CN103130706A - Preparing method of 6-oxo-3-aza-bicyclo[3,2,0]heptane-3-carboxylic acid tert-butyl ester - Google Patents
Preparing method of 6-oxo-3-aza-bicyclo[3,2,0]heptane-3-carboxylic acid tert-butyl ester Download PDFInfo
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- CN103130706A CN103130706A CN2011103907248A CN201110390724A CN103130706A CN 103130706 A CN103130706 A CN 103130706A CN 2011103907248 A CN2011103907248 A CN 2011103907248A CN 201110390724 A CN201110390724 A CN 201110390724A CN 103130706 A CN103130706 A CN 103130706A
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- heptane
- oxo
- carboxylic acid
- butyl ester
- acid tert
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to a preparing method of 6-oxo-3-aza-bicyclo[3,2,0]heptane-3-carboxylic acid tert-butyl ester. The preparing method mainly solves the technical problems that in an existing synthetic process, the route is long, cost is high, experimental operation is inconvenient, and the like. According to the preparing method, N-Boc-3-pyrroline (or pyrroline with various other protecting groups on nitrogen ) and trichloro-acetic chloride are used as raw material, 6,6-dichloro-7-oxo-3-aza-bicyclo[3,2,0]heptane-3-carboxylic acid tert-butyl ester is prepared first by means of the zinc-copper reagent, and then the 6-oxo-3-aza-bicyclo[3,2,0]heptane-3-carboxylic acid tert-butyl ester is prepared with zinc powder as the reducing agent. The 6-oxo-3-aza-bicyclo[3,2,0]heptane-3-carboxylic acid tert-butyl ester prepared with the method is a useful intermediate or product used for synthesis of various kinds of drugs.
Description
Technical field
The present invention relates to the synthetic method of 6-oxo-3-azabicyclo [3,2,0] heptane-3-carboxylic acid tert-butyl ester.
Background technology
6-oxo-3-azabicyclo [3,2,0] heptane-3-carboxylic acid tert-butyl ester and relevant derivative have widespread use in pharmaceutical chemistry and organic synthesis.At present the synthetic method [US2004152724 (A1)] of 6-oxo-3-azabicyclo [3,2,0] heptane-3-carboxylic acid tert-butyl ester is by by 6-oxo-3-(toluene-4-sulphonyl)-3-azabicyclo [3,2,0] heptane, through reduction, takes off Ts, and upper Boc then oxidation obtains.And raw material 6-oxo-3-(toluene-4-sulphonyl)-3-azabicyclo [3,2,0] heptane [Heterocycles, 28 (1), 29-32; 1989] be difficult to obtain, need to be protected through Ts by β-Beta Alanine, esterification, the amine transesterify, alkylation, cyclisation five steps reactions obtain.Mainly also there is following problem in this synthetic method: will use hazardous substance in (1) reaction process, experimental implementation inconvenience; (2) reaction scheme is long, needs 9 steps, and whole yield is very low; (3) cost is higher.Concrete reaction formula is as follows:
Therefore, need a raw material of exploitation to be easy to get, easy to operate, reaction is easy to control, the synthetic method that overall yield is applicable.
Summary of the invention
The objective of the invention is to develop and a kind ofly have raw material and be easy to get, easy to operate, reaction is easy to control, the synthetic method of the 6-oxo that yield is higher-3-azabicyclo [3,2,0] heptane-3-carboxylic acid tert-butyl ester.Mainly solve current synthetic route long, cost is higher, the technical problems such as operation inconvenience.
Technical scheme of the present invention: the present invention in two steps; at first; N-Boc-3-pyrroline and zinc-copper reagent are placed in to anhydrous diethyl ether, under nitrogen protection, drip 1 of trichoroacetic chloride; 2-glycol dimethyl ether (DME) solution; obtain the chloro-7-oxo of 6,6-bis--3-azabicyclo [3,2 under stirring at room; 0] heptane-3-carboxylic acid tert-butyl ester, reaction formula is as follows:
Secondly, by the chloro-7-oxo of 6,6-bis--3-azabicyclo [3,2,0] heptane-3-carboxylic acid tert-butyl ester and ammonium chloride are placed in methyl alcohol, under ice bath, add then stirring at room of zinc powder in batches, finally obtain 6-oxo-3-azabicyclo [3,2,0] heptane-3-carboxylic acid tert-butyl ester, reaction formula is as follows:
Beneficial effect of the present invention: the invention solves the synthesis technique Road line length of both having known at present, yield is low, and reaction is not easy to control, the shortcomings such as experimental implementation inconvenience.Adopt new synthetic method to shorten synthetic route and improved overall yield and be easy to amplification, can realize that 6-oxo-3-azabicyclo [3,2,0] heptane-prepared by 3-carboxylic acid tert-butyl ester laboratory fast.
Embodiment
Reaction formula of the present invention is as follows:
Embodiment 1: compound N-Boc-3-pyrroline (0.5 g, 2.96 mmol) and Zn-Cu reagent (0.55 g, 8.7 mmol) are added in 7 mL anhydrous diethyl ethers, be placed in ice-water bath and stir.At N
2under protection, will be dissolved in trichoroacetic chloride (1.1 g, 6.1 mmol) in the anhydrous DME of 6 mL in 0
ojoin in the mixture of above-mentioned stirring stirring at room 12 hours under C.TLC(sherwood oil: ethyl acetate, V/V=5/1, R
f=0.4) follow the tracks of reaction.Reaction solution, with after diatomite filtration, is added to the water-cooled full NaHCO of ice
3in the aqueous solution (4 mL), by ethyl acetate (3 mL x 3) aqueous layer extracted, after the merging organic layer, with saturated salt solution, wash (4 mL) and use anhydrous Na
2sO
4drying, be spin-dried for.Column chromatography purification (PE: EA, V/V=20: 1 to 5: 1), obtain 0.16 g compound 6, and the chloro-7-oxo of 6-bis--3-azabicyclo [3,2,0] heptane-3-carboxylic acid tert-butyl ester, reclaim 0.22 g N-Boc-3-pyrroline
.
By compound 6, the chloro-7-oxo of 6-bis--3-azabicyclo [3,2,0] heptane-3-carboxylic acid tert-butyl ester (0.16 g, 0.57 mmol) and NH
4cl (0.24 g, 4.5mmol) is added in 5 mL methyl alcohol, and is placed in ice bath and stirs, and Zn powder (0.45 g, 6.9 mmol) is added in said mixture in batches, under room temperature, stirs and spends the night.With diatomite filtration reaction solution concentrated, residuum is dissolved in ethyl acetate (6 mL), after saturated aqueous common salt (3 mL) washing, uses anhydrous Na SO
4drying, column chromatography purification (PE: EA, V/V=20: 1 to 5: 1), obtain 51 mg 6-oxos-3-azabicyclo [3,2,0] heptane-3-carboxylic acid tert-butyl ester (two step yields, 14.6%)
.
Embodiment 2: compound N-Boc-3-pyrroline (5 g, 29.6 mmol) and Zn-Cu reagent (5.5 g, 87 mmol) are added in 70 mL anhydrous diethyl ethers, be placed in ice-water bath and stir.At N
2under protection, will be dissolved in trichoroacetic chloride (11 g, 61 mmol) in the anhydrous DME of 60 mL in 0
ojoin in the mixture of above-mentioned stirring stirred overnight at room temperature under C.TLC(sherwood oil: ethyl acetate, V/V=5: 1, R
f=0.4) follow the tracks of reaction.Reaction solution, with after diatomite filtration, is added to the water-cooled full NaHCO of ice
3in the aqueous solution (40 mL), by ethyl acetate (20 mL x 3) aqueous layer extracted, after the merging organic layer, with saturated salt solution, wash (30 mL) and use anhydrous Na
2the SO4 drying, be spin-dried for.Column chromatography purification (PE: EA, V/V=20: 1 to 5: 1), obtain 1.7 g compounds 6, and the chloro-7-oxo of 6-bis--3-azabicyclo [3,2,0] heptane-3-carboxylic acid tert-butyl ester, reclaim 2.6 g N-Boc-3-pyrrolines
.
By compound 6, the chloro-7-oxo of 6-bis--3-azabicyclo [3,2,0] heptane-3-carboxylic acid tert-butyl ester (1.7 g, 6.1 mmol) and NH
4cl (2.4 g, 45 mmol) is added in 30mL methyl alcohol, and is placed in ice bath and stirs, and Zn powder (4.5 g, 69 mmol) is added in said mixture in batches, under room temperature, stirs and spends the night.With diatomite filtration reaction solution concentrated, residuum is dissolved in ethyl acetate (30 mL), after saturated aqueous common salt for organic layer (10 mL) washing, uses anhydrous Na SO
4drying, column chromatography purification (PE: EA, V/V=20: 1 to 5: 1), obtain 0.56 g compound 6-oxo-3-azabicyclo [3,2,0] heptane-3-carboxylic acid tert-butyl ester (two step yields, 18.6%)
.
Embodiment 3: compound N-Boc-3-pyrroline (50 g, 0.296mol) and Zn-Cu reagent (55 g, 0.87mol) are added in the 700mL anhydrous diethyl ether, be placed in ice-water bath and stir.At N
2under protection, will be dissolved in trichoroacetic chloride (110 g, 0.61 mol) in the anhydrous DME of 600 mL in 0
ojoin in the mixture of above-mentioned stirring stirred overnight at room temperature under C.TLC(sherwood oil: ethyl acetate, V/V=5: 1, R
f=0.4) follow the tracks of reaction.Reaction solution, with after diatomite filtration, is added to the water-cooled full NaHCO of ice
3in the aqueous solution (400 mL), by ethyl acetate (200 mL x 3) aqueous layer extracted, after the merging organic layer, with saturated salt solution, wash (300 mL) and use anhydrous Na
2the SO4 drying, be spin-dried for.Column chromatography purification (PE: EA, V/V=20: 1 to 5: 1), obtain 18 g compounds 6, and the chloro-7-oxo of 6-bis--3-azabicyclo [3,2,0] heptane-3-carboxylic acid tert-butyl ester returns 30 g N-Boc-3-pyrrolines
.
By compound 6, the chloro-7-oxo of 6-bis--3-azabicyclo [3,2,0] heptane-3-carboxylic acid tert-butyl ester (18 g, 0.064 mol) and NH
4c l (27 g, 0.51 mol) is added in 300mL methyl alcohol, and is placed in ice bath and stirs, and Zn powder (45.5 g, 0.7 mol) is added in said mixture in batches, under room temperature, stirs and spends the night.With diatomite filtration reaction solution concentrated, residuum is dissolved in ethyl acetate (300 mL), after saturated aqueous common salt for organic layer (100 mL) washing, uses anhydrous Na SO
4drying, column chromatography purification (PE: EA, V/V=20: 1 to 5: 1), obtain 5.8 g compound 6-oxos-3-azabicyclo [3,2,0] heptane-3-carboxylic acid tert-butyl ester (two step yields, 23.2 %)
.
Claims (1)
1. 6-oxo-3-azabicyclo [3,2,0] preparation method of heptane-3-carboxylic acid tert-butyl ester, comprise the following steps: the first step, N-Boc-3-pyrroline and zinc-copper reagent are placed in to anhydrous diethyl ether, under nitrogen protection, drip 1 of trichoroacetic chloride, 2-glycol dimethyl ether solution, obtain 6 under stirring at room, the chloro-7-oxo of 6-bis--3-azabicyclo [3,2,0] heptane-3-carboxylic acid tert-butyl ester; Second step, by the chloro-7-oxo of 6,6-bis--3-azabicyclo [3,2,0] heptane-3-carboxylic acid tert-butyl ester and ammonium chloride are placed in methyl alcohol, under ice bath, add zinc powder then stirring at room obtain 6-oxo-3-azabicyclo [3,2,0] heptane-3-carboxylic acid tert-butyl ester, reaction formula is as follows:
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006092691A1 (en) * | 2005-03-01 | 2006-09-08 | Pfizer Limited | Use of pde7 inhibitors for the treatment of neuropathic pain |
| WO2010079668A1 (en) * | 2009-01-08 | 2010-07-15 | 第一三共株式会社 | Olefin compound |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006092691A1 (en) * | 2005-03-01 | 2006-09-08 | Pfizer Limited | Use of pde7 inhibitors for the treatment of neuropathic pain |
| WO2010079668A1 (en) * | 2009-01-08 | 2010-07-15 | 第一三共株式会社 | Olefin compound |
Non-Patent Citations (4)
| Title |
|---|
| ADALBERT MAERCKER等: ""Versuche zur Umlagerung von Cyclobutyl- in 3-Butenyl-Anionen: Endocyclische Ringoffnung bei der Reaktion von (3,3-Diphenyl-1-vinylcyclobuty1)methylether mit Alkalimetallen – anionisch oder radikalisch?"", 《CHEM. BER.》 * |
| BLAIR D. JOHNSTON等: ""[2+2] Cycloaddition of Dichloroketone to Allyl Ethers and Thioethers"", 《J. ORG. CHEM.》 * |
| E. LEE-RUFF等: ""Bicyclic Nucleoside Synthesis – A Photochemical Approach"", 《NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS》 * |
| GOVERDHAN METHA等: ""Stereoselective Synthesis of cis- and trans-Bicyclo [6.3.0] undec-4-en-10-ones. Efficient Precursors of 4-Oxo-1,2-Cyclopentane Dipropanoic Acids"", 《SYNTHETIC COMMUNICATIONS》 * |
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Application publication date: 20130605 |