CN101914051A - Synthesis method of 3-phenyl pyrroline derivatives with optical isomerism purity - Google Patents
Synthesis method of 3-phenyl pyrroline derivatives with optical isomerism purity Download PDFInfo
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Abstract
The invention discloses a synthesis method of 3-phenyl pyrroline derivatives with optical isomerism purity, which comprises the steps of: reacting with nitromethane to obtain nitroolefin, with substitutional aromatic aldehyde which is available at low price as a raw material; carrying out an asymmetric Micheal additive reaction with a 1,3-dicarboxy derivative in the presence of an asymmetric catalyst; and obtaining 3-phenyl pyrroline derivatives with optical isomerism purity through cyclization, hydrolysis, secondary cyclization, reduction and protective reaction. The synthesis method of the invention has the advantages of high yield, mild reaction conditions, simple post-processing and low cost, and is a synthesis path with industrial prospects.
Description
Technical field
The present invention relates to a kind of synthetic method of 3-phenylpyrrole quinoline derivant, relate in particular to the synthetic method of the pure 3-phenylpyrrole quinoline derivant of a kind of optical siomerism.
Background technology
The 3-phenylpyrrole quinoline derivant that optical siomerism is pure has following general formula:
Wherein, R2, R3, R4, R5 and R6 are independently selected from substituting groups such as hydrogen, methyl, methoxyl group, fluorine, trifluoromethyl, amino.
R1 is the substituting group on the nitrogen-atoms, can be hydrogen, tertbutyloxycarbonyl, carbobenzoxy-(Cbz), methoxycarbonyl, ethoxycarbonyl, ethanoyl, trifluoroacetyl group, trityl group etc.
The 3-phenylpyrrole quinoline derivant that optical siomerism is pure is a plurality of drug molecule core fragments with lateral reactivity, and a chiral centre is arranged in this structure, has two kinds of steric isomers to exist.In recent years, along with research and progress to aspects such as its pharmacological action and mechanism of action, Pharmaceutical Chemist is synthetic more and more interested in the pure 3-phenylpyrrole quinoline derivant of optical siomerism, the Stereoselective synthesizing process of the 3-phenylpyrrole quinoline derivant that especially optical siomerism is pure more becomes the hot fields of research.
The synthetic method of the 3-phenylpyrrole quinoline derivant that optical siomerism is pure mainly comprises following several:
(1). asymmetric [4+2] cycloaddition method
(J.Org.Chem., 1995,60,3221) such as Scott E.Denmark synthesize the pure 3-phenylpyrrole quinoline of optical siomerism by the vinyl ether of a chirality and [4+2] cycloaddition reaction of nitroolefin.But need to use stoichiometric MAPh (aluminium trimethide-two (2,6-phenylbenzene phenol oxide compound)) in this route, this reagent costs an arm and a leg and is difficult for preparation, makes this route can't realize mass preparation.
(2). the cyclization method of chiral raw material
The chirality Succinic Acid that this route utilizes phenyl to replace is raw material, synthesizes the pure 3-phenylpyrrole quinoline of optical siomerism.But it is very big that the chirality Succinic Acid that phenyl replaces prepares difficulty, makes this route be difficult to realize mass preparation (WO2005/37826).
(3). the asymmetric Michael addition reaction of acetaldehyde and nitroolefin
(Angew.Chem.int.Edi. such as Patricia G.Garcia, 2008,47,4719) reported the asymmetric Michael addition reaction of acetaldehyde and nitroolefin under the catalysis of (S)-diphenylprolinol trimethylsilyl ethers, can obtain the pure 3-phenylpyrrole quinoline of optical siomerism through the hydrogenation cyclization.This method productive rate height, stereoselectivity is good.But only mentioned the thinking of cyclization in the document, do not mentioned the details of cyclization step, Spectrum Analysis data or spectrogram are not provided yet, still still to be tested.
In sum, in recent years,, all exist to be difficult to industrialized unfavorable factor though the synthetic method report of the pure 3-phenylpyrrole quinoline derivant of some optical siomerisms has been arranged.
The present invention will propose a new stereoselectivity route, the 3-phenylpyrrole quinoline derivant that efficient quick ground synthesizing optical isomery is pure, and stereoselectivity is good, mild condition, aftertreatment is easy, is suitable for preparation of industrialization.
Summary of the invention
An object of the present invention is to provide the synthetic method of the pure 3-phenylpyrrole quinoline derivant of a kind of optical siomerism; this route is a raw material with the aromatic aldehyde of replacement cheap and easy to get; with Nitromethane 99Min. react nitroolefin; in the presence of asymmetric catalyst with 1; asymmetric Michael addition reaction takes place in 3-dicarboxyl derivative, through cyclization, and hydrolysis; the secondary cyclization, reduction and protective reaction obtain the pure 3-phenylpyrrole quinoline derivant of optical siomerism.
Synthetic route is as follows:
The preparation of nitroolefin 2 can referring to document (Org.Lett., 2008,10,1389-1391), as solvent, ammonium acetate is as alkali with acetic acid in this reaction, the phenyl aldehyde that replaces and Nitromethane 99Min. are mixed and heated to backflow can be made.
The aromatic aldehyde that replaces has following structure:
R2, R3, R4, R5 and R6 are independently selected from substituting groups such as hydrogen, methyl, methoxyl group, fluorine, trifluoromethyl, amino.
The Michael addition reaction is the important reaction that makes up carbon-carbon bond, compound with α-reactive hydrogen atom, under the effect of alkali, form carbanion, this carbanion can with α, the nucleophilic addition(Adn) of beta-unsaturated carbonyl compound generation conjugation, produce the nucleophilic reagent of carbanion, connect two electron withdrawing groups in its methylene radical both sides, as: ester group, cyano group, carbonyl etc., perhaps only connect a strong electron-withdrawing group, as: nitro etc., these electron-withdrawing groups can help to hold the negative charge of carbanion, make carbanion stable, and be easy to produce.The Michael addition reaction of asymmetry catalysis is the synthetic numerous important chiral synthons and the effective means of pharmaceutical intermediate, has become chiral molecules synthetic important method.The organic catalyst of the asymmetric Michael addition reaction of catalysis mainly contains proline(Pro) and derivative thereof, chiral imidazolidinone, chirality (sulphur) urea, quinine derivative etc.
Asymmetric Michael addition reaction of the present invention is in reaction solvent, under temperature of reaction, add intermediate 2 and 1,2-dicarboxyl compounds, add again chiral catalyst nickelous bromide (II)-two [(S, S)-N, N ' dibenzyl cyclohexyl-1, the 2-diamines] title complex or nickelous bromide (II)-two [(R, R)-N, N '-dibenzyl cyclohexyl-1, the 2-diamines] title complex, until reacting completely.Reaction solvent is a tetrahydrofuran (THF), ethyl acetate, and methylene dichloride, one or more of toluene and ethanol, its consumption are 5-100 times of reaction substrate weight, are preferably 10-50 doubly; 1,2-dicarboxyl compounds is selected from: one or more of dimethyl malonate, diethyl malonate, Diisopropyl malonate, propanedioic acid diisobutyl ester and propanedioic acid dibenzyl ester, its consumption is a 0.5-3 times of molar weight of intermediate 2, is preferably 1-2 times of molar weight; Chiral catalyst nickelous bromide (II)-two [(S, S)-N, N '-dibenzyl cyclohexyl-1, the 2-diamines] title complex or nickelous bromide (II)-two [(S, S)-and N, N '-dibenzyl cyclohexyl-1,2-diamines] title complex, its consumption is the 0.1%-30% molar weight of intermediate 2, is preferably the 0.5-20% molar weight; Temperature of reaction is-the 20-50 degree, is preferably the 0-25 degree.
In asymmetric Michael addition reaction, the chiral catalyst of use has following structure:
Its English chemistry is by name:
Nickel (II)-bis[(S, S)-N, N '-dibenzylcyclohexane-1,2-diamine] Br
2The chinesization formal name used at school: nickelous bromide (II)-two [(S, S)-N, N '-dibenzyl cyclohexyl-1,2-diamines] title complex or following structure:
Its English chemistry is by name:
Nickel(II)-bis[(R，R)-N，N’-dibenzylcyclohexane-1，2-diamine]Br
2
The chinesization formal name used at school: nickelous bromide (II)-two [(R, R)-N, N '-dibenzyl cyclohexyl-1,2-diamines] title complex
The synthetic method of chiral catalyst is seen J.Am.Chem.Soc.2007,129, and 11583-11592
In the ring-closure reaction, nitro at first is reduced into amino, spontaneous intramolecular cyclization takes place then obtain product.Ring-closure reaction is with palladium-carbon, and palladium hydroxide-carbon or Raney's nickel are catalyzer, hydrogen, and ammonium formate, hydrazine hydrate etc. are hydrogen source.Catalyst consumption is the 1-100% weight of substrate, is preferably 5-20% weight.
Hydrolysis reaction at first in alkaline aqueous solution with the ester hydrolysis, the alkali that uses is sodium hydroxide, potassium hydroxide or lithium hydroxide etc., consumption is a 1-20 times of equivalent of substrate, is preferably 2-10 times of equivalent, decarboxylation obtains intermediate 5 in hydrochloric acid then.
The secondary ring-closure reaction carries out in high boiling solvent, forms lactan, and high boiling solvent is a toluene, dimethylbenzene or chlorobenzene etc.
Reduction reaction is the reaction that lactan is reduced to amine in the presence of reductive agent and additive, reductive agent is a lithium aluminium hydride, one or more of sodium borohydride and POTASSIUM BOROHYDRIDE, additive are iodine, boron trifluoride diethyl etherate, aluminum chloride, one or more of trifluoracetic acid and titanium tetrachloride, reductive agent consumption are 1-10 times of equivalent of substrate, are preferably 2-5 times of equivalent, the consumption of additive is a 0.1-5 times of equivalent of substrate, is preferably 0.5-2 times of equivalent.
Protective reaction is to introduce various protecting groups on the free nitrogen-atoms, as: tertbutyloxycarbonyl, carbobenzoxy-(Cbz), methoxycarbonyl, ethoxycarbonyl, ethanoyl, trifluoroacetyl group or trityl group.
The beneficial effect that the present invention realizes:
An object of the present invention is to provide the synthetic method of the pure 3-phenylpyrrole quinoline derivant of a kind of optical siomerism; this route is a raw material with substituted aroma aldehyde cheap and easy to get; with Nitromethane 99Min. react nitroolefin; in the presence of asymmetric catalyst with 1; asymmetric Michael addition reaction takes place in 3-dicarboxyl derivative, through cyclization, and hydrolysis; the secondary cyclization, reduction and protective reaction obtain the pure 3-phenylpyrrole quinoline derivant of optical siomerism.
Synthetic method of the present invention has the productive rate height, the reaction conditions gentleness, and advantage such as aftertreatment is easy, and is with low cost is a synthetic route with industrial prospect.
Embodiment
Below describe technical scheme of the present invention in detail.Only for the explanation concrete grammar, its scale of this method is not subjected to the restriction of embodiment to the embodiment of the invention.
Embodiment 1 (R)-3-phenylpyrrole quinoline
In the flask of 2L, (29.06g 0.377mol), stirs, and it is mixed to add 540ml acetate and amine acetate.(200g 1.887mol), drips the 360ml Nitromethane 99Min. at last to add benzene feedstock formaldehyde again.Under the nitrogen protection, stir and be warming up to 100 ℃.Intact until the raw material total overall reaction, remove heating unit, cooling, after join in the frozen water of 2700ml, stir, and suction filtration, water is given a baby a bath on the third day after its birth time, washes once with sodium bicarbonate again, last water is washed once again, intermediate (E)-(2-nitroolefin) benzene 110.4g.
(110g 0.7375mol) adds in the flask of 2L with acetic acid ethyl dissolution, adds nickelous bromide (II)-two [(S with (E)-(2-nitroolefin) benzene, S)-and N, N '-dibenzyl cyclohexyl-1,2-diamines] title complex 20g, add again diethyl malonate (124g, 0.7744mol), stirring at room to reaction finishes, wash with water, layering, organic phase with the saturated common salt washing once, are used anhydrous sodium sulfate drying again, filter, concentrate product
(R)-2-(2-nitro-1-phenylethyl) diethyl malonate 116.2g
With (R)-2-(2-nitro-1-phenylethyl) dimethyl malonate (116.2g, 0.376mol) with 95% dissolve with ethanol of 500ml, join in the flask of 2L, add Raney-Ni 37g again, fill into hydrogen, normal-temperature reaction finishes to reaction, elimination Raney-Ni, concentrate intermediate (3R)-ethyl 2-oxa--4-phenylpyrrole quinoline-3-carboxylic acid 77g.
(151g 0.6472mol) adds in the flask of 2L, adds 6N HCl 1.5L, is heated to backflow with (3R)-ethyl 2-oxa--4-phenylpyrrole quinoline-3-carboxylic acid.Reaction finishes, and suction filtration is removed solid, concentrates to remove moisture, gets (R)-4-amino-3-phenylbutyric acid hydrochloride 60.8g.
(50g 0.279mol) is suspended in 500ml toluene and the 150ml triethylamine, and backflow is spent the night, and the system concentrating under reduced pressure gets (R)-4-phenylpyrrole quinoline-2-ketone 37.5g with (R)-4-amino-3-phenylbutyric acid hydrochloride.
Get the there-necked flask of 1L, with (R)-4-phenylpyrrole quinoline-2-ketone (37.5g, 0.21404mol) dissolve among the THF of 75ml, (16.27g 0.42mol), is back to reaction and finishes to add Lithium Aluminium Hydride, add the cancellation of NaOH solution, suction filtration is removed solid, filtrate concentrate (R)-3-phenylpyrrole quinoline 30g.Proton nmr spectra (500MHz, CDCl3) δ H 7.0-7.3 (m, 5H), 3.1-4.0 (m, 5H), 2.0-2.5 (m, 2H); Mass spectrum m/z (CI+) 148 (100%, MH+). chiral high performance liquid chromatography analysis condition: Daicel chiral chromatographic column Chiracel AD-H column (250*4.6mm i.d.), moving phase is normal hexane: Virahol (90: 10), detect wavelength 210nm, sample size 1 microlitre, column temperature 28 degree, flow velocity 1.0ml/min.Physics and chemistry and this compound of Spectrum Analysis digital proof are target compound (R)-3-phenylpyrrole quinoline.
Embodiment 2 (S)-3-phenylpyrrole quinoline
Operation is with embodiment 1, and asymmetric catalyst is nickelous bromide (II)-two [(R, R)-N, N '-dibenzyl cyclohexyl-1, a 2-diamines] title complex.Proton nmr spectra (500MHz, CDCl3) δ H 7.0-7.3 (m, 5H), 3.1-4.0 (m, 5H), 2.0-2.5 (m, 2H); Mass spectrum m/z (CI+) 148 (100%, MH+). chiral high performance liquid chromatography analysis condition: Daicel chiral chromatographic column Chiracel AD-H column (250*4.6mm i.d.), moving phase is normal hexane: Virahol (90: 10), detect wavelength 210nm, sample size 1 microlitre, column temperature 28 degree, flow velocity 1.0ml/min.Physics and chemistry and this compound of Spectrum Analysis digital proof are target compound (S)-3-phenylpyrrole quinoline.
Embodiment 3 (S)-3-phenylpyrrole quinoline hydrochloride
(30g 0.1873mol) is dissolved in anhydrous diethyl ether, feeds HCl gas, and the adularescent solid is separated out, and filters, and solid i.e. (S)-3-phenylpyrrole quinoline hydrochloride, the dry 24g that gets with (S)-3-phenylpyrrole quinoline.Proton nmr spectra (500MHz, MeOD) δ H 7.0-7.3 (m, 5H), 3.8-4.0 (m, 4H), 3.14 (t, 1H), 2.2-2.5 (m, 2H); Mass spectrum m/z (CI+) 148 (100%, MH+).Physics and chemistry and this compound of Spectrum Analysis digital proof are target compound (S)-3-phenylpyrrole quinoline hydrochloride.
Embodiment 4 (the R)-tertiary butyl-3-phenylpyrrole quinoline-1-carboxylic acid
(R)-3-phenylpyrrole quinoline (20g) is dissolved in methylene dichloride 300ml, adds the reaction of triethylamine (20ml) and Boc acid anhydrides (25g) under the room temperature and spend the night.Reaction system is through washing, and concentrating under reduced pressure gets 34g (R)-tertiary butyl-3-phenylpyrrole quinoline-1-carboxylic acid.Proton nmr spectra (500MHz, CDCl3) δ H 7.0-7.3 (m, 5H), 3.5-4.0 (m, 4H), 3.2 (t, 1H), 2.0-2.5 (m, 2H), 1.45 (s, 9H); Mass spectrum m/z (CI+) 248 (100%, MH+).Chiral high performance liquid chromatography analysis condition: Daicel chiral chromatographic column Chiracel AD-H column (250*4.6mm i.d.), moving phase is normal hexane: Virahol (95: 5), detect wavelength 210nm, sample size 1 microlitre, column temperature 28 degree, flow velocity 1.0ml/min.Physics and chemistry and this compound of Spectrum Analysis digital proof are target compound (R)-tertiary butyl-3-phenylpyrrole quinoline-1-carboxylic acid.
Embodiment 5 (R)-3-p-methylphenyl pyrroline
Operation is with embodiment 1, and raw material is a p-tolyl aldehyde, and asymmetric catalyst is nickelous bromide (II)-two [(S, S)-N, N '-dibenzyl cyclohexyl-1, a 2-diamines] title complex.Proton nmr spectra (500MHz, CDCl3) δ H 7.0-7.3 (m, 4H), 3.1-4.0 (m, 5H), 2.7 (s, 3H), 2.0-2.5 (m, 2H); Mass spectrum m/z (CI+) 162 (100%, MH+). chiral high performance liquid chromatography analysis condition: Daicel chiral chromatographic column ChiracelAD-H column (250*4.6mm i.d.), moving phase is normal hexane: Virahol (90: 10), detect wavelength 210nm, sample size 1 microlitre, column temperature 28 degree, flow velocity 1.0ml/min.Physics and chemistry and this compound of Spectrum Analysis digital proof are target compound (R)-3-p-methylphenyl pyrroline.
Embodiment 6 (R)-3-(3-p-methoxy-phenyl) pyrroline
Operation is with embodiment 1, and raw material is the 3-methoxybenzaldehyde, and asymmetric catalyst is nickelous bromide (II)-two [(S, S)-N, N '-dibenzyl cyclohexyl-1, a 2-diamines] title complex.Proton nmr spectra (500MHz, CDCl3) δ H 7.0-7.3 (m, 4H), 3.8 (s, 3H), 3.1-4.0 (m, 5H), 2.0-2.5 (m, 2H); Mass spectrum m/z (CI+) 178 (100%, MH+). chiral high performance liquid chromatography analysis condition: Daicel chiral chromatographic column ChiracelAD-H column (250*4.6mm i.d.), moving phase is normal hexane: Virahol (90: 10), detect wavelength 210nm, sample size 1 microlitre, column temperature 28 degree, flow velocity 1.0ml/min.Physics and chemistry and this compound of Spectrum Analysis digital proof are target compound (R)-3-(3-p-methoxy-phenyl) pyrroline.
Embodiment 7 (R)-3-(2, the 5-difluorophenyl) pyrroline
Operation is with embodiment 1, and raw material is 2, and 5-difluorophenyl phenyl aldehyde, asymmetric catalyst are nickelous bromide (II)-two [(S, S)-N, N '-dibenzyl cyclohexyl-1,2-diamines] title complex.Proton nmr spectra (500MHz, CDCl3) δ H 6.8-7.3 (m, 3H), 3.1-4.0 (m, 5H), 2.0-2.5 (m, 2H); Mass spectrum m/z (CI+) 184 (100%, MH+). chiral high performance liquid chromatography analysis condition: Daicel chiral chromatographic column Chiracel AD-Hcolumn (250*4.6mm i.d.), moving phase is normal hexane: Virahol (99: 1), detect wavelength 210nm, sample size 1 microlitre, column temperature 28 degree, flow velocity 1.0ml/min.Physics and chemistry and this compound of Spectrum Analysis digital proof are target compound (R)-3-(2, the 5-difluorophenyl) pyrroline
Embodiment 8 (R)-3-(4-(trifluoromethyl) phenyl) pyrroline
Operation is with embodiment 1, and raw material is 4-(trifluoromethyl) phenyl aldehyde, and asymmetric catalyst is nickelous bromide (II)-two [(S, S)-N, N '-dibenzyl cyclohexyl-1, a 2-diamines] title complex.Proton nmr spectra (500MHz, CDCl3) δ H 6.8-7.3 (m, 4H), 3.1-4.0 (m, 5H), 2.0-2.5 (m, 2H); Mass spectrum m/z (CI+) 216 (100%, MH+). chiral high performance liquid chromatography analysis condition: Daicel chiral chromatographic column Chiracel AD-H column (250*4.6mm i.d.), moving phase is normal hexane: Virahol (98: 2), detect wavelength 210nm, sample size 1 microlitre, column temperature 28 degree, flow velocity 1.0ml/min.Physics and chemistry and this compound of Spectrum Analysis digital proof are target compound (R)-3-(4-(trifluoromethyl) phenyl) pyrroline
Embodiment 9 (S)-3-(3-(trifluoromethyl) phenyl) pyrroline
Operation is with embodiment 1, and raw material is 3-(trifluoromethyl) phenyl aldehyde, and asymmetric catalyst is nickelous bromide (II)-two [(R, R)-N, N '-dibenzyl cyclohexyl-1, a 2-diamines] title complex.Proton nmr spectra (500MHz, CDCl3) δ H 6.8-7.3 (m, 4H), 3.1-4.0 (m, 5H), 2.0-2.5 (m, 2H); Mass spectrum m/z (CI+) 216 (100%, MH+). chiral high performance liquid chromatography analysis condition: Daicel chiral chromatographic column Chiracel AD-H column (250*4.6mm i.d.), moving phase is normal hexane: Virahol (98: 2), detect wavelength 210nm, sample size 1 microlitre, column temperature 28 degree, flow velocity 1.0ml/min.Physics and chemistry and this compound of Spectrum Analysis digital proof are target compound (S)-3-(3-(trifluoromethyl) phenyl) pyrroline
Embodiment 10 (S)-3-(4-fluorophenyl) pyrroline
Operation is with embodiment 1, and raw material is the 4-fluorobenzaldehyde, and asymmetric catalyst is nickelous bromide (II)-two [(R, R)-N, N '-dibenzyl cyclohexyl-1, a 2-diamines] title complex.Proton nmr spectra (500MHz, CDCl3) δ H 7.1-7.3 (m, 4H), 3.1-4.0 (m, 5H), 2.0-2.5 (m, 2H); Mass spectrum m/z (CI+) 166 (100%, MH+). chiral high performance liquid chromatography analysis condition: Daicel chiral chromatographic column Chiracel AD-H column (250*4.6mm i.d.), moving phase is normal hexane: Virahol (97: 3), detect wavelength 210nm, sample size 1 microlitre, column temperature 28 degree, flow velocity 1.0ml/min.Physics and chemistry and this compound of Spectrum Analysis digital proof are target compound (S)-3-(3-(trifluoromethyl) phenyl) pyrroline
Embodiment 11 (S)-3-(3, the 5-Dimethoxyphenyl) pyrroline
Operation is with embodiment 1, and raw material is 3, and 5-dimethoxy benzaldehyde, asymmetric catalyst are nickelous bromide (II)-two [(R, R)-N, N '-dibenzyl cyclohexyl-1,2-diamines] title complex.Proton nmr spectra (500MHz, CDCl3) δ H 7.1-7.3 (s, 3H), 3.85 (s, 3H), 3.79 (s, 3H), 3.1-4.0 (m, 5H), 2.0-2.5 (m, 2H); Mass spectrum m/z (CI+) 208 (100%, MH+). chiral high performance liquid chromatography analysis condition: Daicel chiral chromatographic column Chiracel AD-H column (250*4.6mm i.d.), moving phase is normal hexane: Virahol (95: 5), detect wavelength 210nm, sample size 1 microlitre, column temperature 28 degree, flow velocity 1.0ml/min.Physics and chemistry and this compound of Spectrum Analysis digital proof are target compound (S)-3-(3, the 5-Dimethoxyphenyl) pyrroline.
Claims (12)
1. the synthetic method of the 3-phenylpyrrole quinoline derivant that an optical siomerism is pure, it is characterized in that the aromatic aldehyde to replace is a raw material, with Nitromethane 99Min. react nitroolefin, in the presence of asymmetric catalyst with 1, asymmetric Michael addition reaction takes place in 3-dicarboxyl derivative, through cyclization, and hydrolysis, the secondary cyclization, reduction and protective reaction obtain the pure 3-phenylpyrrole quinoline derivant of optical siomerism; The aromatic aldehyde of described replacement has following structure:
R2, R3, R4, R5 and R6 are independently selected from hydrogen, methyl, methoxyl group, fluorine, trifluoromethyl or amino.
2. the synthetic method of the 3-phenylpyrrole quinoline derivant that optical siomerism according to claim 1 is pure, it is characterized in that described asymmetric Michael addition reaction is in reaction solvent, at following described nitroolefin and 1 of temperature of reaction, 2-dicarboxyl compounds, add chiral catalyst nickelous bromide (II)-two [(S again, S)-N, N '-dibenzyl cyclohexyl-1, the 2-diamines] title complex or nickelous bromide (II)-two [(R, R)-N, N '-dibenzyl cyclohexyl-1, the 2-diamines] title complex, until reacting completely.
3. the synthetic method of the 3-phenylpyrrole quinoline derivant that optical siomerism according to claim 2 is pure is characterized in that described reaction solvent is a tetrahydrofuran (THF), ethyl acetate, methylene dichloride, one or more of toluene and ethanol.
4. the synthetic method of the 3-phenylpyrrole quinoline derivant that optical siomerism according to claim 2 is pure is characterized in that 5-100 that described reaction solvent consumption is a reaction substrate weight doubly.
5. the synthetic method of the 3-phenylpyrrole quinoline derivant that optical siomerism according to claim 2 is pure, it is characterized in that described 1,2-dicarboxyl compounds is one or more of dimethyl malonate, diethyl malonate, Diisopropyl malonate, propanedioic acid diisobutyl ester and propanedioic acid dibenzyl ester, and consumption is a 0.5-3 times of molar weight of described nitroolefin.
6. the synthetic method of the 3-phenylpyrrole quinoline derivant that optical siomerism according to claim 2 is pure, it is characterized in that described chiral catalyst nickelous bromide (II)-two [(S, S)-N, N '-dibenzyl cyclohexyl-1, the 2-diamines] title complex or nickelous bromide (II)-two [(S, S)-N, N '-dibenzyl cyclohexyl-1, the 2-diamines] title complex, consumption is described nitroolefin 0.1%-30% molar weight.
7. the synthetic method of the 3-phenylpyrrole quinoline derivant that optical siomerism according to claim 1 is pure, it is characterized in that in the described ring-closure reaction, with palladium-carbon, one or more of palladium hydroxide-carbon and Raney's nickel are catalyzer, with hydrogen, one or more of ammonium formate and hydrazine hydrate are hydrogen source, and described catalyst consumption is the 1-100% of substrate weight.
8. the synthetic method of the 3-phenylpyrrole quinoline derivant that optical siomerism according to claim 1 is pure, it is characterized in that the alkali that described hydrolysis reaction uses is selected from sodium hydroxide, one or more of potassium hydroxide and lithium hydroxide, consumption are 1-20 times of equivalent of substrate.
9. the synthetic method of the 3-phenylpyrrole quinoline derivant that optical siomerism according to claim 1 is pure is characterized in that described secondary ring-closure reaction at toluene, carries out in the high boiling solvents such as dimethylbenzene or chlorobenzene.
10. the synthetic method of the 3-phenylpyrrole quinoline derivant that optical siomerism according to claim 1 is pure is characterized in that described reduction reaction is in the presence of reductive agent and additive lactan to be reduced to amine.
11. the synthetic method of the 3-phenylpyrrole quinoline derivant that optical siomerism according to claim 10 is pure is characterized in that described reductive agent is a lithium aluminium hydride, one or more of sodium borohydride and POTASSIUM BOROHYDRIDE, consumption are 1-10 times of equivalent of reaction substrate.
12. the synthetic method of the 3-phenylpyrrole quinoline derivant that optical siomerism according to claim 10 is pure, it is characterized in that described additive is an iodine, boron trifluoride diethyl etherate, aluminum chloride, one or more of trifluoracetic acid and titanium tetrachloride, consumption are 0.1-5 times of equivalent of reaction substrate.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110511170A (en) * | 2019-09-10 | 2019-11-29 | 杭州澳赛诺生物科技有限公司 | A kind of synthetic method of chirality nafoxidine -3- carboxylic acid |
| CN111393312A (en) * | 2020-03-11 | 2020-07-10 | 福建科宏生物工程股份有限公司 | Preparation method for synthesizing 4-amino-3-phenylbutyric acid hydrochloride by one-pot method and product prepared by same |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2005037826A1 (en) * | 2003-10-17 | 2005-04-28 | Incyte Corporation | Substituted cyclic hydroxamates as inhibitors of matrix metalloproteinases |
| CN101747252A (en) * | 2009-12-28 | 2010-06-23 | 嘉兴宜博生物医药科技有限公司 | Synthetic method of R-structured Rolipram |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005037826A1 (en) * | 2003-10-17 | 2005-04-28 | Incyte Corporation | Substituted cyclic hydroxamates as inhibitors of matrix metalloproteinases |
| CN101747252A (en) * | 2009-12-28 | 2010-06-23 | 嘉兴宜博生物医药科技有限公司 | Synthetic method of R-structured Rolipram |
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| 《药物合成技术》 20090131 唐跃平等 酰胺还原为胺 人民卫生出版社 172-174 1-12 , 1 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110511170A (en) * | 2019-09-10 | 2019-11-29 | 杭州澳赛诺生物科技有限公司 | A kind of synthetic method of chirality nafoxidine -3- carboxylic acid |
| CN111393312A (en) * | 2020-03-11 | 2020-07-10 | 福建科宏生物工程股份有限公司 | Preparation method for synthesizing 4-amino-3-phenylbutyric acid hydrochloride by one-pot method and product prepared by same |
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