CN107827811B - Method for preparing N-substituted-1, 2,3, 6-tetrahydropyridine - Google Patents
Method for preparing N-substituted-1, 2,3, 6-tetrahydropyridine Download PDFInfo
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- CN107827811B CN107827811B CN201711133334.6A CN201711133334A CN107827811B CN 107827811 B CN107827811 B CN 107827811B CN 201711133334 A CN201711133334 A CN 201711133334A CN 107827811 B CN107827811 B CN 107827811B
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- -1 N-substituted-1, 2,3, 6-tetrahydropyridine Chemical class 0.000 title claims abstract description 37
- 238000000034 method Methods 0.000 title claims abstract description 14
- 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
- 238000003756 stirring Methods 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 239000002904 solvent Substances 0.000 claims description 20
- 239000007787 solid Substances 0.000 claims description 19
- 239000000706 filtrate Substances 0.000 claims description 18
- 238000001914 filtration Methods 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical group CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 8
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 6
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 claims description 6
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical group CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 claims description 5
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 5
- 230000001476 alcoholic effect Effects 0.000 abstract description 2
- 125000003342 alkenyl group Chemical group 0.000 abstract description 2
- 231100000481 chemical toxicant Toxicity 0.000 abstract description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 2
- 239000003440 toxic substance Substances 0.000 abstract description 2
- 238000007796 conventional method Methods 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 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 compound C1CC=CCN1C(=O)OCC1=CC=CC=C1 YWKYQRWNOXUYJK-UHFFFAOYSA-N 0.000 description 6
- SIRJFTFGHZXRRZ-UHFFFAOYSA-N 1-benzyl-3,6-dihydro-2h-pyridine Chemical compound C=1C=CC=CC=1CN1CCC=CC1 SIRJFTFGHZXRRZ-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- SHHHRQFHCPINIB-UHFFFAOYSA-N tert-butyl 3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC=CC1 SHHHRQFHCPINIB-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
- JKIUUDJOCYHIGY-UHFFFAOYSA-N benzyl 4-hydroxypiperidine-1-carboxylate Chemical compound C1CC(O)CCN1C(=O)OCC1=CC=CC=C1 JKIUUDJOCYHIGY-UHFFFAOYSA-N 0.000 description 3
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- BPPZXJZYCOETDA-UHFFFAOYSA-N 1-benzylpiperidin-4-ol Chemical compound C1CC(O)CCN1CC1=CC=CC=C1 BPPZXJZYCOETDA-UHFFFAOYSA-N 0.000 description 2
- FTAHXMZRJCZXDL-UHFFFAOYSA-N 3-piperideine Chemical compound C1CC=CCN1 FTAHXMZRJCZXDL-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- PWQLFIKTGRINFF-UHFFFAOYSA-N tert-butyl 4-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(O)CC1 PWQLFIKTGRINFF-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 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
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000007547 defect 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
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification 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
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 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
Abstract
The invention discloses a method for preparing N-substituted-1, 2,3, 6-tetrahydropyridine, belonging to the technical field of organic chemistry. Taking N-substituted-4-piperidinol as a raw material, reacting with triphenylphosphine and azodicarboxylic diester to convert alcoholic hydroxyl into alkenyl to obtain N-substituted-1, 2,3, 6-tetrahydropyridine. The method has the advantages of easily available raw materials, simple operation and high product purity, avoids the need of high temperature conditions and the use of highly toxic chemicals in the conventional method, and has potential route advantages.
Description
The technical field is as follows:
the invention relates to a method for preparing N-substituted-1, 2,3, 6-tetrahydropyridine, belonging to the technical field of organic synthesis.
Background art:
many piperidine derivatives have a variety of pharmacological activities such as antibacterial activity, antitumor activity, treatment of senile dementia and anesthesia, and also are one of the important drugs for treating viral infections (including AIDS) and diabetes. The N-substituted-1, 2,3, 6-tetrahydropyridine or the derivative thereof is an important intermediate, is widely used for synthesizing pharmaceutical intermediates such as kinase inhibitors and the like, and has important significance in developing a synthetic method suitable for industrial production.
The current synthesis method of the compound mainly comprises the following two methods: 1) the 1,2,3, 6-tetrahydropyridine directly reacts with a protecting group to obtain N-substituted-1, 2,3, 6-tetrahydropyridine (Tetrahedron,2014,70, 3893-3900; chem, 1991,56, 3133-; commun, 2015,45, 2259-2265), which is simple and convenient to operate and only has one-step reaction, the source of the raw material 1,2,3, 6-tetrahydropyridine is limited and is not easily available.
Secondly, heating N-substituted-4-piperidine sulfonate and strong base DUB or potassium tert-butoxide in a high boiling point solvent to about 75-150 ℃ for elimination to obtain N-substituted-1, 2,3, 6-tetrahydropyridine (WO201371697, WO 2010/16005; Tetrahedron Lett.,2010,51,5191-5194), wherein the reaction temperature is close to 150 ℃, and the energy consumption is serious; the N-substituted-4-piperidine sulfonic acid ester is prepared by reacting N-substituted-4-piperidinol with methanesulfonyl chloride or p-toluenesulfonyl chloride, the methanesulfonyl chloride or the p-toluenesulfonyl chloride has pungent odor and strong corrosivity, and meanwhile, the methanesulfonyl chloride belongs to a highly toxic chemical, is limited in purchase and is not environment-friendly, and the amplified synthesis of the compound is restricted.
The invention content is as follows:
in order to overcome the defects, the invention aims to provide a preparation method of N-substituted-1, 2,3, 6-tetrahydropyridine, which takes N-substituted-4-piperidinol as a raw material to react with triphenylphosphine and azodicarboxylic diester to convert alcoholic hydroxyl into alkenyl to obtain the N-substituted-1, 2,3, 6-tetrahydropyridine.
A method for preparing N-substituted-1, 2,3, 6-tetrahydropyridine is obtained by one-step reaction, and adopts the following technical scheme:
dissolving N-substituted-4-piperidinol and triphenylphosphine in an organic solvent, dropwise adding azodicarboxylic acid diester, and stirring at room temperature for reaction; and after the reaction is finished, cooling to separate out a solid, filtering, distilling the solvent from the filtrate, adding an alkane solvent, stirring, filtering out the solid again, spin-drying the filtrate, and carrying out reduced pressure distillation to obtain the N-substituted-1, 2,3, 6-tetrahydropyridine.
Further, the N-substituted-4-piperidinol has N substituent selected from Boc, Cbz or benzyl; the azodicarboxylic acid diester is selected from azodicarboxylic acid diethyl ester or azodicarboxylic acid diisopropyl ester.
Further, the organic solvent is selected from tetrahydrofuran, ethylene glycol dimethyl ether or dichloromethane.
Further, the molar ratio of the N-substituted-4-piperidinol, triphenylphosphine and azodicarboxylic acid diester is in the range of 1: 1-2: 1-2. The molar ratio of triphenylphosphine to azodicarboxylic acid diester is 1: 1. during the post-treatment, PPh3O/(NHCO2R)2 which is a byproduct generated after the reaction of triphenylphosphine and azodicarboxylic acid diester can form a good crystal complex, the crystal is precipitated at low temperature (below minus 20 ℃), the once removal rate can reach 85-93% after the filtration, and the solid obtained by the filtration is confirmed to be a complex of the triphenylphosphine oxide and the hydrazinedicarboxylic acid diester by GC-MS.
Further, the alkane solvent is selected from n-heptane or n-hexane.
Advantageous effects of the invention
(1) The method has the advantages of easily available raw materials, simple operation, saved production cost, and greatly shortened time;
(2) the reaction condition is mild, the high-temperature reaction required by the prior method is avoided, and the energy is saved; (3) the product has high purity, the reaction has potential cost and route advantages, the environment is friendly, the method is more suitable for industrial production, and the market competitiveness of the products can be improved.
Detailed Description
Example 1
Synthesis of N-benzyl-1, 2,3, 6-tetrahydropyridine
Dissolving N-benzyl-4-piperidinol (38.3g, 0.2mol) and triphenylphosphine (78.7g, 0.3mol) in 400mL of dichloromethane in a 500mL three-necked flask, adding diisopropyl azodicarboxylate (60.7g, 0.3mol) dropwise at-5-0 deg.C, stirring at room temperature for 4 hr, and reactingAfter the reaction is finished, the temperature is reduced to below minus 20 ℃, solid is separated out by stirring, the mixture is filtered, 89.7g of PPh3O/(NHCO2i-Pr)2 complex is filtered, the solvent is distilled out of the filtrate, N-heptane is added, the mixture is stirred for 1 hour at 0 ℃, 4.8g of solid complex is filtered out, the filtrate is concentrated out of the solvent, and then the mixture is distilled under reduced pressure to obtain 28.8g (95-98 ℃/5mmHg) of colorless oily matter N-benzyl-1, 2,3, 6-tetrahydropyridine, the yield is 83.5 percent, GC: the mass ratio of the mixture to the mixed solution is 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)。
example 2
Synthesis of N-benzyl-1, 2,3, 6-tetrahydropyridine
Dissolving N-benzyl-4-piperidinol (38.3g, 0.2mol) and triphenylphosphine (63.0g, 0.24mol) in 400mL tetrahydrofuran, dropwise adding diethyl azodicarboxylate (41.8g, 0.24mol) at-5-0 ℃, stirring at room temperature for 4 hours after dropwise adding, cooling to-20 ℃ after reaction, stirring to separate out a solid, filtering to remove 80.5g of PPh3O/(NHCO2Et)2 complex, distilling the solvent from the filtrate, adding N-hexane, stirring at 0 ℃ for 1 hour, filtering to remove 6.1g of the solid complex, concentrating the solvent from the filtrate, and distilling under reduced pressure to obtain colorless oily matter N-benzyl-1, 2,3, 6-tetrahydropyridine (28.5 g, 95-98 ℃/5mmHg), wherein the yield is 82.3%, and GC: 98.8 percent.
Example 3
Synthesis of N-Boc-1,2,3, 6-tetrahydropyridine
Dissolving N-Boc-4-piperidinol (40.3g, 0.2mol) and triphenylphosphine (104.9g, 0.4mol) in 400mL tetrahydrofuran in a 500mL three-necked flask, dropwise adding diisopropyl azodicarboxylate (80.9g, 0.4mol) at-5-0 ℃, stirring at room temperature for 4 hours after dropwise adding, cooling to below-20 ℃ after the reaction is finished, stirring to separate out a solid, filtering, and filtering to remove PPh3O/(NHCO2i-Pr)2 complex 80.0g, distilling the solvent from the filtrate, adding N-heptane, stirring at 0 deg.C for 1 hour, filtering out solid complex 6.9g, concentrating the filtrate to remove the solvent, and distilling under reduced pressure to obtain light yellow oily substance N-Boc-1,2,3, 6-tetrahydropyridine 31.2g (55-57 deg.C/3 mmHg), yield 85.1%, GC detection: the purity of the product is 98.5 percent,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)。
example 4
Synthesis of N-Boc-1,2,3, 6-tetrahydropyridine
Dissolving N-Boc-4-piperidinol (40.3g, 0.2mol) and triphenylphosphine (78.7g, 0.3mol) in 400mL of ethylene glycol dimethyl ether in a 500mL three-necked bottle, dropwise adding diethyl azodicarboxylate (52.2g, 0.3mol) at-5-0 ℃, stirring at room temperature for 4 hours after dropwise adding, cooling to-20 ℃ after reaction is finished, stirring to separate out a solid, filtering to remove a PPh3O/(NHCO2Et)2 complex 78.2g, distilling the solvent from the filtrate, adding N-hexane, stirring at 0 ℃ for 1 hour, filtering to remove a solid complex 9.1g, concentrating the filtrate to obtain a solvent, and distilling under reduced pressure to obtain a pale yellow oily substance N-Boc-1,2,3, 6-tetrahydropyridine 30.7g (55-57 ℃/3mmHg), wherein the yield is 83.8%, and performing GC detection: the purity is 98.6%.
Example 5
Synthesis of N-Cbz-1,2,3, 6-tetrahydropyridine
Dissolving N-Cbz-4-piperidinol (47.0g, 0.2mol) and triphenylphosphine (52.5g, 0.2mol) in 400mL ethylene glycol dimethyl ether in a 500mL three-neck flask, dropwise adding diethyl azodicarboxylate (34.8g, 0.2mol) at-5-0 ℃, stirring at room temperature for 4 hours after dropwise adding, cooling to below-20 ℃ after the reaction is finished, stirring to separate out a solid, filtering to remove 77.3g of PPh3O/(NHCO2Et)2 complex, distilling the solvent from the filtrate, adding N-hexane, and stirring at 0 ℃ for 1 hourThen, 9.8g of a solid complex was filtered off, and the filtrate was concentrated to give a pale yellow oily substance, N-Cbz-1,2,3, 6-tetrahydropyridine (35.7 g, 63-66 ℃ C./3 mmHg), in a yield of 82.2%, GC: the content of the active carbon is 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)。
example 6
Synthesis of N-Cbz-1,2,3, 6-tetrahydropyridine
Dissolving N-Cbz-4-piperidinol (47.0g, 0.2mol) and triphenylphosphine (104.9g, 0.4mol) in 400mL dichloromethane in a 500mL three-necked flask, dropwise adding diisopropyl azodicarboxylate (80.9g, 0.4mol) at-5-0 ℃, stirring for 4 hours at room temperature after dropwise adding, after the reaction is finished, cooling to-20 ℃ below after the reaction is finished, stirring to separate out a solid, filtering to remove 88.7g of PPh3O/(NHCO2i-Pr)2 complex, distilling the filtrate to remove the solvent, adding N-heptane, stirring for 1 hour at 0 ℃, filtering to remove 4.9g of the solid complex, concentrating the filtrate to remove the solvent, and distilling under reduced pressure to obtain a pale yellow oily substance N-Cbz-1,2,3, 6-tetrahydropyridine (37.2 g (63-66 ℃/3), wherein the yield is 85.6%, and GC: 98.5 percent.
Example 7
Synthesis of N-Cbz-1,2,3, 6-tetrahydropyridine
Dissolving N-Cbz-4-piperidinol (472g, 2mol) and triphenylphosphine (1049g, 4mol) in 4L dichloromethane in a 5L reaction kettle, dropwise adding diisopropyl azodicarboxylate (809g, 4mol) at-5-0 ℃, stirring at room temperature for 4 hours after dropwise adding, after the reaction is finished, cooling to below-20 ℃ after the reaction is finished, stirring to separate out a solid, filtering to remove PPh3O/(NHCO2i-Pr)2 complex 895g, distilling the solvent from the filtrate, adding N-heptane, stirring at 0 ℃ for 1 hour, filtering to remove solid complex 52g, concentrating the solvent from the filtrate, and distilling under reduced pressure to obtain pale yellow oily matter N-Cbz-1,2,3, 6-tetrahydropyridine 370g (63-66 ℃/3mmHg), wherein the yield is 85.3%, and GC: 98.6 percent.
The foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (5)
1. A process for preparing N-substituted-1, 2,3, 6-tetrahydropyridines, comprising the steps of: dissolving N-substituted-4-piperidinol and triphenylphosphine in an organic solvent, dropwise adding azodicarboxylic acid diester, and stirring at room temperature for reaction; after the reaction is finished, cooling to separate out a solid, filtering, distilling the solvent from the filtrate, adding an alkane solvent, stirring, filtering out the solid again, spin-drying the filtrate, and carrying out reduced pressure distillation to obtain the N-substituted-1, 2,3, 6-tetrahydropyridine; wherein the molar ratio of the triphenylphosphine to the azodicarboxylic acid diester is 1: 1; in the N-substituted-4-piperidinol, a substituent on N is selected from Boc, Cbz or benzyl.
2. The process according to claim 1, wherein the reaction is carried out in the presence of a compound selected from the group consisting of: the azodicarboxylic acid diester is selected from azodicarboxylic acid diethyl ester or azodicarboxylic acid diisopropyl ester.
3. The process according to claim 1, wherein the reaction is carried out in the presence of a compound selected from the group consisting of: the organic solvent is selected from tetrahydrofuran, glycol dimethyl ether or dichloromethane.
4. The process according to claim 1, wherein the reaction is carried out in the presence of a compound selected from the group consisting of: the molar ratio of the N-substituted-4-piperidinol to the triphenylphosphine to the azodicarboxylic acid diester is 1: 1-2: 1-2.
5. The process according to claim 1, wherein the reaction is carried out in the presence of a compound selected from the group consisting of: the alkane solvent is selected from n-heptane or n-hexane.
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