CN106478487B - Pyrrolidines and its synthetic method - Google Patents
Pyrrolidines and its synthetic method Download PDFInfo
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- CN106478487B CN106478487B CN201610831473.5A CN201610831473A CN106478487B CN 106478487 B CN106478487 B CN 106478487B CN 201610831473 A CN201610831473 A CN 201610831473A CN 106478487 B CN106478487 B CN 106478487B
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- benzyl
- pyrrolidines
- cyclic imide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/62—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/72—4,7-Endo-alkylene-iso-indoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Indole Compounds (AREA)
Abstract
A kind of pyrrolidines and its synthetic method, the cyclic imide class compound being dissolved in organic solvent is mixed with the silicon hydrogen reagent as reducing agent and the lewis acid as catalyst, aromatic rings and cycloaliphatic ring pyrrolidines are prepared under conditions of reflux.Synthetic route of the present invention is succinct, and efficiently and economical, mild condition, applicability is wide, will play great impetus to the later period industrialized production of pyrrolidines.
Description
Technical field
The present invention relates to a kind of technology of chemical field, specifically a kind of Louis acid catalysis cyclic imide class
The silicon hydrogenation for closing object prepares the synthetic method of pyrrolidines.
Background technique
Pyrrolidines are one of heterocyclic compound important kinds, are prevalent in some natural products, medicine
Object intermediate, drug molecule, in functional material, thus the synthesis of pyrrolidines have in terms of organic synthesis it is important
Meaning.
It is most straightforward approach by restoring imide analog compounds come synthesis of pyrrolidine class compound, prepares pyrroles at present
The classical restoring method of alkyl compound is to use the compounds such as Lithium Aluminium Hydride, borine as reducing agent to realize.Due to acyl
There are multiple intermediates for the reduction of imine compound, and the formation of by-product, and this kind of reduction are caused using this kind of reducing agent
The functional group compatibility of reagent is poor.Simultaneously because the activity of reducing agent is higher, the disadvantages of to water sensitive, need the reaction usually
It is strict controlled in the environment of anhydrous and low temperature and carries out, and the post-processing step reacted is comparatively laborious.
Summary of the invention
The present invention In view of the above shortcomings of the prior art, proposes a kind of pyrrolidines and its synthetic method,
It is reducing agent, boron-containing compound as catalyst using the silicon hydrogen species compound of cheap and simple from imide analog compounds
Catalyzed hydrosilation restores cyclic imide class compound and realizes that synthetic route is succinct, mild condition, is suitable for large scale quantities
It produces.
The present invention is achieved by the following technical solutions:
The present invention relates to a kind of pyrrolidines, structural formulas are as follows:Or
Wherein:
R1For benzyl containing different substituents, alkane, alkene, alkynyl, aryl or contain all kinds of functional groups (cyano, halogen, carbonyl
Base, alkoxy, amino, hydroxyl) alkyl chain；
R2For halogen, alkoxy, carbonyl, naphthalene nucleus, amino or protection amino；
R3For benzyl containing different substituents, alkane, alkene, alkynyl, aryl or contain all kinds of functional groups (cyano, halogen, carbonyl
Base, alkoxy, amino, hydroxyl) alkyl chain；
R4For hydrogen, cycloalkane, norbornane, norbornene or hexahydropyridine.
The present invention relates to the synthetic method of above-mentioned pyrrolidines, the cyclic imide that will be dissolved in organic solvent
Class compound is mixed with the silicon hydrogen reagent as reducing agent and the lewis acid as catalyst, is prepared under conditions of reflux
It is as follows to aromatic rings and cycloaliphatic ring pyrrolidines, reaction equation:
The lewis acid is further preferred are as follows: three-(pentafluorophenyl group) boron, phenyl boric acid, substituted phenyl boric acid or trifluoro
Change borate ether etc..
The reducing agent is more preferably three silicon hydrogen of aryl, three silicon hydrogen of alkyl, diaryl silicon hydrogen, dialkyl group silicon hydrogen,
1,1,3,3- tetramethyl disiloxane, PMHS (containing hydrogen silicone oil) or triaryl silicon hydrogen etc..
The organic solvent is toluene, 1,4- dioxane, 1,2- dichloroethanes or chloroform.
The reaction molar ratio of the amount of hydrogen is 1/6-1/4, catalysis in the cyclic imide class compound and silicon hydrogen reagent
The dosage of agent is the 0.1-2.0mol% of cyclic imide.
The reflux refers to that water is added after the reaction was completed and quenches remaining silicon hydrogen examination for the back flow reaction under 110 DEG C of environment
Agent is concentrated after extracting organic layer, and direct column chromatographs to obtain target product.
The present invention relates to the applications for the pyrrolidines that the above method is prepared, will be in pyrrolidines
Manufacture of at least one compound for the important segment of Moxifloxacin, Mitiglinide Calcium and procyclidine etc..
Technical effect
Compared with prior art, the present invention with " highly selective " for background, using mild cheap reducing agent silicon hydrogen reagent,
In the presence of a lewis acid catalyst, preferably using common toluene as solvent, various substituted pyrroles are prepared in the case where reflux
Cough up alkyl compound.Compared to existing preparation process, reducing agent used in the present invention is easy to operate, and highly selective, substrate is suitable
Wide, the high income with property.
Specific embodiment
Embodiment 1
The present embodiment is related to N- benzyl isoindolineSynthesis, the specific steps of which are as follows:
It is added in reaction tube N- benzylphthalimide (237.3mg, 1.0mmol), B (C6F5)3(10.2mg,
2.0mol%), silicon hydrogen reagent TMDS (335.8mg, 2.5mmol) slowly is added in system after toluene (2mL) stirring and dissolving, it will
Reaction temperature rises to 110 DEG C of reflux.It has reacted and the remaining silicon hydrogen reagent of water quenching is added, be concentrated after extracting organic layer, direct column
Chromatography obtains target product, yield: 95%.1H NMR(400MHz,CDCl3)δ7.44–7.42(m,2H),7.38–7.34(m,
2H),7.31–7.26(m,1H),7.18(s,4H),3.94(s,4H),3.92(s,2H).13C NMR(100MHz,CDCl3)δ
140.3,139.2,128.89,128.5,127.2,126.7,122.4,60.4,59.0.
Embodiment 2
The present embodiment is related to N- ((4- trifluoromethyl) benzyl) isoindolineSynthesis, tool
Steps are as follows for body:
According to operation same as Example 1, target compound is obtained, yield: 90%.1H NMR(400MHz,CDCl3)δ
7.62–7.60(m,2H),7.55–7.53(m,2H),7.20(s,4H),3.97(s,2H),3.94(s,4H).13C NMR
(100MHz,CDCl3) δ 143.5,140.1,129.5 (q, J=32.1Hz), 129.0,126.9,125.5 (q, J=3.7Hz),
124.4 (q, J=270.1Hz), 122.5,59.9,59.1.
Embodiment 3
The present embodiment is related to 2,6- dibenzyl -1,2,3,5,6,7- hexahydrobenzene parallel connection pyrroles
Synthesis, the specific steps of which are as follows:
According to operation same as Example 1, target compound is obtained, yield: 90%.1H NMR(400MHz,CDCl3)δ
7.41–7.39(m,4H),7.36–7.32(m,4H),7.29–7.27(m,2H),6.97(s,2H),3.89(s,4H),3.87(s,
8H).13C NMR(100MHz,CDCl3)δ139.2,139.0,128.9,128.5,127.2,116.5,60.5,58.9.
Embodiment 4
The present embodiment is related to N- benzyl -2,3- dihydro-benzisoindolineSynthesis, tool
Steps are as follows for body:
According to operation same as Example 1, target compound is obtained, yield: 89%.1H NMR(400MHz,CDCl3)δ
7.81–7.79(m,2H),7.63(s,2H),7.49–7.39(m,6H),7.35–7.32(m,1H),4.06(s,4H),3.97(s,
2H).13C NMR(100MHz,CDCl3)δ139.4,139.1,133.1,129.0,128.5,127.8,127.3,125.4,
120.6,60.6,58.7.
Embodiment 5
The present embodiment is related to N- benzyl -4,7- endo-methylene group-hexahydroisoindolineSynthesis, tool
Steps are as follows for body:
According to operation same as Example 1, target compound is obtained, yield: 94%.1H NMR(400MHz,CDCl3)δ
7.36-7.28 (m, 4H), 7.24-7.21 (m, 1H), 3.52 (s, 2H), 2.76 (d, J=10.0Hz, 2H), 2.35-2.34 (m,
2H),2.11(s,2H),2.02–1.98(m,2H),1.77–1.75(m,2H),1.41–1.33(m,2H),1.26–1.24(m,
2H).13C NMR(100MHz,CDCl3)δ140.5,128.5,128.2,126.7,60.7,55.4,44.1,42.3,41.4,
24.1.
Embodiment 6
The present embodiment is related to N- benzyl hexahydroisoindolineSynthesis, the specific steps of which are as follows:
According to operation same as Example 1, target compound is obtained, yield: 90%.1H NMR(400MHz,CDCl3)δ
7.38–7.32(m,4H),7.29–7.24(m,1H),3.76(s,2H),2.83–2.79(m,2H),2.57–2.53(m,2H),
2.21–2.15(m,2H),1.60–1.46(m,6H),1.38–1.30(m,2H).13C NMR(100MHz,CDCl3)δ139.9,
128.8,128.3,126.9,61.4,58.4,37.3,27.0,23.0.
Embodiment 7
The present embodiment is related to N- benzyl-pyrrole alkaneSynthesis, the specific steps of which are as follows:
According to operation same as Example 1, target compound is obtained, yield: 82%.1H NMR(400MHz,CDCl3)δ
7.35–7.23(m,5H),3.65(s,2H),2.55–2.53(m,4H),1.82–1.78(m,4H).13C NMR(100MHz,
CDCl3)δ139.2,129.0,128.3,127.0,60.8,54.2,23.5.
Embodiment 8
The present embodiment is related to 6- benzyl octahydro pyrrolo- [3,4-B] pyridineSynthesis, it is specific
Steps are as follows:
According to operation same as Example 1, target compound is obtained, yield: 85%.1H NMR(400MHz,CDCl3)δ
7.34–7.29(m,4H),7.27–7.22(m,1H),3.82–3.69(m,2H),3.28–3.26(m,1H),3.04–3.00(m,
1H),2.87–2.84(m,1H),2.80–2.75(m,1H),2.71–2.55(m,3H),2.29–2.21(m,1H),1.69–1.64
(m,2H),1.52–1.43(m,2H).13C NMR(100MHz,CDCl3)δ139.0,128.7,128.2,126.9,60.5,
59.8,56.1,55.0,43.8,36.2,23.9,21.4.
Above-mentioned specific implementation can by those skilled in the art under the premise of without departing substantially from the principle of the invention and objective with difference
Mode carry out local directed complete set to it, protection scope of the present invention is subject to claims and not by above-mentioned specific implementation institute
Limit, each implementation within its scope is by the constraint of the present invention.
Claims (1)
1. a kind of synthetic method of pyrrolidines, which is characterized in that the structural formula of the pyrrolidines includes:
N- benzyl isoindoline
N- ((4- trifluoromethyl) benzyl) isoindoline
2,6- dibenzyl -1,2,3,5,6,7- hexahydrobenzene parallel connection pyrroles
N- benzyl -2,3- dihydro-benzisoindoline
N- benzyl -4,7- endo-methylene group-hexahydroisoindoline
N- benzyl hexahydroisoindoline
N- benzyl-pyrrole alkaneOr
6- benzyl octahydro pyrrolo- [3,4-B] pyridine
The synthetic method, by the cyclic imide class compound being dissolved in toluene and 1,1,3,3- tetra- as reducing agent
Tetramethyldisiloxane and B (C as catalyst6F5)3Mixing, is prepared aromatic rings and cycloaliphatic ring under conditions of reflux
Pyrrolidines, reaction equation are as follows:
The reaction molar ratio of the amount of hydrogen is 1/ in the cyclic imide class compound and 1,1,3,3- tetramethyl disiloxane
6-1/4；
B (the C6F5)3Dosage be cyclic imide 0.1-2.0mol%；
The reflux refers to that water quenching remaining 1,1,3,3- tetra- is added in the back flow reaction under 110 DEG C of environment after the reaction was completed
Tetramethyldisiloxane is concentrated after extracting organic layer, and direct column chromatographs to obtain target product.
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Citations (2)
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|---|---|---|---|---|
| CN103497138A (en) * | 2013-10-18 | 2014-01-08 | 河南中医学院 | Method of preparing cis-octahydroisoindole by zinc chloride and potassium borohydride |
| CN103772320A (en) * | 2013-12-24 | 2014-05-07 | 浙江海翔药业股份有限公司 | Method for synthesizing tertiary amine by using alpha-amino acid as raw material |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103497138A (en) * | 2013-10-18 | 2014-01-08 | 河南中医学院 | Method of preparing cis-octahydroisoindole by zinc chloride and potassium borohydride |
| CN103772320A (en) * | 2013-12-24 | 2014-05-07 | 浙江海翔药业股份有限公司 | Method for synthesizing tertiary amine by using alpha-amino acid as raw material |
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| Selective Catalytic Monoreduction of Phthalimides and Imidazolidine-2,4-diones;Shoubhik Das,et al.;《Angew. Chem. Int. Ed.》;20110824;第50卷;9180-9184 |
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