CN106905162A - A kind of preparation method of the formyl cyclohexene of 3 benzyloxymethyl, 4 aromatic radical, 5 nitro 1 - Google Patents
A kind of preparation method of the formyl cyclohexene of 3 benzyloxymethyl, 4 aromatic radical, 5 nitro 1 Download PDFInfo
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- CN106905162A CN106905162A CN201710029566.0A CN201710029566A CN106905162A CN 106905162 A CN106905162 A CN 106905162A CN 201710029566 A CN201710029566 A CN 201710029566A CN 106905162 A CN106905162 A CN 106905162A
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- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
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Abstract
The present invention relates to a kind of preparation method of the formyl cyclohexene of 5 nitro of 3 benzyloxymethyl, 4 aromatic radical 1, the formoxyl cyclohexene formula of 3 benzyloxymethyl, 4 aromatic radical, 5 nitro 1 is as shown in I：R is a substitution, two substitutions, three substitutions and quaternary halogen, nitro, amino, 1 10 carbon alkyl or 1 10 alkoxies in formula；Preparation method includes as follows：3 benzyloxy propionic aldehyde, (E) (2 nitroethylene) aromatic compound are mixed with secondary amine and solvent; after being reacted 1 24 hours in 0~25 DEG C; scrubbed, extraction, separation, obtain the formyl cyclohexene of 3 benzyloxymethyl, 4 aromatic radical, 5 nitro 1；
Description
Technical field
The present invention relates to a kind of preparation method of 3- benzyloxymethyls -4- aromatic radicals -5- nitro -1- formyl cyclohexenes, category
In compound synthesis technical field.
Background technology
Polysubstituted hexamethylene olefine aldehydr be widely present with natural products and the structure of medicine with bioactivity.They are also
Very useful organic synthesis intermediate.Its newest synthetic method is that such complexity is synthesized by many meters of Lip rivers of organic catalysis
Structure.It is many with three components of simple aldehyde that Enders etc. is catalyzed alpha, beta-unsaturated aldehyde, nitro compds hydrocarbon compound by secondary amine
Meter Luo has been synthesized three substitutions and quaternary hexamethylene olefine aldehydr (Adv.Synth.Catal.2008,350,267-279)；Gong
Three substitutions have been synthesized Deng by many meters of Lip rivers of four components of secondary amine catalysis simple alcohols, crotonaldehyde and nitro compds hydrocarbon compound
Hexamethylene olefine aldehydr (Chem.Eur.J.2009,15,6815-6818)；Chen etc. is catalyzed alpha, beta-unsaturated aldehyde and 2- by secondary amine
[3+3] cycloaddition reaction of the α of nitro allyl acetate, γ-regioselectivity synthesizes such polysubstituted hexamethylene olefine aldehydr
(Org.Lett.2016,18,116-119)。
However, these synthetic method yields are not high, the reaction time is long, and the shortcomings of some reaction raw materials complexity, this nothing
Doubt and limit its application.
The content of the invention
It is an object of the invention to solve the deficiencies in the prior art, there is provided a kind of 3- benzyloxymethyls -4- aromatic radical -5- nitre
The preparation method of base -1- formyl cyclohexenes.
The technical solution adopted for the present invention to solve the technical problems is：
A kind of preparation method of 3- benzyloxymethyls -4- aromatic radicals -5- nitro -1- formyl cyclohexenes,
3- benzyloxymethyls -4- aromatic radicals -5- nitro -1- formoxyl cyclohexene the formulas are as shown in I：
R is a substitution, two substitutions, three substitutions and quaternary halogen, nitro, amino, 1- in formula
10 carbon alkyl or 1-10 alkoxies；
Preparation method includes as follows：By 3- benzyloxies propionic aldehyde, (E)-(2- nitroethylenes) aromatic compound and secondary amine and
Solvent mixes, and after being reacted 1-24 hours in 0~25 DEG C, scrubbed, extraction, separation obtain 3- benzyloxymethyl -4- aromatic radicals -5-
Nitro -1- formyl cyclohexenes；
Preferably, the mol ratio of 3- benzyloxies propionic aldehyde and (E)-(2- nitroethylenes) aromatic compound is 2~5:1；
Secondary amine is α, the α-diphenylprolinol that racemization, R configurations and S configurations oxygen are trimethyl silane protection, respectively such as
Shown in formula C1, C2 and C3, its consumption is the 1~100% of (E)-(2- nitroethylenes) aromatic compound mole dosage；
Organic solvent is dichloromethane, chloroform, ether, tetrahydrofuran, toluene, ethanol, n-hexane, petroleum ether or different
Propyl alcohol, consumption of organic solvent is 3~20 times of substrate gross weight, and reaction temperature is -20 DEG C~40 DEG C,
Preferably, secondary amine consumption is 1~30%, You Jirong of (E)-(2- nitroethylenes) aromatic compound mole dosage
Agent consumption is 3~10 times of substrate gross weight.
Preferably, the 3- benzyloxymethyls -4- aromatic radicals -5- nitro -1- formyls cyclohexene is individual isomer.
The beneficial effects of the invention are as follows：The synthetic method for providing of the invention is simple to operate, reaction condition is gentle, it is not necessary to nothing
Water, anaerobic treatment, it is not required that cryogenic refrigeration.Target product yield is high, and gained target product is individual isomer, in optics
The enantioselectivity reacted under pure catalyst is more than 99%ee.
Specific embodiment
Below by specific embodiment, technical scheme is described in further detail.
Technical scheme described in detail below.The embodiment of the present invention only for explanation specific method, the method its
Scale should not be limited by the examples.
Embodiment 1：3- benzyloxymethyl -4- phenyl -5- nitro -1- formyl cyclohexenes
3- benzyloxies propionic aldehyde (82.1mg, 0.5mmol), (E)-(2- nitroethylenes) benzene are added in 100mL reaction bulbs
(29.8mg, 0.2mmol), catalyst C1 (13mg, 0.04mmol) and 10mL n-hexanes, are placed in 0 DEG C and stir 24 hours, TLC inspections
Survey reaction complete.Column chromatography (leacheate after reaction solution concentration：Petrol ether/ethyl acetate=10/1 to 5/1) obtain target product
Thing 3- benzyloxymethyl -4- aromatic radical -5- nitro -1- formyl cyclohexene 53mg, yield 75%.
Embodiment 2：(3S, 4S, 5S) -3- benzyloxymethyl -4- phenyl -5- nitro -1- formyl cyclohexenes
Method similar to Example 1：In 100mL reaction bulbs add 3- benzyloxies propionic aldehyde (82.1mg, 0.5mmol),
(E)-(2- nitroethylenes) benzene (29.8mg, 0.2mmol), catalyst C2 (13mg, 0.04mmol) and 10mL n-hexanes, are placed in 0
DEG C stirring 24 hours, TLC detection reactions are complete.Column chromatography (leacheate after reaction solution concentration：Petrol ether/ethyl acetate=10/1
To 5/1) obtain target product (3S, 4S, 5S) -3- benzyloxymethyl -4- aromatic radical -5- nitro -1- formyl cyclohexenes
53.5mg, yield 76%,>99%ee.
Embodiment 3：(3R, 4R, 5R) -3- benzyloxymethyl -4- phenyl -5- nitro -1- formyl cyclohexenes
Method similar to Example 1：In 100mL reaction bulbs add 3- benzyloxies propionic aldehyde (82.1mg, 0.5mmol),
(E)-(2- nitroethylenes) benzene (29.8mg, 0.2mmol), catalyst C3 (13mg, 0.04mmol) and 10mL n-hexanes, are placed in 0
DEG C stirring 24 hours, TLC detection reactions are complete.Column chromatography (leacheate after reaction solution concentration：Petrol ether/ethyl acetate=10/1
To 5/1) obtain target product (3R, 4R, 5R) -3- benzyloxymethyl -4- aromatic radical -5- nitro -1- formyl cyclohexenes
53.4mg, yield 76%,>99%ee.
Embodiment 4：(3S, 4S, 5S) -3- benzyloxymethyls -4- (p-fluorophenyl) -5- nitro -1- formyl cyclohexenes
Method similar to Example 1：In 100mL reaction bulbs add 3- benzyloxies propionic aldehyde (82.1mg, 0.5mmol),
(E) the fluoro- 4- of -1- (2- nitroethylenes) benzene (33.4mg, 0.2mmol), catalyst C2 (13mg, 0.04mmol) and 10mL just oneself
Alkane, is placed in 0 DEG C and stirs 24 hours, and TLC detection reactions are complete.Column chromatography (leacheate after reaction solution concentration：Petroleum ether/acetic acid second
Ester=10/1 to 5/1) obtain target product (3S, 4S, 5S) -3- benzyloxymethyls -4- (p-fluorophenyl) -5- nitro -1- formyls
Cyclohexene 57.6mg, yield 78%,>99%ee.
Embodiment 5：(3S, 4S, 5S) -3- benzyloxymethyls -4- (rubigan) -5- nitro -1- formyl cyclohexenes
Method similar to Example 1：In 100mL reaction bulbs add 3- benzyloxies propionic aldehyde (82.1mg, 0.5mmol),
(E) the chloro- 4- of -1- (2- nitroethylenes) benzene (36.7mg, 0.2mmol), catalyst C2 (13mg, 0.04mmol) and 10mL just oneself
Alkane, is placed in 0 DEG C and stirs 24 hours, and TLC detection reactions are complete.Column chromatography (leacheate after reaction solution concentration：Petroleum ether/acetic acid second
Ester=10/1 to 5/1) obtain target product (3S, 4S, 5S) -3- benzyloxymethyls -4- (rubigan) -5- nitro -1- formyls
Cyclohexene 56.3mg, yield 73%,>99%ee.
Embodiment 6：(3S, 4S, 5S) -3- benzyloxymethyls -4- (aminomethyl phenyl) -5- nitro -1- formyl cyclohexenes
Method similar to Example 1：In 100mL reaction bulbs add 3- benzyloxies propionic aldehyde (82.1mg, 0.5mmol),
(E) -1- methyl -3- (2- nitroethylenes) benzene (32.6mg, 0.2mmol), catalyst C2 (13mg, 0.04mmol) and 10mL just oneself
Alkane, is placed in 0 DEG C and stirs 24 hours, and TLC detection reactions are complete.Column chromatography (leacheate after reaction solution concentration：Petroleum ether/acetic acid second
Ester=10/1 to 5/1) obtain target product (3S, 4S, 5S) -3- benzyloxymethyls -4- (aminomethyl phenyl) -5- nitro -1- first
Acyl group cyclohexene 51.2mg, yield 70%,>99%ee.
Embodiment 7：(3S, 4S, 5S) -3- benzyloxymethyls -4- (m-bromophenyl) -5- nitro -1- formyl cyclohexenes
Method similar to Example 1：In 100mL reaction bulbs add 3- benzyloxies propionic aldehyde (82.1mg, 0.5mmol),
(E) the bromo- 3- of -1- (2- nitroethylenes) benzene (45.6mg, 0.2mmol), catalyst C2 (13mg, 0.04mmol) and 10mL just oneself
Alkane, is placed in 0 DEG C and stirs 24 hours, and TLC detection reactions are complete.Column chromatography (leacheate after reaction solution concentration：Petroleum ether/acetic acid second
Ester=10/1 to 5/1) obtain target product (3S, 4S, 5S) -3- benzyloxymethyls -4- (m-bromophenyl) -5- nitro -1- formyls
Cyclohexene 57.6mg, yield 67%,>99%ee.
The present invention is not limited to the above embodiments, described in above-described embodiment and specification simply to illustrate that this hair
Bright principle, without departing from the spirit and scope of the present invention, the present invention also has the change of various unsubstantialities and changes
Enter, these are both fallen within the scope of protection of present invention.
Claims (4)
1. a kind of preparation method of 3- benzyloxymethyls -4- aromatic radicals -5- nitro -1- formyl cyclohexenes, it is characterised in that：
3- benzyloxymethyls -4- aromatic radicals -5- nitro -1- formoxyl cyclohexene the formulas are as shown in I：
R is a substitution, two substitutions, three substitutions and quaternary halogen, nitro, amino, 1-10 carbon in formula
Alkyl or 1-10 alkoxies；
Preparation method includes as follows：By 3- benzyloxies propionic aldehyde, (E)-(2- nitroethylenes) aromatic compound and secondary amine and solvent
Mixing, in 0~25 DEG C reaction 1-24 hour after, it is scrubbed, extraction, separation, obtain 3- benzyloxymethyl -4- aromatic radical -5- nitros -
1- formyl cyclohexenes；
2. the preparation method of 3- benzyloxymethyls -4- aromatic radicals -5- nitros -1- formyl cyclohexenes according to claim 1, its
It is characterised by：
The mol ratio of 3- benzyloxies propionic aldehyde and (E)-(2- nitroethylenes) aromatic compound is 2~5:1；
Secondary amine be racemization, R configurations and S configurations oxygen be trimethyl silane protection α, α-diphenylprolinol, respectively as formula C1,
Shown in C2 and C3, its consumption is the 1~100% of (E)-(2- nitroethylenes) aromatic compound mole dosage；
Organic solvent is dichloromethane, chloroform, ether, tetrahydrofuran, toluene, ethanol, n-hexane, petroleum ether or isopropyl
Alcohol, consumption of organic solvent is 3~20 times of substrate gross weight, and reaction temperature is -20 DEG C~40 DEG C,
3. the preparation method of 3- benzyloxymethyls -4- aromatic radicals -5- nitros -1- formyl cyclohexenes according to claim 2, its
It is characterised by, secondary amine consumption is the 1~30% of (E)-(2- nitroethylenes) aromatic compound mole dosage, consumption of organic solvent
It is 3~10 times of substrate gross weight.
4. the preparation method of 3- benzyloxymethyls -4- aromatic radicals -5- nitros -1- formyl cyclohexenes according to claim 1, its
It is characterised by, the 3- benzyloxymethyls -4- aromatic radicals -5- nitro -1- formyls cyclohexene is individual isomer.
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| CN113173946A (en) * | 2021-04-16 | 2021-07-27 | 西安国睿新药安全评价研究中心有限公司 | Synthesis and application of polyfunctional group cyclohexene aldehyde compound |
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| CN102046592A (en) * | 2008-05-30 | 2011-05-04 | 学校法人东京理科大学 | Process for producing oseltamivir phosphate and intermediate compound |
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| CN102046592A (en) * | 2008-05-30 | 2011-05-04 | 学校法人东京理科大学 | Process for producing oseltamivir phosphate and intermediate compound |
Non-Patent Citations (3)
| Title |
|---|
| BO HAN ET AL.: "Asymmetric Michael Addition of γ,γ-Disubstituted α,β-Unsaturated Aldehydes to Nitroolefins via Dienamine Catalysis", 《ORG. LETT.》 * |
| DIETER ENDERS ET AL.: "Control of four stereocentres in a triple cascade organocatalytic reaction", 《NATURE》 * |
| DIETER ENDERS ET AL.: "Organocatalytic asymmetric synthesis of polyfunctionalized 3-(cyclohexenylmethyl)-indoles via a quadruple domino Friedel–Crafts-type/Michael/Michael/aldol condensation reaction", 《CHEM. COMM.》 * |
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| CN113173946A (en) * | 2021-04-16 | 2021-07-27 | 西安国睿新药安全评价研究中心有限公司 | Synthesis and application of polyfunctional group cyclohexene aldehyde compound |
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Effective date of registration: 20190725 Address after: 310000 Room 311, Building No. 688, Bin'an Road, Changhe Street, Binjiang District, Hangzhou City, Zhejiang Province Patentee after: Hangzhou Li'an Biological Technology Co., Ltd. Address before: 324000 North Road, Quzhou, Zhejiang, No. 78, No. nine Patentee before: Quzhou University |