CN101914051B - 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 the research and development 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, the expensive and difficult preparation of this reagent is so that this route can't be realized extensive preparation.
(2). the cyclization method of chiral raw material
This route utilizes the chirality Succinic Acid of phenyl substituted to be raw material, synthesizes the pure 3-phenylpyrrole quinoline of optical siomerism.But it is very large that the chirality Succinic Acid of phenyl substituted prepares difficulty, so that this route is difficult to realize extensive preparation (WO2005/37826).
(3). the asymmetric Michael addition reaction of acetaldehyde and nitroolefin
(the Angew.Chem.int.Edi. such as Patricia G.Garcia, 2008,47,4719) report 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.The method productive rate is high, and 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, although the synthetic method report of the pure 3-phenylpyrrole quinoline derivant of some optical siomerisms has been arranged, all exist to be difficult to industrialized unfavorable factor.
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 take the aromatic aldehyde of replacement cheap and easy to get as raw material; react to get nitroolefin with Nitromethane 99Min.; in the presence of asymmetric catalyst with 1; asymmetric Michael addition reaction occurs 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, so that carbanion is stable, and be easy to produce.The Michael addition reaction of asymmetry catalysis is synthetic numerous important chiral synthons and the effective means of pharmaceutical intermediate, has become the synthetic important method of chiral molecules.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 adds chiral catalyst nickelous bromide (II)-two [(S, S)-N again, 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 react completely.Reaction solvent is tetrahydrofuran (THF), ethyl acetate, and methylene dichloride, one or more of toluene and ethanol, its consumption is 5-100 times of reaction substrate weight, is 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 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)-and N, N '-dibenzylcyclohexane-1,2-diamine] Br
2Chinesization 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
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.2007,129,11583-11592
In the ring-closure reaction, nitro at first is reduced into amino, then spontaneous intramolecular cyclization occurs 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.The consumption of catalyzer is the 1-100% weight of substrate, is preferably 5-20% weight.
Hydrolysis reaction at first is hydrolyzed ester in alkaline aqueous solution, and the alkali that uses is sodium hydroxide, potassium hydroxide or lithium hydroxide etc., and consumption is 1-20 times of equivalent of substrate, is preferably 2-10 times of equivalent, then decarboxylation obtains intermediate 5 in hydrochloric acid.
The secondary ring-closure reaction carries out in high boiling solvent, forms lactan, and high boiling solvent is 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 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 0.1-5 times of equivalent of substrate, is preferably 0.5-2 times of equivalent.
Protective reaction is to introduce various protecting groups at 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 take substituted aroma aldehyde cheap and easy to get as raw material; react to get nitroolefin with Nitromethane 99Min.; in the presence of asymmetric catalyst with 1; asymmetric Michael addition reaction occurs 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 advantages such as synthetic method of the present invention has the productive rate height, and reaction conditions is gentle, and aftertreatment is easy, and is with low cost are synthetic routes with industrial prospect.
Embodiment
Below describe technical scheme of the present invention in detail.Only for the explanation concrete grammar, its scale of the 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, add 540ml acetic acid and amine acetate (29.06g, 0.377mol), stir, it is mixed.Add again benzene feedstock formaldehyde (200g, 1.887mol), drip at last the 360ml Nitromethane 99Min..Under the nitrogen protection, stir and be warming up to 100 ℃.Until the raw material total overall reaction is complete, remove heating unit, the cooling, after join in the frozen water of 2700ml, stir, and suction filtration, wash with water three times, wash once with sodium bicarbonate, last water is washed once again, gets intermediate (E)-(2-nitroolefin) benzene 110.4g again.
(E)-(2-nitroolefin) benzene (110g, 0.7375mol) is added with acetic acid ethyl dissolution in the flask of 2L, add nickelous bromide (II)-two [(S, S)-and N, N '-dibenzyl cyclohexyl-1,2-diamines] title complex 20g, add diethyl malonate (124g, 0.7744mol), stirring at room to reaction finishes again, wash with water, layering, organic phase with the saturated common salt washing once, are used anhydrous sodium sulfate drying again, filter, concentrate to get 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 again Raney-Ni 37g, be charged into hydrogen, normal-temperature reaction finishes to reaction, and elimination Raney-Ni concentrates to get intermediate (3R)-ethyl 2-oxa--4-phenylpyrrole quinoline-3-carboxylic acid 77g.
(3R)-ethyl 2-oxa--4-phenylpyrrole quinoline-3-carboxylic acid (151g, 0.6472mol) is added in the flask of 2L, add 6N HCl 1.5L, be heated to backflow.Reaction finishes, and suction filtration is removed solid, and is concentrated except moisture, gets (R)-4-Amino-3-phenylbutyric acid hydrochloride 60.8g.
(R)-4-Amino-3-phenylbutyric acid hydrochloride (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.
Get the there-necked flask of 1L, with (R)-4-phenylpyrrole quinoline-2-ketone (37.5g, 0.21404mol) dissolve among the THF of 75ml, add Lithium Aluminium Hydride (16.27g, 0.42mol), be back to reaction and finish, add the cancellation of NaOH solution, suction filtration is removed solid, and filtrate concentrates to get (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-1,2-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
(S)-3-phenylpyrrole quinoline (30g, 0.1873mol) is dissolved in anhydrous diethyl ether, passes into HCl gas, the adularescent solid is separated out, and filters, and solid i.e. (S)-3-phenylpyrrole quinoline hydrochloride, the dry 24g that gets.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 p-tolyl aldehyde, and asymmetric catalyst is nickelous bromide (II)-two [(S, S)-N, N '-dibenzyl cyclohexyl-1,2-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 m-methoxybenzaldehyde, and asymmetric catalyst is nickelous bromide (II)-two [(S, S)-N, N '-dibenzyl cyclohexyl-1,2-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-(2,5-difluorophenyl) pyrroline
Operation is with embodiment 1, and raw material is 2,5-difluorophenyl phenyl aldehyde, and asymmetric catalyst is 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-(2,5-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-1,2-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-1,2-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-1,2-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-(3,5-Dimethoxyphenyl) pyrroline
Operation is with embodiment 1, and raw material is 3,5-dimethoxy benzaldehyde, and asymmetric catalyst is 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-(3,5-Dimethoxyphenyl) pyrroline
Claims (1)
1. the synthetic method of (R)-3-Phenylpyrrolidine is characterized in that preparing as follows:
In the flask of 2L, add 540ml acetic acid and 29.06g amine acetate, stir, it is mixed; Add again 200g benzene feedstock formaldehyde, drip at last the 360ml Nitromethane 99Min.; Under the nitrogen protection, stir and be warming up to 100 ℃; Until the raw material total overall reaction is complete, remove heating unit, the cooling, after join in the frozen water of 2700ml, stir, and suction filtration, wash with water three times, wash once with sodium bicarbonate, last water is washed once again, gets intermediate (E)-(2-nitroethylene) benzene 110.4g again;
In the flask of ethyl acetate with 110g described (E)-(2-nitroethylene) benzene dissolving and adding 2L, add 20g nickelous bromide (II)-two [(S, S)-N, N '-dibenzyl cyclohexyl-1, the 2-diamines] title complex, add again the 124g diethyl malonate, 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 to get product (R)-2-(2-nitro-1-phenylethyl) diethyl malonate 116.2g;
With 95% dissolve with ethanol of 116.2g gained (R)-2-(2-nitro-1-phenylethyl) diethyl malonate with 500ml, join in the flask of 2L, add again Raney-Ni 37g, be charged into hydrogen, normal-temperature reaction to reaction finishes, elimination Raney-Ni concentrates to get intermediate (3R)-2-oxa--4-Phenylpyrrolidine-3-carboxylic acid, ethyl ester 77g;
Described (the 3R)-2-oxa-of 151g-4-Phenylpyrrolidine-3-carboxylic acid, ethyl ester is added in the flask of 2L, add 6N HCl1.5L, be heated to backflow; Reaction finishes, and suction filtration is removed solid, and is concentrated except moisture, gets (R)-4-Amino-3-phenylbutyric acid hydrochloride 60.8g;
50g (R)-4-Amino-3-phenylbutyric acid hydrochloride 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-Phenylpyrrolidine-2-ketone 37.5g;
Get the there-necked flask of 1L, 37.5g (R)-4-Phenylpyrrolidine-2-ketone is dissolved among the THF of 75ml, add the 16.27g Lithium Aluminium Hydride, be back to reaction and finish, add the cancellation of NaOH solution, suction filtration, remove solid, filtrate concentrates to get (R)-3-Phenylpyrrolidine 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+, the 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-Phenylpyrrolidine.
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| CA2541509C (en) * | 2003-10-17 | 2014-06-10 | Incyte Corporation | Substituted cyclic hydroxamates as inhibitors of matrix metalloproteinases |
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| 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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| Title |
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| 唐跃平等.酰胺还原为胺.《药物合成技术》.人民卫生出版社,2009,172-174. * |
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