CN107915668A - A kind of preparation method of 5,5 dimethyl, 3 methylene pyrrolidine, 2 ketone - Google Patents
A kind of preparation method of 5,5 dimethyl, 3 methylene pyrrolidine, 2 ketone Download PDFInfo
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- CN107915668A CN107915668A CN201711037837.3A CN201711037837A CN107915668A CN 107915668 A CN107915668 A CN 107915668A CN 201711037837 A CN201711037837 A CN 201711037837A CN 107915668 A CN107915668 A CN 107915668A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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
- C07D207/36—Oxygen or sulfur atoms
- C07D207/38—2-Pyrrolones
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Abstract
The invention discloses a kind of preparation method of 3 methylene pyrrolidine of 5,5 dimethyl, 2 ketone, comprise the following steps：S1, under the effect of strong organic base, condensation reaction occurs for formaldehyde and chemical compounds I, obtains compound ii；Halogenating reaction occurs for S2, compound ii and halide reagent, obtains compound III；S3, under the effect of strong organic base, substitution reaction occurs for compound III and 2 nitropropanes, obtains the compounds Ⅳ containing nitro；S4, compounds Ⅳ carry out reduction nitro and the Domino reaction of cyclization, obtain 5,5 dimethyl, 3 methylene pyrrolidine, 2 ketone under the action of catalyst and reducing agent；Synthesis step is few, simple and practicable, without harshness reaction condition, process route is novel, yield is more than 50%, and reaction heat and gas produce to obtain good control, has the characteristics that process route is novel, reaction condition is relatively mild, is easy to amplification, can be mass produced.
Description
Technical field
The present invention relates to organic chemical synthesis field, more particularly, to one kind 5,5- dimethyl -3- methylene pyrroles
The preparation method of alkane -2- ketone.
Background technology
5,5- dimethyl -3- methylene pyrrolidine -2- ketone is a kind of important medicine intermediate.Go out from this intermediate
Hair, can synthesize the spirane structure of a variety of novel fragments containing pyrrolones, the synthesis for a variety of drug candidates.
The synthetic route of this compound of 5,5- dimethyl -3- methylene pyrrolidines -2- ketone there is no report at present.According to it
The synthetic route of analog, can design process route one, but the route steps are long, and cost is higher, it is difficult to meets new drug
The demand of research and development：；
Other equally have the problem of being difficult to production amplification similar to route two：
；
In conclusion 5,5- dimethyl -3- this compound of methylene pyrrolidine -2- ketone are reported without document route, it is difficult to are met
The demand of new drug development.
The content of the invention
In view of the deficiencies of the prior art, it is this compound design of improvement 5,5- dimethyl -3- methylene pyrrolidine -2- ketone
Route steps are long, it is of high cost, be difficult to the problem of production amplification, the present invention provides one kind 5,5- dimethyl -3- methylene pyrroles
The preparation method of alkane -2- ketone.
The present invention is realized by the following technical programs：
The preparation method of one kind 5,5- dimethyl -3- methylene pyrrolidine -2- ketone, comprises the following steps：
S1, under the effect of strong organic base, condensation reaction occurs for formaldehyde and chemical compounds I, obtains compound ii；
Halogenating reaction occurs for S2, compound ii and halide reagent, obtains compound III；
S3, under the effect of strong organic base, substitution reaction occurs for compound III and 2- nitropropanes, obtains the compound containing nitro
Ⅳ；
S4, compounds Ⅳ carry out reduction nitro and the Domino reaction of cyclization, obtain 5 under the action of catalyst and reducing agent,
5- dimethyl -3- methylene pyrrolidine -2- ketone；
Wherein：Chemical compounds I is, compound ii is, compound III is,
Compounds Ⅳ is；
Synthetic route is as follows：
；
R and R2 in structural formula are respectively alkyl substituent, and X is halogen.
Further, in step S1, the strong organic base is 1,8- diazabicylos, 11 carbon -7- alkene（DBU）, 1,4- bis-
Azabicyclic [2.2.2] octane（DABCO）, tri- azabicyclics of 1,5,7- [4.4.0] decyl- 5- alkene（TBD）Or 1- methyl isophthalic acids, 5,7-
Three azabicyclics [4.4.0] decyl- 5- alkene（MTBD）In one kind.
Further, in step S1, the strong organic base is preferably 1- methyl isophthalic acids, 5,7- tri- azabicyclic [4.4.0] decyl-s
5- alkene（MTBD）.
Further, in step S1, the condensation reaction time is 5-9 h.
Further, in step S2, the halide reagent for phosphorus tribromide, phosphorus pentabromide, 48% hydrobromic acid, thionyl chloride,
One kind in concentrated hydrochloric acid or phosphorus oxychloride.
Further, in step S2, the halide reagent is preferably 48% hydrobromic acid.
Further, in step S3, the strong organic base is 1,8- diazabicylos, 11 carbon -7- alkene（DBU）, 1,4- bis-
Azabicyclic [2.2.2] octane（DABCO）, tri- azabicyclics of 1,5,7- [4.4.0] decyl- 5- alkene（TBD）Or 1- methyl isophthalic acids, 5,7-
Three azabicyclics [4.4.0] decyl- 5- alkene（MTBD）In one kind.
Further, in step S3, the strong organic base is preferably 1,5,7- tri- azabicyclic [4.4.0] decyl- 5- alkene
（TBD）.
Further, the catalyst is palladium.
Further, the reducing agent is ammonium formate or hydrogen.
Compared with prior art, the invention has the advantages that：
1st, synthesis step is few, simple and practicable, relatively mild without harshness reaction condition, reaction condition；
2nd, process route is novel, and yield is more than 50%, and reaction heat and gas produce to obtain good control, new with process route
Grain husk, be easy to amplification, the features such as being mass produced.
Embodiment
Presently preferred embodiments of the present invention is described in detail below, so that advantages and features of the invention are more easy to by this area skill
Art personnel understand, so as to make apparent define to protection scope of the present invention.
Embodiment 1
1st, the synthesis of 2- hydroxymethylacrylates methyl esters
3.0 grams of paraformaldehydes, 15 milliliters of methyl acrylates are dissolved in 25 milliliters of dioxane, then 3.2 gram 1 of addition, and 5,7- tri-
Azabicyclic [4.4.0] decyl- 5- alkene（TBD）, when room temperature reaction 5 is small.Reaction solution is concentrated to dryness, and adds a small amount of polymerization inhibitor, decompression
Distillation obtains 10.2 grams of 2- hydroxymethylacrylates methyl esters, yield 68%.
2nd, the synthesis of 2- bromomethyls methyl acrylate
10.2 grams of 2- hydroxymethylacrylate methyl esters obtained in the previous step is dissolved in 150 milliliters of acetonitriles, is then carefully added into 4 milliliters
Phosphorus tribromide.After adding, continue room temperature reaction 4 it is small when.Carefully it is quenched with water, precipitation removes acetonitrile.Residue adds 100 milliliters
Water, is extracted with ethyl acetate 2 times, precipitation, obtains 13.5 grams of colourless liquid, yield 86%.
3rd, the synthesis of 4- methyl -2- methylene -4- nitro methyl valerates
6.0 grams of 2- nitropropanes are dissolved in 60 milliliters of tetrahydrofurans, are then carefully added into 8.0 grams of 1- methyl isophthalic acids, 5,7- tri-
Azabicyclic [4.4.0] decyl- 5- alkene（MTBD）.Then be added dropwise 2- bromomethyl methyl acrylates, continue room temperature reaction 4 it is small when.It is small
Heart precipitation removes tetrahydrofuran, and residue adds 100 milliliters of water, is extracted with ethyl acetate 2 times, precipitation, obtains crude product colourless liquid
8.5 grams, yield 95%.
4th, the synthesis of 5,5- dimethyl -3- methylene pyrrolidines -2- ketone
8.5 grams of 4- methyl -2- methylene -4- nitros methyl valerate obtained in the previous step is dissolved in 100 ml methanols, Ran Houjia
Enter 2.5 gram of 10% palladium charcoal and 2.5 grams of ammonium formates, be heated to back flow reaction 8 it is small when.After question response, palladium charcoal is filtered to remove, is taken off
Molten removing methanol.Product is evaporated under reduced pressure, and obtains 4.5 grams of colourless liquid.Yield is 85%.
Embodiment 2
1st, the synthesis of 2- hydroxymethylacrylates ethyl ester
7.0 grams of formalins, 15 milliliters of ethyl acrylates are dissolved in 25 milliliters of tetrahydrofurans, then add 5.5 grams of 1,8- bis-
11 carbon -7- alkene of azabicyclic（DBU）, when room temperature reaction 6 is small.Reaction solution is concentrated to dryness, and adds a small amount of polymerization inhibitor, vacuum distillation
Obtain 10.6 grams of 2- hydroxymethylacrylates ethyl ester, yield 71%.
2nd, the synthesis of 2- chloromethyl propylenes acetoacetic ester
10.6 grams of 2- hydroxymethylacrylate ethyl esters obtained in the previous step are dissolved in 50 milliliters of toluene, are then gradually added at room temperature
15 grams of thionyl chlorides.After adding, when heating reaction 9 is small.Reaction solution adds 100 milliliters of water, and liquid separation, precipitation, obtains colourless liquid 11.5
Gram, yield 72%.
3rd, the synthesis of 4- methyl -2- methylene -4- nitro ethyl valerates
6.0 grams of 2- nitropropanes are dissolved in 60 milliliters of glycol dimethyl ethers, are then carefully added into 8.0 gram 1,5,7- tri- azepines
Two rings [4.4.0] decyl- 5- alkene（TBD）.Then be added dropwise 2- chloromethyl propylene acetoacetic esters, continue room temperature reaction 4 it is small when.Carefully take off
Molten removing glycol dimethyl ether, residue add 100 milliliters of water, are extracted with ethyl acetate 2 times, precipitation, obtain 9.5 grams of colourless liquid,
Yield 90%.
4th, the synthesis of 5,5- dimethyl -3- methylene pyrrolidines -2- ketone
9.5 grams of 4- methyl -2- methylene -4- nitros ethyl valerate obtained in the previous step is dissolved in 100 ml methanols, Ran Houjia
Enter 2.5 gram of 10% palladium charcoal, hydrogen displacement, when normal pressure hydrogenation back flow reaction 8 is small.After question response, palladium charcoal, precipitation are filtered to remove
Remove methanol.Product is evaporated under reduced pressure, and obtains 5.5 grams of colourless liquid.Yield is 93%.
It these are only the preferred embodiment of the present invention, be not intended to limit the scope of the invention, it is every to utilize this hair
The equivalent structure or equivalent flow shift that bright specification is made, is directly or indirectly used in other related technical areas,
Similarly it is included within the scope of the present invention.
Claims (7)
1. one kind 5, the preparation method of 5- dimethyl -3- methylene pyrrolidine -2- ketone, it is characterised in that：
Comprise the following steps,
S1, under the effect of strong organic base, condensation reaction occurs for formaldehyde and chemical compounds I, obtains compound ii；
Halogenating reaction occurs for S2, compound ii and halide reagent, obtains compound III；
S3, under the effect of strong organic base, substitution reaction occurs for compound III and 2- nitropropanes, obtains the compound containing nitro
Ⅳ；
S4, compounds Ⅳ carry out reduction nitro and the Domino reaction of cyclization, obtain 5 under the action of catalyst and reducing agent,
5- dimethyl -3- methylene pyrrolidine -2- ketone；
Wherein：Chemical compounds I is, compound ii is, compound III is, compounds Ⅳ is；
Synthetic route is as follows：
；
R and R2 in structural formula are respectively alkyl substituent, and X is halogen.
2. the preparation method of 5,5- dimethyl -3- methylene pyrrolidine -2- ketone according to claim 1, it is characterised in that：
In step S1, the strong organic base is 1,8- diazabicylos, 11 carbon -7- alkene, Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane, 1,
Tri- azabicyclics of 5,7- [4.4.0] decyl- 5- alkene or 1- methyl isophthalic acids, one kind in tri- azabicyclics of 5,7- [4.4.0] decyl- 5- alkene.
3. the preparation method of 5,5- dimethyl -3- methylene pyrrolidine -2- ketone according to claim 2, it is characterised in that：
In step S1, the condensation reaction time is 5-9 h.
4. the preparation method of 5,5- dimethyl -3- methylene pyrrolidine -2- ketone according to claim 1, it is characterised in that：
In step S2, the halide reagent is phosphorus tribromide, phosphorus pentabromide, 48% hydrobromic acid, thionyl chloride, concentrated hydrochloric acid or phosphorus oxychloride
In one kind.
5. the preparation method of 5,5- dimethyl -3- methylene pyrrolidine -2- ketone according to claim 1, it is characterised in that：
In step S3, the strong organic base is 1,8- diazabicylos, 11 carbon -7- alkene, Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane, 1,
Tri- azabicyclics of 5,7- [4.4.0] decyl- 5- alkene or 1- methyl isophthalic acids, one kind in tri- azabicyclics of 5,7- [4.4.0] decyl- 5- alkene.
6. the preparation method of 5,5- dimethyl -3- methylene pyrrolidine -2- ketone according to claim 1, it is characterised in that：
The catalyst is palladium.
7. the preparation method of 5,5- dimethyl -3- methylene pyrrolidine -2- ketone according to claim 1, it is characterised in that：
The reducing agent is ammonium formate or hydrogen.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009044245A2 (en) * | 2007-10-01 | 2009-04-09 | Cargill, Incorporated | Production of monatin enantiomers |
| CN103113226A (en) * | 2012-12-28 | 2013-05-22 | 中国科学院上海有机化学研究所 | Tert-butyl methacrylate monomer and polymer, synthesis method and application thereof |
-
2017
- 2017-10-30 CN CN201711037837.3A patent/CN107915668A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009044245A2 (en) * | 2007-10-01 | 2009-04-09 | Cargill, Incorporated | Production of monatin enantiomers |
| CN103113226A (en) * | 2012-12-28 | 2013-05-22 | 中国科学院上海有机化学研究所 | Tert-butyl methacrylate monomer and polymer, synthesis method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| KA YOUNG LEE 等: "Synthesis of β，r-Disubstituted α-Methylene-y-butyrolactams Starting from the Baylis-Hillman Adducts", 《BULL. KOREAN CHEM. SOC.》 * |
| ROBERTO BALLINI 等: "Chemoselective SN2" reaction of nitroallcanes to dialkyl 2-(bromomethyl)fumarates under cetyltrimethylammonium hydroxide (CTAOH) catalysis", 《TETRAHEDRON LETTERS》 * |
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Application publication date: 20180417 |