triphenylphosphine dissolved are added dropwise azoformic acid diester, reaction are stirred at room temperature in organic solvent；After completion of the reaction,
Cooling separates out solid, filtering, filtrate solvent distillation, after then adding alkane solvent stirring, filters out solid, filtrate rotation again
Dry, vacuum distillation obtains N- and substitutes -1,2,3,6- tetrahydropyridines.
2. one kind according to claim 1 prepares the method that N- substitutes -1,2,3,6- tetrahydropyridines, it is characterised in that：Institute
State in N- substitution -4- piperidine alcohols, the upper substituents of N are selected from Boc, Cbz or benzyl；Azoformic acid diester is selected from azoformic acid two
Ethyl ester or diisopropyl azodiformate.
3. one kind according to claim 1 prepares the method that N- substitutes -1,2,3,6- tetrahydropyridines, it is characterised in that：Institute
State organic solvent and be selected from tetrahydrofuran, glycol dimethyl ether or dichloromethane.
4. one kind according to claim 1 prepares the method that N- substitutes -1,2,3,6- tetrahydropyridines, it is characterised in that：Institute
The mol ratio for stating N- substitution -4- piperidine alcohols, triphenylphosphine and azoformic acid diester is 1：1-2：1-2；Triphenylphosphine and azo
Dicarboxylate mol ratio is 1：1.
5. one kind according to claim 1 prepares the method that N- substitutes -1,2,3,6- tetrahydropyridines, it is characterised in that：Institute
State alkane solvent and be selected from normal heptane or n-hexane.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101696187A (en) * | 2009-09-30 | 2010-04-21 | 徐州工业职业技术学院 | Synthesizing method of N-substituent-1,2,3,6-tetrahydropyridine |
| US20110144084A1 (en) * | 2008-08-06 | 2011-06-16 | Pfizer Inc | 6 substituted 2- heterocyclylamino pyrazine compounds as chk-1 inhibitors |
| CN104903308A (en) * | 2013-01-10 | 2015-09-09 | 默克专利股份有限公司 | Piperidinylcarbazole as antimalarial |
| US20160108048A1 (en) * | 2013-06-07 | 2016-04-21 | Merck Sharp & Dohme Corp. | Imidazole derivatives and methods of use thereof for improving the pharmacokinetics of a drug |
-
2017
- 2017-11-15 CN CN201711133334.6A patent/CN107827811B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110144084A1 (en) * | 2008-08-06 | 2011-06-16 | Pfizer Inc | 6 substituted 2- heterocyclylamino pyrazine compounds as chk-1 inhibitors |
| CN101696187A (en) * | 2009-09-30 | 2010-04-21 | 徐州工业职业技术学院 | Synthesizing method of N-substituent-1,2,3,6-tetrahydropyridine |
| CN104903308A (en) * | 2013-01-10 | 2015-09-09 | 默克专利股份有限公司 | Piperidinylcarbazole as antimalarial |
| US20160108048A1 (en) * | 2013-06-07 | 2016-04-21 | Merck Sharp & Dohme Corp. | Imidazole derivatives and methods of use thereof for improving the pharmacokinetics of a drug |
Non-Patent Citations (2)
| Title |
|---|
| STEPHEN D. ROUGHLEY等: "Fatty acid amide hydrolase inhibitors. 2. Novel synthesis of sterically hinderedazabenzhydryl ethers and an improved synthesis of VER-156084", 《TETRAHEDRON LETTERS》 * |
| 仉文陞,等: "三苯基膦-偶氮二甲酸二乙酯用于糖的环氧环合成研究", 《北京大学学报(医学版)》 * |
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