CN103450072A - Pyrrole derivative of R-proline with cyclopropane structure and preparation method of pyrrole derivative - Google Patents
Pyrrole derivative of R-proline with cyclopropane structure and preparation method of pyrrole derivative Download PDFInfo
- Publication number
- CN103450072A CN103450072A CN2013104119725A CN201310411972A CN103450072A CN 103450072 A CN103450072 A CN 103450072A CN 2013104119725 A CN2013104119725 A CN 2013104119725A CN 201310411972 A CN201310411972 A CN 201310411972A CN 103450072 A CN103450072 A CN 103450072A
- Authority
- CN
- China
- Prior art keywords
- hexane
- azabicyclo
- tertbutyloxycarbonyl
- reaction
- pyrroles
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Indole Compounds (AREA)
Abstract
The invention provides a synthesis method of a pyrrole derivative of R-proline with a cyclopropane structure. The method comprises the following steps of: step 1, performing a Simmons-Smith cyclopropane reaction on (R)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrole ethyl formate; step 2, respectively performing esterolysis reactions on enantiomers obtained by the step 1; step 3, respectively performing amide condensation actions on reaction products obtained by the step 2; step 4, respectively performing amino-removal protecting actions on the reaction products obtained by the step 3; and step 5, respectively performing reduction reactions on the reaction products obtained by the step 4, thereby obtaining the pyrrole derivative of the R-proline with the cyclopropane structure. The method is reasonable in process, simple to operate and low in cost, and can be used for obtaining the enantiomer products with optical purity while chiral preparation and separation are not required further. Thus, the method is ideal for synthesis of the pyrrole derivative of the R-proline with the cyclopropane structure.
Description
Technical field
The present invention relates to the compound preparing technical field, relate in particular to pyrrole derivative of a kind of novel R-proline(Pro) with cyclopropane structure and preparation method thereof.
Background technology
The asymmetric reaction of organic micromolecule compound catalysis obtains swift and violent development in more than ten years in the past, become the potential method of asymmetric synthesis of the 3rd class that generally acknowledged and organo-metallic catalysis, enzyme catalysis have par.Yet existing organic micromolecule compound is mostly to utilize natural product cheap and easy to get for chiral source, its structure type is limited.Under the prerequisite that does not change its catalytic activity, modification and the implementation structure diversity aspect of its structure had some limitations again, thereby caused the problems such as less and universality catalyzed reaction of catalyzed reaction type is limited.
The people such as Barbas III be take the asymmetric Michael addition reaction that nitro propylene aryl is electrophilic reagent and aldehyde, to proline derivative carry out the catalytic performance screening (Org.Lett., 2001,3,3737-3740).Result shows: the pyrrole derivative of S-proline(Pro) has catalytic activity and enantioselectivity preferably, but, due to sterically hindered little, cis-selectivity is poor.
Based on above-mentioned result of study, our imagination at the ortho position of pyrrole ring by and the mode of ring introduce the chiral cyclopropane group that rigidity is strong, rigidity and sterically hindered the solving not to enantioselectivity in catalyzed reaction and the poor problem of cis-selectivity of the chiral catalyst of the pyrrole derivative of hope increase proline(Pro), have high catalytic activity and the stereoselective new catalyst of broad-spectrum high efficacy to obtaining.
1997, H.Stephen group successfully synthesized first and has had cyclopropane structure S-proline(Pro) for studying its Zinc metallopeptidase Zace1 rejection (Angew.Chem.Int.Ed.Engl.1997,36,1881), due to cyclization reagent Me
3snCH
2the cost costliness, toxicity is large, and it is low to generate the enantiomer proportion of products, and it has developed the Simmons-Smith cyclopropane reaction (Bioorganic& based on this compound subsequently; Medicinal Chemistry Letters8 (1998) 2123-2128), its synthetic route is as follows:
In this synthetic route, be reduced into the olefin product productive rate lower, reagent cost is higher, processing condition are required harsh, in cyclization process, lower (the structure A: structure B=1:4) need further chirality preparation and split, being not suitable for industrial scale operation of enantioselectivity.
Use for reference the preparation method of above-mentioned chiral cyclopropane structure S-proline(Pro), overcome the above-mentioned synthetic problem existed in the method for cyclopropane structure S-proline(Pro) that has simultaneously, we provide a kind of synthetic method of the novel pyrrole derivative with cyclopropane structure R-proline(Pro), its technique is reasonable, simple to operate, with low cost, do not need further chirality preparation and split the enantiomorph product that obtains optical purity, corresponding body structure selectivity is stronger, is the desirable synthetic method with pyrrole derivative of cyclopropane structure R-proline(Pro).
Summary of the invention
The object of the invention is to for the deficiencies in the prior art, a kind of chiral organic micromolecule compound of the novel pyrrole derivative with cyclopropane structure R-proline(Pro) is provided, its technique is reasonable, simple to operate, with low cost, do not need further to carry out the enantiomorph product that chirality preparation and fractionation obtain optical purity, it is the chiral organic micromolecule compound of the pyrrole derivative of the desirable synthetic R-proline(Pro) with cyclopropane structure, this pyrrole derivative with R-proline(Pro) of cyclopropane structure has rigidity and sterically hindered as chiral catalyst, thereby can solution never to enantioselectivity in catalyzed reaction and the poor problem of cis-selectivity, there is high catalytic activity and broad-spectrum high efficacy stereoselectivity.
For solving the problems of the technologies described above, the invention provides a kind of pyrrole derivative chiral organic micromolecule compound with R-proline(Pro) of cyclopropane structure, its structural formula is as shown in Formula I:
In Formula I, the chiral configuration of mark * carbon can be a kind of in R or S;
The chirality of C-1 and C-5 must be a kind of in R or S simultaneously.
For solving the problems of the technologies described above, the invention provides the synthetic method of pyrrole derivative of the R-proline(Pro) with cyclopropane structure of above-mentioned chemical formulation, its step comprises:
The first step, with (R)-1-N-tertbutyloxycarbonyl-2,3-dihydro-2-minaline ethyl ester carries out the reaction of Simmons-Smith cyclopropane, obtains enantiomer;
Second step, the enantiomer that the first step is obtained is carried out respectively ester hydrolysis reaction;
The 3rd step, the reaction product that second step is obtained is carried out respectively amide condensed reaction;
The 4th step, the reaction product that the 3rd step is obtained is carried out respectively the deaminizating protective reaction;
The 5th step, the reaction product that the 4th step is obtained is carried out respectively reduction reaction; Acquisition has the pyrrole derivative of cyclopropane structure R-proline(Pro).
Wherein, the described the first step is specially the tertbutyloxycarbonyl-2 by (R)-1-N-, 3-dihydro-2-minaline ethyl ester and zinc ethyl (ZnEt
2) and chloroiodomethane (CH
2clI) hybrid reaction, obtain enantiomer (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate and (1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate, the corresponding isomer mixture obtained adopts the aqueous solution of ethylenediamine tetraacetic acid (EDTA) and the amine aqueous solution to process, improve both enantioselectivity, enantiomer (1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate and (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] mol ratio>25:1 of hexane-3-ethyl formate, adopt subsequently the mixing leacheate of volume ratio ethyl acetate/normal heptane=1/20 to carry out the separation of chromatography post, obtain respectively product (1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate and (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate.
Wherein, in the described the first step, (R)-1-N-tertbutyloxycarbonyl-2,3-dihydro-2-minaline ethyl ester and zinc ethyl (ZnEt
2) and chloroiodomethane (CH
2clI) according to mol ratio 1:0.5～2:1～2, mix, further preferably 1/0.5/1 or 1/1/1 or 1/1/2 or 1/2/2, maintain under the condition of temperature of reaction-20 ℃～-15 ℃, react 22～24h.
Wherein, described second step is specially (1S, 3R, 5S)-N-tertbutyloxycarbonyl of the first step acquisition-2-azabicyclo [3,1,0] hexane-3-ethyl formate and (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-ethyl formate separately with lithium hydroxide (LiOH) hybrid reaction, carry out the hydrolysis reaction under alkaline condition, obtain respectively (1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-formic acid and (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-formic acid.
Wherein, described the 3rd step is specially the product (1S that second step is obtained, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-formic acid and (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-formic acid separately with pyrroles, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloric acid (EDCI), I-hydroxybenzotriazole (HOBT) and triethylamine (Et
3n) mix and carry out amidate action, obtain respectively (1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles and (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles.
Wherein, described (1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-formic acid and (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-formic acid and pyrroles, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloric acid (EDCI), I-hydroxybenzotriazole (HOBT), triethylamine (Et
3n) molar reactive is than being 1:1.5～2.0:1.5～2.0:1.5～2.0:1.5～2.0, and reaction conditions is 15～25 ℃ of reaction 14～16h for keeping temperature.
Wherein, described the 4th step is specially product (1S, the 3R that the 3rd step is obtained, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles and (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles mixes with trifluoroacetic acid separately, carries out the amide hydrolysis under acidic conditions, keep subsequently 5 ℃ of reaction 2～4h of temperature, obtain respectively (1S, 3R, 5S)-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles and (1R, 3R, 5R)-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles.
Wherein, described the 5th step is specially the product (1S, 3R, 5S) of the 4th step acquisition-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles and (1R, 3R, 5R)-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles separately with tetrahydrochysene lithium aluminium (LiAlH
4) mix, carry out the reduction reaction under alkaline condition, obtain (1S, 3R, 5S)-2-azabicyclo [3,1,0] hexane-3-methylpyrrole and (1R, 3R, 5R)-2-azabicyclo [3,1,0] hexane-3-methylpyrrole.
The pyrrole derivative of the R-proline(Pro) with cyclopropane structure that the present invention also provides the synthetic method of the pyrrole derivative that adopts the above-mentioned R-proline(Pro) with cyclopropane structure to prepare is as the application of catalyzer.
Beneficial effect of the present invention:
The synthetic method of the pyrrole derivative of the novel R-proline(Pro) with cyclopropane structure provided by the invention, its technique is reasonable, simple to operate, with low cost, do not need further to carry out the enantiomorph product that chirality preparation and fractionation obtain optical purity, corresponding body structure selectivity is stronger, it is the method for the pyrrole derivative of the desirable synthetic R-proline(Pro) with cyclopropane structure, this pyrrole derivative with R-proline(Pro) of cyclopropane structure has rigidity and sterically hindered as chiral catalyst, thereby can solution never to enantioselectivity in catalyzed reaction and the poor problem of cis-selectivity, there is high catalytic activity and broad-spectrum high efficacy stereoselectivity.
The accompanying drawing explanation
The high-efficient liquid phase chromatogram that Fig. 1 is compound 1 and compound 2 (HPLC).
Embodiment
The invention provides a kind of pyrrole derivative chiral organic micromolecule compound with R-proline(Pro) of cyclopropane structure, its structural formula is as shown in Formula I:
In Formula I, the chiral configuration of mark * carbon can be a kind of in R or S;
The chirality of C-1 and C-5 must be a kind of in R or S simultaneously.
The synthetic route of the pyrrole derivative of the R-proline(Pro) with cyclopropane structure provided by the present invention is as follows:
Its synthesis step comprises:
The first step, with (R)-1-N-tertbutyloxycarbonyl-2,3-dihydro-2-minaline ethyl ester carries out the reaction of Simmons-Smith cyclopropane, obtains enantiomer;
Second step, the enantiomer that the first step is obtained is carried out respectively ester hydrolysis reaction;
The 3rd step, the reaction product that second step is obtained is carried out respectively amide condensed reaction;
The 4th step, the reaction product that the 3rd step is obtained is carried out respectively the deaminizating protective reaction;
The 5th step, the reaction product that the 4th step is obtained is carried out respectively reduction reaction; Acquisition has the pyrrole derivative of cyclopropane structure R-proline(Pro).
The described the first step is specially the tertbutyloxycarbonyl-2 by (R)-1-N-, 3-dihydro-2-minaline ethyl ester and zinc ethyl (ZnEt
2) and chloroiodomethane (CH
2clI) according to mol ratio 1:0.5～2:1～2, mix, further preferably 1/0.5/1 or 1/1/1 or 1/1/2 or 1/2/2, maintain under the condition of temperature of reaction-20～-15 ℃, reaction 22～24h, obtain enantiomer (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate and (1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate, the corresponding isomer mixture obtained adopts the aqueous solution of ethylenediamine tetraacetic acid (EDTA) and the amine aqueous solution to process, improve both enantioselectivity, the amine aqueous solution is ethamine, diethylamine, triethylamine, propylamine, any one in Isopropylamine and the TERTIARY BUTYL AMINE aqueous solution, enantiomer (1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate: (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] mol ratio of hexane-3-ethyl formate>25: 1, its ratio is far above document (Bioorganic & Medicinal Chemistry Letters8 (1998) 2123-2128) ratio of reporting 4: 1, adopt subsequently ethyl acetate/normal heptane to form mixed solution according to volume ratio 1/20, mix leacheate and carry out the separation of chromatography post, obtain respectively product (1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-ethyl formate and (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-ethyl formate.
The described the first step is further preferably at N
2under protection, add (R)-1-N-tertbutyloxycarbonyl-2 in dry reaction flask, 3-dihydro-2-minaline ethyl ester, add methylene chloride (DCM) subsequently, is cooled to-20 ℃～-15 ℃, drips zinc ethyl (ZnEt
2), dropwise rear stirring 0.5h, drip and be dissolved in the chloroiodomethane (CH in methylene dichloride (DCM) solvent subsequently
2clI), maintain temperature-20～-15 ℃ and stir 22h～24h, after completion of the reaction with the aqueous solution cancellation reaction that adds the ethylenediamine tetraacetic acid (EDTA) (EDTA) that mass percentage concentration is 13%, be warming up to 20～25 ℃, stir 2～3h, standing 20 minutes, extraction, merge organic phase, obtain yellow oil, adding mass percentage concentration is that 30% diethylamine aqueous solution stirs 12h, concentrating under reduced pressure, the appropriate anhydrous sodium sulfate drying of organic layer, carry out wash-out with the mixing elutriant of ethyl acetate (EA)/normal heptane (h-heptane)=1/20, wash-out is complete, collect product, obtain respectively product (1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate and (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate, (1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate and (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate mol ratio>25: 1.
Described second step is specially the (1S that the first step is obtained, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate and (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate is 1: 1.0～1.5 to mix with lithium hydroxide (LiOH) according to mol ratio separately, carry out the hydrolysis reaction under alkaline condition, react 14～18h under the condition that the maintenance temperature is 15～25 ℃, obtain respectively (1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-formic acid and (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-formic acid.
Described the 3rd step is specially the product (1S that second step is obtained, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-formic acid and (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-formic acid separately with pyrroles, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloric acid (EDCI), I-hydroxybenzotriazole (HOBT) and triethylamine (Et
3n) mix and carry out amidate action according to mol ratio 1: 1.5～2.0: 1.5～2.0: 1.5～2.0: 1.5～2.0, keep subsequently 15～25 ℃ of reaction 14～16h of temperature, obtain respectively (1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles and (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles.
Described the 3rd step is the product (1S for adding respectively second step to obtain in the reaction flask of different dryings further, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-formic acid or (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-formic acid, add separately subsequently methylene dichloride to dissolve, controlling temperature is 15～25 ℃, adds separately pyrroles, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloric acid (EDCI), I-hydroxybenzotriazole (HOBT) and triethylamine (Et under whipped state
3n), mix, form mixing solutions, keep subsequently 15～25 ℃ of temperature to stir 16h, adopt ethyl acetate/normal heptane to form the mixing leacheate according to volume ratio 1/10 and carry out the separation of chromatography post, thick product continues with saturated sodium hydrogen carbonate solution and water washing, removes residual I-hydroxybenzotriazole, obtains respectively (1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles and (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles.
Described the 4th step is specially the product (1S that the 3rd step is obtained, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-methane amide pyrroles and (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 01 hexane-3-methane amide pyrroles mixes according to mol ratio 1: 1.0～1.5 with trifluoroacetic acid separately, carry out the amide hydrolysis under acidic conditions, keep subsequently 5 ℃ of reaction 2～4h of temperature, obtain respectively (1S, 3R, 5S)-2-azabicyclo [3, 1, 0] hexane-3-methane amide pyrroles and (1R, 3R, 5R)-2-azabicyclo [3, 1, 0] hexane-3-methane amide pyrroles.
Described the 4th step further is specially at N
2under protection, in the reaction flask of different dryings, add respectively the 3rd step to obtain (1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-methane amide pyrroles and (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-methane amide pyrroles, add subsequently methylene dichloride (DCM), maintain 5 ℃ and drip trifluoroacetic acid (TFA), dropwise rear stirring reaction 3h, add saturated ammonium chloride solution, concentrating under reduced pressure, obtain faint yellow solid, be respectively (1S, 3R, 5S)-2-azabicyclo [3, 1, 0] hexane-3-methane amide pyrroles and (1R, 3R, 5R)-2-azabicyclo [3, 1, 0] hexane-3-methane amide pyrroles.
Described the 5th step be specially product (1S, 3R, 5S) that the 4th step is obtained-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles and (1R, 3R, 5R)-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles separately with tetrahydrochysene lithium aluminium (LiAlH
4) according to mol ratio, be 1: 1.0～2.0 mixing, carry out the reduction reaction under alkaline condition, under the condition that the maintenance temperature is 15～25 ℃, react 2～4h, obtain (1S, 3R, 5S)-2-azabicyclo [3,1,0] hexane-3-methylpyrrole and (1R, 3R, 5R)-2-azabicyclo [3,1,0] hexane-3-methylpyrrole.
Described the 5th step further is preferably the product (1S that adds respectively the 4th step to obtain in the reaction flask of different dryings, 3R, 5S)-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles and (1R, 3R, 5R)-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles, add separately anhydrous tetrahydro furan, controlling temperature is 15～25 ℃, successively adds on a small quantity tetrahydrochysene lithium aluminium (LiAlH under whipped state
4), keep subsequently 15～25 ℃ of temperature to stir 4 hours, the concentrating under reduced pressure tetrahydrofuran (THF), drip 1% dilute hydrochloric acid after concentrated the end, divide and remove the upper strata organic layer, add again methylene dichloride (DCM) in water layer, then stir 10～20 minutes, divide the sub-cloud organic layer, add again methylene dichloride (DCM) in water layer, divide the sub-cloud organic layer, merge organic layer, and use appropriate anhydrous sodium sulfate drying, continue to be concentrated into dry, white solid, be respectively (1S, 3R, 5S)-2-azabicyclo [3, 1, 0] hexane-3-methylpyrrole and (1R, 3R, 5R)-2-azabicyclo [3, 1, 0] hexane-3-methylpyrrole.
The pyrrole derivative of the R-proline(Pro) with cyclopropane structure that the present invention also provides the synthetic method of the pyrrole derivative that adopts the above-mentioned R-proline(Pro) with cyclopropane structure to prepare is as the application of catalyzer.
Preferably adopt the pyrrole derivative of this R-proline(Pro) as the asymmetric Michael addition reaction of catalyst.
Below adopt embodiment to describe embodiments of the present invention in detail, to the present invention, how the utilisation technology means solve technical problem whereby, and the implementation procedure of reaching technique effect can fully understand and implement according to this.
Embodiment 1
The preparation of (1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-ethyl formate 1 and (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-ethyl formate 2
At N
2under protection, add (1R)-1-N-tertbutyloxycarbonyl-2 in two mouthfuls of reaction flasks of dry 250ml, (Shanghai Aladdin reagent company limited produces 3-dihydro-2-minaline ethyl ester, No. CAS: 72925-16-7) (24.1g, 0.1mol) be dissolved in 200ml methylene dichloride (DCM), be cooled to-15 ℃, drip zinc ethyl (Et
2zn) (1.2eq, 0.12mol), dropwise rear stirring reaction 0.5h, drips chloroiodomethane (CH
2clI) (1.1eq, 0.11mol) methylene dichloride (DCM) solution, holding temperature stirs 24h at-15 ℃, after completion of the reaction with adding ethylenediamine tetraacetic acid (EDTA) (EDTA) aqueous solution cancellation reaction that mass percentage concentration is 13%, be warming up to 25 ℃, stir 2h, standing 20 minutes, extraction, merge organic phase, obtain yellow oil, adding mass percentage concentration is that 30% diethylamine aqueous solution stirs 12h, concentrating under reduced pressure, the appropriate anhydrous sodium sulfate drying of organic layer, by ethyl acetate (EA)/normal heptane (h-heptane)=1/20 (volume ratio, ) elutriant carries out wash-out, wash-out is complete, till being collected into product point and substantially finishing.Faint yellow oily matter 1, i.e. (1S, 3R; 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-ethyl formate; 19.4g, faint yellow oily matter 2, i.e. (1R; 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1; 0] hexane-3-ethyl formate, 1.03g, the overall yield 80% of compound 1 and compound 2; the mol ratio of compound 1/ compound 2 > 25/1, this ratio is far above document (Bioorganic& Medicinal Chemistry Letters8 (1998) 2123-2128) the ratio 4:1 of report, prove that employing preparation method of the present invention is stronger to the selectivity of enantiomer.
The nuclear magnetic spectrogram data of (1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-ethyl formate 1 are:
1HNMR(400MHz，CDCl
3)：δ=1.19-1.35(3H，m)，1.40-1.54(9H，m)，2.53-2.75(2H，m)，2.95-3.18(2H，m)，4.10-4.33(2H，m)，4.50-4.70(1H，m)，4.85-4.99(1H，m)，6.46-6.71(1H，m)。
13CNMR(400MHz，CDCl
3)：δ=173.31，171.30，83.54，61.64，58.93，31.14，27.86，25.62，21.53，14.16。
The nuclear magnetic spectrogram data of (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-ethyl formate 2 are:
1HNMR(400MHz，CDCl
3)：δ=1.19-1.35(3H，m)，1.40-1.54(9H，m)，2.53-2.75(2H，m)，2.95-3.18(2H，m)，4.10-4.33(2H，m)，4.50-4.70(1H，m)，4.85-4.99(1H，m)，6.46-6.71(1H，m)。
13CNMR(400MHz，CDCl
3)：δ=173.31，171.30，83.54，61.64，58.93，31.14，27.86，25.62，21.53，14.16。
Fig. 1 is compound 1:(1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-ethyl formate and compound 2:(1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] high-efficient liquid phase chromatogram of hexane-3-ethyl formate, in figure, the material that the material of 17.62 peak reflections is compound 1,21.73 peak reaction is compound 2.
Embodiment 2
The preparation of (1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-formic acid 3
Add (1S in three mouthfuls of reaction flasks, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate 1 (25.5g, 0.10mol) and dehydrated alcohol, control temperature at 20 ℃, stir the lower aqueous solution that drips anhydrous (1.5eq0.15mol) lithium hydroxide (LiOH), 20 ℃ of insulated and stirred are about 16 hours subsequently, concentrating under reduced pressure ethanol, methylate tertbutyl ether (MTBE) after concentrated the end, divide and remove the upper strata organic layer, add again methylene dichloride (DCM) in water layer, 1N HCl regulator solution pH value is 1.5, then stir 20 minutes, divide the sub-cloud organic layer, add again DCM in water layer, divide the sub-cloud organic layer, merge organic layer, and use appropriate anhydrous sodium sulfate drying, continue to be concentrated into dry, add normal heptane, obtain yellow solid 3, i.e. (1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-formic acid 19.7g, productive rate 87%.
The nuclear magnetic spectrogram data of (1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-formic acid are:
1H?NMR(300MHz，CDCl
3)：δ=4.37-4.22(m，1H)，3.57-3.39(m，2H)，2.70-1.89(m，4H)，1.48-1.40(m，9H)。
Embodiment 3
The preparation of (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-formic acid 4
Add (1R in three mouthfuls of reaction flasks, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate 2 (2.55g, 0.01mol) and dehydrated alcohol, control temperature at 20 ℃, stir lower anhydrous lithium hydroxide (LiOH) aqueous solution (1.5eq0.015mol) that drips, 20 ℃ of insulated and stirred are about 16 hours subsequently, concentrating under reduced pressure ethanol, methylate tertbutyl ether (MTBE) after concentrated the end, divide and remove the upper strata organic layer, add again methylene dichloride (DCM) in water layer, 1N HCl regulator solution pH value is 1.5, then stir 20 minutes, divide the sub-cloud organic layer, add again DCM in water layer, divide the sub-cloud organic layer, merge organic layer, and use appropriate anhydrous sodium sulfate drying, continue to be concentrated into dry, add normal heptane, obtain yellow solid 4, i.e. (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-formic acid 1.8g, productive rate 86%.
The nuclear magnetic spectrogram data of (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-formic acid are:
1H?NMR(300MHz，CDCl
3)：δ=4.37-4.22(m，1H)，3.57-3.39(m，2H)，2.70-1.89(m，4H)，1.48-1.40(m，9H)。
Embodiment 4
(1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles's 5 preparation
Add (1S in three mouthfuls of reaction flasks of drying, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-formic acid 3 (2.27g, 10mmol), add methylene dichloride (50ml), controlling temperature is 25 ℃, adds respectively pyrroles (1.3mL under whipped state, 15mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloric acid (EDCI) (2.7g, 15mmol), I-hydroxybenzotriazole (HOBT) (1.9g, 15mmol), Et
3n (2.1mL, 15mmol), keep subsequently 25 ℃ of temperature to stir 16 hours, adopt ethyl acetate/normal heptane=1/10 (volume ratio) to mix leacheate and carry out the separation of chromatography post, thick product continues with saturated sodium hydrogen carbonate solution and water washing, remove residual I-hydroxybenzotriazole, obtain 1.91g (1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles 5, productive rate 70%.
(1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles's nuclear magnetic spectrogram data:
1H-NMR(400MHz，CDCl
3)δ=4.48-4.35(m，1H)，3.30-3.78(m，6H)，1.72-2.24(m，8H)，1.46-1.40(m，9H)
13C?NMR(100MHz，CDCl
3)：δ=170.5，66.2，56.4，45.7，41.8，34.3，18.2，15.1。
Embodiment 5
(1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles's 6 preparation
Add (1R in three mouthfuls of reaction flasks of drying, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-formic acid 4 (1.15g, 5mmol), add methylene dichloride (50ml), controlling temperature is 25 ℃, adds respectively morpholine (0.65mL under whipped state, 7.5mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloric acid (EDCI) (1.6g, 7.5mmol), I-hydroxybenzotriazole (HOBT) (0.98g, 7.5mmol), Et
3n (1.6mL, 7.5mmol), keep subsequently 25 ℃ of temperature to stir 16 hours, adopt ethyl acetate/normal heptane=1/10 (volume ratio) to mix leacheate and carry out the separation of chromatography post, thick product continues with saturated sodium hydrogen carbonate solution and water washing, remove residual I-hydroxybenzotriazole, obtain 0.95g (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-methane amide morpholine 6, productive rate 69%
(1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles's nuclear magnetic spectrogram data are:
1H-NMR(300MHz，CDCl
3)δ=4.29(1H，m)，3.46(1H，s)，3.38(1H，m)，2.97(1H，m)，2.85(1H，m)，2.57(2H，m)，2.49(2H，m)，1.87(1H，m)，1.79(2H，m)，1.38(9H，m)，1.34(1H，m)，1.27(1H，m)，1.14(1H，m)。
13C?NMR(100MHz，CDCl
3)：δ=171.5，158.1，80.1，66.2，56.4，45.7，41.8，34.3，29.3，18.2，15.1。
Embodiment 6
(1S, 3R, 5S)-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles's 7 preparation
At N
2under protection, in two mouthfuls of reaction flasks of dry 250ml, add (1S, 3R; 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3; 1,0] hexane-3-methane amide pyrroles 5 (2.80g, 10mmol) is dissolved in DCM (20ml); 5 ℃; drip trifluoroacetic acid (TFA) (1.2eq, 10mmol), dropwise rear stirring reaction 3h; add saturated ammonium chloride solution; dichloromethane extraction, concentrating under reduced pressure, faint yellow solid 7; i.e. (1S; 3R, 5S)-2-azabicyclo [3,1; 0] hexane-3-methane amide pyrroles 1.80g, productive rate 100%.
(1S, 3R, 5S)-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles's nuclear magnetic spectrogram data are:
1H-NMR(400MHz，CDCl
3)δ＝3.75(dd，J＝6.4，8.1Hz，1H)，3.34-3.58(m，4H)，3.19(m，1H)，2.82(m，1H)，2.52(brs，1H，NH)，2.09(m，1H)，1.59-2.03(m，7H)，
13C?NMR(100MHz，CDCl
3)：δ＝173.4，56.7，47.4，41.5，34.925.7，17.3，15.0。
Embodiment 7
(1R, 3R, 5R)-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles's 8 preparation
At N
2under protection, in two mouthfuls of reaction flasks of dry 250ml, add (1R, 3R; 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3; 1,0] hexane-3-methane amide pyrroles 6 (1.40g, 5mmol) be dissolved in methylene dichloride (DCM) (20ml) in; 5 ℃; drip trifluoroacetic acid (TFA) (1.2eq, 6mmol), dropwise rear stirring reaction 3h; add saturated ammonium chloride solution; dichloromethane extraction, concentrating under reduced pressure, faint yellow solid 8; i.e. (1R; 3R, 5R)-2-azabicyclo [3,1; 0] hexane-3-methane amide pyrroles 0.1g, productive rate 100%.
(1R, 3R, 5R)-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles's nuclear magnetic spectrogram data are:
1H-NMR(400MHz，CDCl
3)δ＝3.75(dd，J＝6.4，8.1Hz，1H)，3.34-3.58(m，4H)，3.19(m，1H)，2.82(m，1H)，2.52(brs，1H，NH)，2.09(m，1H)，1.59-2.03(m，7H)。
13C?NMR(100MHz，CDCl
3)：δ＝173.4，56.7，47.4，41.5，34.925.7，17.3，15.0。
Embodiment 8
The preparation of (1S, 3R, 5S)-2-azabicyclo [3,1,0] hexane-3-methylpyrrole 9
At N
2under protection; add (1S in two mouthfuls of reaction flasks of dry 250ml; 3R; 5S)-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles 7 (1.80g; 10mmol); add anhydrous tetrahydro furan (50ml), controlling temperature is 25 ℃, successively adds on a small quantity tetrahydrochysene lithium aluminium (LiAlH under whipped state
4) (0.38g, 10mmol), keep subsequently 25 ℃ of temperature to stir 4 hours, the concentrating under reduced pressure tetrahydrofuran (THF), drip 1% dilute hydrochloric acid (20ml) after concentrated the end, divides and remove the upper strata organic layer, add again methylene dichloride (20ml) in water layer, then stir 10 minutes, minute sub-cloud organic layer adds methylene dichloride (20ml) in water layer again, divide the sub-cloud organic layer, merge organic layer, and use appropriate anhydrous sodium sulfate drying, continue to be concentrated into dry, white solid, be (1S, 3R, 5S)-2-azabicyclo [3,1,0] hexane-3-methylpyrrole 9,1.56g, 95%.
The nuclear magnetic spectrogram data of (1S, 3R, 5S)-2-azabicyclo [3,1,0] hexane-3-methylpyrrole are:
1H-NMR(400MHz，CDCl
3)δ＝3.21(quintet，J＝6.7Hz，1H)，2.98(m，1H)，2.86(m，1H)，2.42-2.63(m，5H)，2.35(dd，J＝12Hz，J＝5.3Hz，1H)，1.88(m，1H)，1.53-1.80(m，6H)，1.24-1.41(m，1H)
13C?NMR(100MHz，CDCl
3)：δ＝60.5，54.4，54.0，36.5，35.3，23.7，18.2，15.9。
Embodiment 9
The preparation of (1R, 3R, 5R)-2-azabicyclo [3,1,0] hexane-3-methylpyrrole 10
At N
2under protection; add (1R in two mouthfuls of reaction flasks of dry 250ml; 3R; 5R)-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles 8 (0.90g; 5mmol); add anhydrous tetrahydro furan (50ml), controlling temperature is 25 ℃, successively adds on a small quantity tetrahydrochysene lithium aluminium (LiAlH under whipped state
4) (0.19g, 5mmol), keep subsequently 25 ℃ of temperature to stir 4 hours, the concentrating under reduced pressure tetrahydrofuran (THF), drip 1% dilute hydrochloric acid (20ml) after concentrated the end, divides and remove the upper strata organic layer, add again methylene dichloride (20ml) in water layer, then stir 10 minutes, minute sub-cloud organic layer adds methylene dichloride (20ml) in water layer again, divide the sub-cloud organic layer, merge organic layer, and use appropriate anhydrous sodium sulfate drying, continue to be concentrated into dry, white solid, be (1R, 3R, 5R)-2-azabicyclo [3,1,0] hexane-3-methylpyrrole 10,0.03_g, 94%.
The nuclear magnetic spectrogram data of (1R, 3R, 5R)-2-azabicyclo [3,1,0] hexane-3-methylpyrrole are:
1H-NMR(400MHz，CDCl
3)δ＝3.21(quintet，J＝6.7Hz，1H)，2.98(m，1H)，2.86(m，1H)，2.42-2.63(m，5H)，2.35(dd，J＝12Hz，J＝5.3Hz，1H)，1.88(m，1H)，1.53-1.80(m，6H)，1.24-1.41(m，1H)
13C?NMR(100MHz，CDCl
3)：δ＝60.5，54.4，54.0，36.5，35.3，23.7，18.2，15.9。
The compound (1S, 3R, 5S) that will be prepared by embodiment 8-2-azabicyclo [3,1,0] hexane-3-methylpyrrole is used for the asymmetric Michael addition reaction of catalysis as catalyzer, under its reaction formula and conditional filtering are shown in:
Add successively methylene dichloride (1mL) under 0 ℃ in the reaction flask of 3mL, catalyzer (0.01mmol), DIPEA DIPEA (1.75 μ L, 0.01mmol) and butyraldehyde-n (0.2mmol).System adds nitroethylene benzene substrate (0.2mmol) after stirring 5min.Keep subsequently reaction to carry out under 0 ℃, TLC monitoring reaction is until react complete.After reaction finishes, by Rotary Evaporators pressure reducing and steaming solvent.Crude product through silica gel column chromatography separate (sherwood oil PE: ethyl acetate EA=8:1) obtain catalysate 39.78mg, productive rate 90%, the ee value is 87%, the cis-selectivity of product obtains by the analysis of crude product nuclear-magnetism 1H NMR.The ee value of product is that the HPLC analysis by crossing the post product obtains.(Chiralcel?OD-H)，Hexane/i-PrOH＝91：9，UV230nm，0.9mL/min，syn：t
R1＝32.96min(major)and?t
R2＝24.73min(minor).
The nuclear magnetic spectrogram data of product are as follows:
1HNMR(400MHz，)δ9.71(d，J＝2.5Hz，1H)，7.72-7.04(m，5H)，4.67(ddd，J＝22.3，12.7，7.4Hz，2H)，3.79(td，J＝9.8，5.0Hz，1H)，2.68(dddd，J＝10.0，7.5，5.0，2.6Hz，1H)，1.58-1.44(m，2H)，0.83(t，J＝7.5Hz，3H).
Embodiment 11
The compound (1R, 3R, 5R) prepared divided by example 9-2-azabicyclo [3,1,0] compound (1S, 3R in hexane-3-methylpyrrole alternate example 10,5S)-2-azabicyclo [3,1,0] outside hexane-3-methylpyrrole, other steps are identical with embodiment 10, utilize 20 ℃ of best methylene dichloride of effect for the asymmetric Michael addition reaction of catalysis, obtain product 40.22mg, productive rate 91%, the ee value is 91%.
Embodiment 12
Divided by-20 ℃, as outside in the reaction conditions alternate embodiment 11 in embodiment 12 20 ℃, other step is identical with embodiment 10, for the asymmetric Michael addition reaction of catalysis, obtains product 39.78mg, productive rate 90%, and the ee value is 97%.
Comparative Examples 1
Divided by the S-proline(Pro), as a comparative example outside the catalyzer in 1 reaction conditions alternate embodiment 12, other step is identical with embodiment 10, for the asymmetric Michael addition reaction of catalysis, obtains product 35.73mg, productive rate 83%, and the ee value is 75%.
The catalysis experimental data is in Table 1.
Table 1
| Group | Temperature (℃) | Yield (%) | Ee(％) a |
| |
0 | 90％ | 87％ |
| Embodiment 11 | 20 | 91％ | 91％ |
| Embodiment 12 | -20 | 90％ | 97％ |
| Comparative Examples 1 | -20 | 83％ | 75％ |
aDetermined?by?chiral?HPLC?using?a?chiralpak?AD-H?column
All above-mentioned these intellecture properties of primary enforcement, do not set restriction this product innovation of other forms of enforcement and/or novel method.Those skilled in the art will utilize this important information, and foregoing is revised, to realize similar implementation status.But all modifications or transformation belong to the right of reservation based on product innovation of the present invention.
The above, be only preferred embodiment of the present invention, is not the present invention to be done to the restriction of other form, and any those skilled in the art may utilize the technology contents of above-mentioned announcement to be changed or be modified as the equivalent embodiment of equivalent variations.But every technical solution of the present invention content that do not break away from, any simple modification, equivalent variations and the remodeling above embodiment done according to technical spirit of the present invention, still belong to the protection domain of technical solution of the present invention.
Claims (10)
1. the pyrrole derivative chiral organic micromolecule compound with R-proline(Pro) of cyclopropane structure is characterized in that:
Described organic micromolecule compound structural formula is as shown in Formula I:
In Formula I, the chiral configuration of mark * carbon can be a kind of in R or S;
The chirality of C-1 and C-5 must be a kind of in R or S simultaneously.
2. the preparation method of the pyrrole derivative of the R-proline(Pro) with cyclopropane structure claimed in claim 1, is characterized in that, comprising:
The first step, with (R)-1-N-tertbutyloxycarbonyl-2,3-dihydro-2-minaline ethyl ester carries out the reaction of Simmons-Smith cyclopropane, obtains enantiomer;
Second step, the enantiomer that the first step is obtained is carried out respectively ester hydrolysis reaction;
The 3rd step, the reaction product that second step is obtained is carried out respectively amide condensed reaction;
The 4th step, the reaction product that the 3rd step is obtained is carried out respectively the deaminizating protective reaction;
The 5th step, the reaction product that the 4th step is obtained is carried out respectively reduction reaction; Acquisition has the pyrrole derivative of cyclopropane structure R-proline(Pro).
3. preparation method as claimed in claim 1, it is characterized in that: the described the first step is specially the tertbutyloxycarbonyl-2 by (R)-1-N-, 3-dihydro-2-minaline ethyl ester and zinc ethyl (ZnEt
2) and chloroiodomethane (CH
2clI) hybrid reaction, obtain enantiomer (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate and (1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate, the corresponding isomer mixture obtained adopts the aqueous solution of ethylenediamine tetraacetic acid (EDTA) and the amine aqueous solution to process, improve both enantioselectivity, enantiomer (1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate and (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] mol ratio of hexane-3-ethyl formate>25: 1, adopt subsequently the mixing leacheate of volume ratio ethyl acetate/normal heptane=1/20 to carry out the separation of chromatography post, obtain respectively product (1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate and (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate.
4. preparation method as claimed in claim 2 is characterized in that: in the described the first step, and (R)-1-N-tertbutyloxycarbonyl-2,3-dihydro-2-minaline ethyl ester and zinc ethyl (ZnEt
2) and chloroiodomethane (CH
2clI) according to mol ratio 1: 0.5～2: 1～2, mix, further preferably 1/0.5/1 or 1/1/1 or 1/1/2 or 1/2/2, maintain under the condition of temperature of reaction-20 ℃～-15 ℃, react 22～24h.
5. preparation method as described as claim 2 to 4, it is characterized in that: described second step is specially the (1S that the first step is obtained, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate and (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate separately with lithium hydroxide (LiOH) hybrid reaction, carry out the hydrolysis reaction under alkaline condition, obtain respectively (1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-formic acid and (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-formic acid.
6. preparation method as described as claim 2 to 5, it is characterized in that: described the 3rd step is specially the product (1S that second step is obtained, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-formic acid and (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-formic acid separately with pyrroles, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloric acid (EDCI), I-hydroxybenzotriazole (HOBT) and triethylamine (Et
3n) mix and carry out amidate action, obtain respectively (1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles and (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles.
7. preparation method as described as claim 2 to 6, it is characterized in that: described (1S, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-formic acid and (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-formic acid and pyrroles, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloric acid (EDCI), I-hydroxybenzotriazole (HOBT), triethylamine (Et
3n) molar reactive ratio is 1: 1.5～2.0: 1.5～2.0: 1.5～2.0: 1.5～2.0, and reaction conditions is 15～25 ℃ of reaction 14～16h for keeping temperature.
8. preparation method as described as claim 2 to 7, it is characterized in that: described the 4th step is specially the product (1S that the 3rd step is obtained, 3R, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-methane amide pyrroles and (1R, 3R, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-methane amide pyrroles mixes with trifluoroacetic acid separately, carry out the amide hydrolysis under acidic conditions, keep subsequently 5 ℃ of reaction 2～4h of temperature, obtain respectively (1S, 3R, 5S)-2-azabicyclo [3, 1, 0] hexane-3-methane amide pyrroles and (1R, 3R, 5R)-2-azabicyclo [3, 1, 0] hexane-3-methane amide pyrroles.
9. preparation method as described as claim 2 to 8, it is characterized in that: described the 5th step is specially the product (1S that the 4th step is obtained, 3R, 5S)-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles and (1R, 3R, 5R)-2-azabicyclo [3,1,0] hexane-3-methane amide pyrroles separately with tetrahydrochysene lithium aluminium (LiAlH
4) mix, carry out the reduction reaction under alkaline condition, obtain (1S, 3R, 5S)-2-azabicyclo [3,1,0] hexane-3-methylpyrrole and (1R, 3R, 5R)-2-azabicyclo [3,1,0] hexane-3-methylpyrrole.
10. the pyrrole derivative of the R-proline(Pro) with cyclopropane structure that adopts the described preparation method of claim 2 to 9 to prepare is as the application of catalyzer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013104119725A CN103450072A (en) | 2013-09-09 | 2013-09-09 | Pyrrole derivative of R-proline with cyclopropane structure and preparation method of pyrrole derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013104119725A CN103450072A (en) | 2013-09-09 | 2013-09-09 | Pyrrole derivative of R-proline with cyclopropane structure and preparation method of pyrrole derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103450072A true CN103450072A (en) | 2013-12-18 |
Family
ID=49732966
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2013104119725A Pending CN103450072A (en) | 2013-09-09 | 2013-09-09 | Pyrrole derivative of R-proline with cyclopropane structure and preparation method of pyrrole derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103450072A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104177284A (en) * | 2014-08-01 | 2014-12-03 | 常州大学 | Method for synthesizing 3-azabicyclo[3,1,0]hexyl-1-aldehyde |
| WO2023114200A3 (en) * | 2021-12-14 | 2023-07-27 | Alexion Pharmaceuticals, Inc. | Methods for the synthesis of complement factor d inhibitors and intermediates thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102753540A (en) * | 2009-12-29 | 2012-10-24 | 苏文生命科学有限公司 | A4ss2 neuronal nicotinic acetylcholine receptor ligands |
-
2013
- 2013-09-09 CN CN2013104119725A patent/CN103450072A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102753540A (en) * | 2009-12-29 | 2012-10-24 | 苏文生命科学有限公司 | A4ss2 neuronal nicotinic acetylcholine receptor ligands |
Non-Patent Citations (4)
| Title |
|---|
| JUAN M. BETANCORT 等: "Catalytic Direct Asymmetric Michael Reactions: Taming Naked Aldehyde Donors", 《ORG. LETT.》 * |
| PAUL HA-YEON CHEONG等: "Catalysis of the Hajos_Parrish_Eder_Sauer_Wiechert Reaction by cis- and trans-4,5-Methanoprolines: Sensitivity of Proline Catalysis to Pyrrolidine Ring Conformation", 《ADV. SYNTH. CATAL.》 * |
| STEPHEN HANESSIAN等: "Optimization of the Catalytic Asymmetric Addition of Nitroalkanes to Cyclic Enones with trans-4,5-Methano-L-proline", 《ORG. LETT.》 * |
| 李宁 等: "有机催化不对称Michael 加成反应", 《有机化学》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104177284A (en) * | 2014-08-01 | 2014-12-03 | 常州大学 | Method for synthesizing 3-azabicyclo[3,1,0]hexyl-1-aldehyde |
| CN104177284B (en) * | 2014-08-01 | 2016-08-24 | 常州大学 | The method of synthesis 3-azabicyclic [3,1,0] hexyl-1-formaldehyde |
| WO2023114200A3 (en) * | 2021-12-14 | 2023-07-27 | Alexion Pharmaceuticals, Inc. | Methods for the synthesis of complement factor d inhibitors and intermediates thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Wei-Li et al. | Novel functionalized guanidinium ionic liquids: Efficient acid–base bifunctional catalysts for CO2 fixation with epoxides | |
| CN103962183B (en) | A kind of PNN ligand-metal complex Catalysts and its preparation method and application | |
| CN101723771B (en) | Novel method for preparing beta-aminoketone, ester, nitrile and amide derivatives through catalysis of functional ionic liquid | |
| CN109718851B (en) | Chiral quaternary phosphonium salt phase transfer catalyst and preparation method and application thereof | |
| CN102892505B (en) | Chiral heterogeneous catalyst for asymmetric nitroaldol reaction | |
| CN103450072A (en) | Pyrrole derivative of R-proline with cyclopropane structure and preparation method of pyrrole derivative | |
| CN110615811B (en) | Method for preparing chiral sulfinamide monophosphine ligand in large scale | |
| CN110878099B (en) | Preparation method of pyrrole [1,2, alpha ] indole alkaloid derivative | |
| Zhao et al. | Cu-catalyzed enantioselective conjugate addition of diethylzinc to cyclic enones with chiral phosphite ligands derived from 1, 2: 5, 6-di-O-cyclohexylidene-d-mannitol | |
| CN103435536A (en) | Pyrrole derivative of S-proline having cyclopropane structure and preparation method of pyrrole derivative | |
| CN103467360A (en) | Morpholine derivative with R-proline in cyclopropane structure and preparation method thereof | |
| CN103435535A (en) | Preparation method of R-proline having cyclopropane structure | |
| EP3106453B1 (en) | Method for producing optically active compound, and novel metal-diamine complex | |
| CN103242375A (en) | High-activity bifunctional catalyst for preparing chiral epoxy alkane and diol and application thereof | |
| CN103450073A (en) | R-diphenyl prolinol chiral organic small molecule compound with cyclopropane structure and synthesis method of R-diphenyl prolinol chiral organic small molecule compound | |
| CN107721858B (en) | Method for catalyzing asymmetric alpha-benzoylation of beta-keto ester by phase transfer | |
| CN103467361A (en) | Morpholine derivative with S-proline in cyclopropane structure and preparation method thereof | |
| CN103450074A (en) | R-L-prolinol chiral organic small molecule compound with cyclopropane structure and synthesis method of R-L-prolinol chiral organic small molecule compound | |
| CN103435534A (en) | Preparation method of S-proline having cyclopropane structure | |
| CN103435533A (en) | Chiral organic small molecular compound of S-prolinol having cyclopropane structure and synthetic method of chiral organic small molecular compound | |
| CN107915653A (en) | Catalysis ester and amine carry out the method that reaction prepares acid amides | |
| CN102140071A (en) | Method for synthesizing 2-(4-tert-butyl-phenyl) malonic mononitrile (2-methoxyl) ethyl ester | |
| CN103787921B (en) | A kind of method preparing trans 1, the 2-ring diamines of high-optical-purity | |
| CN103467362A (en) | S-diphenyl prolinol chiral small organic molecular compound with cyclopropane structure and synthetic method thereof | |
| JP2005041791A (en) | OPTICALLY ACTIVE QUATERNARY AMMONIUM SALT, METHOD FOR PRODUCING THE SAME AND METHOD FOR PRODUCING OPTICALLY ACTIVE alpha-AMINO ACID DERIVATIVE USING THE SAME |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C05 | Deemed withdrawal (patent law before 1993) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20131218 |