CN104557583B - A kind of method synthesizing γ-aminobutyric acid class chipal compounds - Google Patents

A kind of method synthesizing γ-aminobutyric acid class chipal compounds Download PDF

Info

Publication number
CN104557583B
CN104557583B CN201510053178.7A CN201510053178A CN104557583B CN 104557583 B CN104557583 B CN 104557583B CN 201510053178 A CN201510053178 A CN 201510053178A CN 104557583 B CN104557583 B CN 104557583B
Authority
CN
China
Prior art keywords
compound
catalyst
aminobutyric acid
acid class
nitroolefin
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.)
Expired - Fee Related
Application number
CN201510053178.7A
Other languages
Chinese (zh)
Other versions
CN104557583A (en
Inventor
鄢明
董雪娇
张学景
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
National Sun Yat Sen University
Original Assignee
National Sun Yat Sen University
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by National Sun Yat Sen University filed Critical National Sun Yat Sen University
Priority to CN201510053178.7A priority Critical patent/CN104557583B/en
Publication of CN104557583A publication Critical patent/CN104557583A/en
Application granted granted Critical
Publication of CN104557583B publication Critical patent/CN104557583B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Abstract

The invention discloses a kind of method synthesizing γ-aminobutyric acid class chipal compounds, the method comprises the following steps: under catalyst A and additive exist, nitroolefin and malonate are added in solvent, nitroolefin and malonate generation conjugate addition reaction, selectively obtain compound V, compound V obtains Compound II per after there is hydro-reduction reaction, decarboxylation, amidatioon under the effect of catalyst B and hydrogen, and Compound II per acidolysis can obtain compound I.The inventive method adopts quinidine derivative cheap and easy to get to be catalyst, and alkali is additive, and prepared γ-aminobutyric acid class chiral drug yield is high, enantioselectivity is high;The inventive method reaction condition is gentle, simple to operate, is the green synthesis process of a synthesis γ-aminobutyric acid class chiral drug.

Description

A kind of method synthesizing γ-aminobutyric acid class chipal compounds
Technical field
The invention belongs to organic synthesis field, be specifically related to a kind of method synthesizing γ-aminobutyric acid class chipal compounds.
Background technology
The chirality γ-aminobutyric acid of beta substitution and lactam derivatives thereof have physiologically active widely, are clinically used for tranquilizing soporific, antidepressant, skeletal muscle solution spasm, anti-senile dementia and antiepileptic etc..Wherein, representational medicine includes skeletal muscle relaxation reconciliation anticonvulsant drug baclofen, the non-Buddhist nun's Boot of epilepsy, anxiety and neuralgia pharmaceutical pregabaline, anxiety and insomnia drug, antidepressant drug rolipram.
For the synthesis of this kind of chiral drug, existing main method has: 1) chiral separation (WO9638405, WO2009147528;WO2010061403;CN101362696A);2) (Tetrahedron:Asymmetry2008,19,651 is synthesized from chiral raw material;J.Org.Chem.2007,72,7390;CN101585778A);3) chiral auxiliary synthesis (Heterocycles2005,66,385 is adopted;Tetrahedron:Asymmetry2004,15,2039;Synlett2006,1589);4) transition metal-catalyzed asymmetric synthesis (WO2001055090;J.Am.Chem.Soc.2003.125,10219;J.Am.Chem.Soc.2004,126,9920).These methods also exist the defects such as cost height, complex synthetic route, waste discharge amount be big.
Recent years, several research groups also report the method (J.Am.Chem.Soc.2004,126,9906 being synthesized γ-aminobutyric acid class chiral drug by organic catalysis method;J.Am.Chem.Soc.2005,127,119;Org.Lett.2007,9,5307;Org.Lett.2010,12,1280;Org.Lett.2012,14,1516;CN101333168A and CN102701987A), wherein the asymmetric conjugated reaction of Nitrocarbol. and olefine aldehydr is the committed step building chiral centre, and the catalyst that these methods adopt is price Thiourea catalyst costly, diphenylprolinol silicon ether catalyst and sulfo-prolineamide type catalyst.
McQuade and Kataja group reports the method preparing baclofen and Pregabalin by the asymmetric conjugated reaction reaction of nitroolefin Yu malonate respectively, have employed the Ni of chirality (II) catalyst (J.Am.Chem.Soc.2007,129,9216;ARKIVOC2010, ii, 205).Thereafter, the thiourea catalyst that Takemoto group adopts quinine derivative completes this reaction, it is thus achieved that enantioselectivity (J.Am.Chem.Soc.2005,127,119) preferably.But, the Thiourea catalyst price that Ni (II) catalyst of chirality and quinine derive all costly, reduces the industrial application value of this route.
Summary of the invention
It is an object of the invention to provide a kind of method synthesizing γ-aminobutyric acid class chipal compounds, the method is to employ additive on the basis of existing technology, by follow-up several steps reaction, obtain a series of γ-aminobutyric acid class chipal compounds with excellent productivity and enantioselectivity.
The purpose of the present invention is achieved through the following technical solutions:
A kind of method synthesizing γ-aminobutyric acid class chipal compounds, comprises the following steps:
Under catalyst A and additive exist, nitroolefin (Compound II per I) and malonate (compounds Ⅳ) are added in solvent, nitroolefin and malonate generation conjugate addition reaction, selectively obtain compound V, compound V obtains Compound II per after there is hydro-reduction reaction, decarboxylation, amidatioon under the effect of catalyst B and hydrogen, and Compound II per acidolysis can obtain compound I;
Course of reaction is shown below:
In compound I, II, III, V, R1For phenyl, substituted-phenyl, naphthyl, thienyl, furyl, pyridine radicals, benzofuranyl, benzothienyl, quinolyl, the straight chain of C1-C6 or branched alkyl;Described substituted-phenyl is the phenyl containing 1-3 substituent group, and substituent group is selected from fluorine, chlorine, bromine, the straight chain of C1-C6 or branched alkyl, the straight chain of C1-C6 or branched alkoxy, nitro, trifluoromethyl, phenyl;
γ-aminobutyric acid class chipal compounds of the present invention includes compound I and II, and common γ-aminobutyric acid class chipal compounds is as follows:
In compounds Ⅳ, V, R2For methyl, ethyl, isopropyl, n-pro-pyl, butyl, isobutyl group, the tert-butyl group;
Catalyst A has following structure formula:
Wherein R3For hydrogen, pi-allyl, benzyl, trimethyl silicon based, triethyl group is silica-based, benzoyl, acetyl group or p-toluenesulfonyl;
Catalyst A preferably 6 '-demethylation quinidine, 9-O-pi-allyl-6 '-demethylation quinidine or 9-benzoyl-6 '-demethylation quinidine;
Described additive is sodium carbonate, potassium carbonate, potassium phosphate, triethylamine, N, N-diisopropylethylamine, piperidines, 1,4-diazabicylo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene, 4-dimethylamino pyridine, N-Methylimidazole., preferred DIPEA;
Described solvent is ether, dipropyl ether, Di Iso Propyl Ether, oxolane, t-butyl methyl ether, dioxane, dichloromethane, dichloroethanes, chloroform, normal hexane, methanol, ethanol, isopropanol, toluene, water, it is preferable that oxolane;
Described catalyst B is Raney's nickel, palladium carbon or platinum carbon, it is preferable that Raney's nickel;
In described conjugate addition reaction, the mol ratio of nitroolefin III and malonate IV is 1:1~1:5, it is preferable that 1:3;The mol ratio of catalyst A and nitroolefin III is 1:2~1:20, it is preferable that 1:10;
Conjugate addition reaction can carry out at 0-60 DEG C, it is preferable that carries out at 25 DEG C;
In described hydro-reduction reaction, hydrogenation pressure is 1-20 atmospheric pressure, it is preferred to 3 atmospheric pressure;Temperature is 0-120 DEG C, it is preferred to 80 DEG C.
The present invention has such advantages as relative to prior art and effect:
The inventive method adopts quinidine derivative cheap and easy to get to be catalyst, and alkali is additive, and prepared γ-aminobutyric acid class chiral drug yield is high, enantioselectivity is high;The inventive method reaction condition is gentle, simple to operate, is the green synthesis process of a synthesis γ-aminobutyric acid class chiral drug.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in further detail, but embodiments of the present invention are not limited to this.
Embodiment 1
A kind of method synthesizing baclofen, comprises the following steps:
(1) by parachloronitrobenzene ethylene (3.66g, 20.0mmol), dimethyl malenate (7.92g, 60.0mmol), 6 '-demethylation quinidine (0.62g, 10mol%) and N, N-diisopropylethylamine (0.52g, 20mol%) it is dissolved in THF (100mL), stir 24 hours under room temperature, react complete concentration, column chromatography (ethyl acetate/petroleum ether=1/10) purification, obtain (R)-2-(1-(4-chlorobenzene)-2-nitro-ethyl) dimethyl maleate (6.00g, yield 95%, ee94%).
The structural characterization data of product are as follows:
1HNMR(400MHz,CDCl3): δ 7.31 (d, J=8.4Hz, 2H), 7.18 (d, J=8.4Hz, 2H), 4.91 (dd, J=4.8,12.8Hz, 1H), 4.85 (dd, J=8.4,13.6Hz, 1H), 4.23 (dt, J=4.8,9.2Hz, 1H), 3.83 (d, J=9.2Hz, 1H), 3.77 (s, 3H), 3.60 (s, 3H);13CNMR(100MHz,CDCl3): δ 167.6,167.0,134.6,134.4,129.3,129.2,77.1,54.4,53.0,52.9,42.3.chiralHPLC:DaicelchiralcelOD-HColumn, Hexane/2-propanol=80/20,0.8mL/min, λ 220nm, tR(major)=14.7min, tR(minor)=16.0min. determines that product is (R)-2-(1-(4-chlorobenzene)-2-nitro-ethyl) dimethyl maleate, and structure is as follows:
(2) inside hydrogenation reaction kettle, (R)-2-(1-(4-chlorobenzene)-2-nitro-ethyl) dimethyl maleate (3.15g is added, 10.0mmol), Raney's nickel (2.0mg) and ethanol (10mL), with hydrogen exchange three times, react 18 hours under 80 DEG C and three atmospheric pressure.Reactant liquor uses washing with alcohol after filtering with kieselguhr, obtains lactam compound (1.81g, yield 93%).
The structural characterization data of product are as follows:
M.P.109-111 DEG C;[α]D 30–39.0(c1.00,CHCl3);1HNMR(400MHz,CDCl3) δ 7.32 (d, J=7.9Hz, 2H), 7.19 (t, J=8.2Hz, 2H), 6.15 (s, 1H), 3.79 (t, J=8.9Hz, 1H), 3.68 (m, 1H), 3.38 (t, J=8.4Hz, 1H), 2.74 (dd, J=9.0,16.9Hz, 1H), 2.45 (dd, J=8.6,16.8Hz, 1H);13CNMR(100MHz,CDCl3) δ 177.5,140.7,132.9,129.0,128.1,49.3,39.6,37.8;MS (ESI): 196 (MH+). determine that the structure of product is as follows:
(3) take lactam compound (1.17g, 6.0mmol), add the HCl (20mL) of 5M, react 18 hours at 90 DEG C, extracting by ethyl acetate (4 × 50mL) after cooling, aqueous phase concentrates to obtain yellow solid (1.43g, yield 95%).
The structural characterization data of product are as follows:
M.P.188-189 DEG C;[α]D 25–3.79(c0.65,H2O);1HNMR(400MHz,DMSO-d6) δ 12.26 (s, 1H), 8.13 (s, 3H), 7.57-7.13 (m, 4H), 3.15-3.07 (m, 1H), 3.04-2.92 (m, 1H), 2.85 (dd, J=5.5,16.2Hz, 1H), 2.56 (dd, J=9.5,16.5Hz, 1H);13CNMR(100MHz,DMSO-d6) δ 172.5,139.5,131.9,130.0,128.7,128.6,128.0,43.1,39.1,37.8;MS (ESI): 214 (MH+). determine that the structure of product is as follows:
Comparative example 1
A kind of method synthesizing baclofen, comprises the following steps:
(1) by parachloronitrobenzene ethylene (3.66g, 20.0mmol), dimethyl malenate (7.92g, 60.0mmol) and 6 '-demethylation quinidine (0.62g, 20mol%) it is dissolved in THF (100mL), stir 36 hours under room temperature, react complete concentration, column chromatography (ethyl acetate/petroleum ether=1/10) purification, obtain (R)-2-(1-(4-chlorobenzene)-2-nitro-ethyl) dimethyl maleate (6.13g, yield 97%, ee78%).The structural characterization data consistent with Example 1 of product.
(2) this step is with embodiment 1.
(3) this step is with embodiment 1.
Embodiment 1 and comparative example 1 are distinctive in that have additive-free in the process preparing compound V, and the yield of both prepared compound V is close, but embodiment 1 is having additive to deposit in case, and the ee value of compound V is greatly improved.
Embodiment 2
A kind of method synthesizing baclofen, comprises the following steps:
(1) by parachloronitrobenzene ethylene (3.66g, 20.0mmol), dimethyl malenate (7.92g, 60.0mmol), 9-O-pi-allyl-6 '-demethylation quinidine (0.67g, 10mol%) and N, N-diisopropylethylamine (0.52g, 20mol%) it is dissolved in THF (100mL), stir 24 hours under room temperature, react complete concentration, column chromatography (ethyl acetate/petroleum ether=1/10) purification, obtain (R)-2-(1-(4-chlorobenzene)-2-nitro-ethyl)) dimethyl maleate (6.13g, yield 97%, ee97%).The structural characterization data consistent with Example 1 of product.
(2) this step is with embodiment 1.
(3) this step is with embodiment 1.
Embodiment 3
A kind of method synthesizing baclofen, comprises the following steps:
(1) by parachloronitrobenzene ethylene (3.66g; 20.0mmol), dimethyl malenate (7.92g; 60.0mmol), 9-benzoyl-6 '-demethylation quinidine (0.82g; 2.0mmol) with 4-dimethylamino pyridine (0.26g; 2.0mmol) it is dissolved in THF (100mL); stir 24 hours under room temperature; react complete concentration; column chromatography (ethyl acetate/petroleum ether=1/10) purification; obtain (R)-2-(1-(4-chlorobenzene)-2-nitro-ethyl) dimethyl maleate (5.87g; yield 93%, ee88%).The structural characterization data consistent with Example 1 of product.
(2) this step is with embodiment 1.
(3) this step is with embodiment 1.
Embodiment 4
A kind of method synthesizing baclofen, comprises the following steps:
(1) by parachloronitrobenzene ethylene (3.66g, 20.0mmol), dimethyl malenate (7.92g, 60.0mmol), 9-O-pi-allyl-6 '-demethylation quinidine (0.67g, 2.0mmol) and N, N-diisopropylethylamine (0.52g, 20mol%) it is dissolved in t-butyl methyl ether (100mL), stir 24 hours under room temperature, react complete concentration, column chromatography (ethyl acetate/petroleum ether=1/10) purification, obtain (R)-2-(1-(4-chlorobenzene)-2-nitro-ethyl dimethyl maleate (5.81g, yield 92%, ee85%).The structural characterization data consistent with Example 1 of product.
(2) this step is with embodiment 1.
(3) this step is with embodiment 1.
Embodiment 5
A kind of method synthesizing baclofen, comprises the following steps:
(1) by parachloronitrobenzene ethylene (3.66g, 20.0mmol), dimethyl malenate (7.92g, 60.0mmol), 9-O-pi-allyl-6 '-demethylation quinidine (0.67g, 10mol%) and N, N-diisopropylethylamine (0.52g, 20mol%) it is dissolved in ether (100mL), stir 24 hours under room temperature, react complete concentration, column chromatography (ethyl acetate/petroleum ether=1/10) purification, obtain (R)-2-(1-(4-chlorobenzene)-2-nitro-ethyl) dimethyl maleate (5.81g, yield 92%, ee84%).The structural characterization data consistent with Example 1 of product.
(2) this step is with embodiment 1.
(3) this step is with embodiment 1.
Embodiment 6
A kind of method synthesizing baclofen, comprises the following steps:
(1) by parachloronitrobenzene ethylene (3.66g, 20.0mmol), dimethyl malenate (7.92g, 60.0mmol), 9-O-pi-allyl-6 '-demethylation quinidine (0.67g, 10mol%) and N-Methylimidazole. (0.33g, 20mol%) it is dissolved in THF (100mL), stir 24 hours under room temperature, react complete concentration, column chromatography (ethyl acetate/petroleum ether=1/10) purification, obtain (R)-2-(1-(4-chlorobenzene)-2-nitro-ethyl) dimethyl maleate (5.87g, yield 93%, ee85%).The structural characterization data consistent with Example 1 of product.
(2) this step is with embodiment 1.
(3) this step is with embodiment 1.
Embodiment 7
A kind of method synthesizing Pregabalin, comprises the following steps:
(1) by 4-methyl nitro amylene (2.58g, 20.0mmol), dimethyl malenate (7.92g, 60.0mmol), 9-O-pi-allyl-6 '-demethylation quinidine (0.67g, 10mol%) and N, N-diisopropylethylamine (0.52g, 10mol%) it is dissolved in THF (100mL), stir 24 hours under room temperature, post-processing approach is with the step (1) of embodiment 1, obtain (R)-2-(4-methyl nitro amyl group) dimethyl maleate (4.80g, yield 92%, ee92%).
The structural characterization data of product are as follows:
1HNMR(400MHz,CDCl3) δ 4.70-4.63 (m, 1H), 4.53-4.46 (m, 1H), 3.77 (s, 3H), 3.76 (s, 3H), 3.63-3.61 (m, 1H), 2.98-2.92 (m, 1H), 1.67-1.61 (m, 1H), 1.31-1.26 (m, 2H), 0.91-0.87 (m, 6H);13CNMR(100MHz,CDCl3) δ 168.6,168.4,76.9,53.1,52.9,52.5,39.1,35.1,25.3,22.6,22.4. determines that product is (R)-2-(4-methyl nitro amyl group) dimethyl maleate, structure is as follows:
(2) inside hydrogenation reaction kettle, (R)-2-(4-methyl nitro amyl group) dimethyl maleate (2.60g is added, 10.0mmol), Raney's nickel (2.0mg) and ethanol (10mL), with hydrogen exchange three times, react 18 hours under 80 DEG C and three atmospheric pressure.Reactant liquor uses washing with alcohol after filtering with kieselguhr, obtains (S)-4-isobutyl group pyrroles's-2-ketone (1.27g, yield 90%).
The structural characterization data of product are as follows:
1HNMR(400MHz,CDCl3) δ: 6.56 (br, 1H), 3.41 (t, J=8.7Hz, 1H), 2.92 (dd, J=9.3,7.2Hz, 1H), 2.47 (m, 1H), 2.34 (dd, J=16.5,8.4Hz, 1H), 1.91 (dd, J=16.2,8.4Hz, 1H), 1.51 (d, J=7.2Hz, 1H), 1.28 (t, J=7.5Hz, 2H), 0.84 (d, J=6.6Hz, 3H), 0.82 (d, J=6.6Hz, 3H);13CNMR(100MHz,CDCl3) δ: 22.4,22.6,26.1,32.9,36.9,43.8,48.3,178.6. determine that the structure of product is as follows:
(3) (S)-4-isobutyl group pyrroles-2-ketone (1.13g, 8.0mmol), add the HCl (20mL) of 5M, react 18 hours at 90 DEG C, extract by ethyl acetate (4 × 50mL) after cooling, aqueous phase concentrates to obtain hydrochloric acid Pregabalin (1.17g, yield 92%).
The structural characterization data of product are as follows:
[α]D 25=+9.6 (c=1.0, H2O).1HNMR(400MHz,CD3OD) δ 2.95-2.92 (d, J=6.0Hz, 2H), 2.34 (dd, J=7.0,6.4Hz, 2H), 2.21-2.16 (m, 1H), 1.68-1.61 (m, 1H), 1.24-1.20 (m, 2H), 0.96-0.89 (m, 6H);13CNMR(100MHz,CD3OD) δ 175.8,44.5,41.9,37.1,32.5,26.1,23.2,22.4. determines that the structure of product is as follows:
Comparative example 2
A kind of method synthesizing Pregabalin, comprises the following steps:
(1) by 4-methyl nitro amylene (2.58g, 20.0mmol), dimethyl malenate (7.92g, 60.0mmol) and 9-O-pi-allyl-6 '-demethylation quinidine (0.67g, 10mol%) it is dissolved in THF (100mL), stir 24 hours under room temperature, post-processing approach is with the step (1) of embodiment 7, obtain (R)-2-(4-methyl nitro amyl group) dimethyl maleate (4.28g, yield 82%, ee74%).The structural characterization data consistent with Example 7 of product.
(2) this step is with embodiment 7.
(3) this step is with embodiment 7.
Embodiment 7 and comparative example 2 are distinctive in that have additive-free in the process preparing compound V, and the yield of both prepared compound V is close, but embodiment 7 is having additive to deposit in case, and the ee value of compound V is greatly improved.
Embodiment 8
A kind of method synthesizing non-Buddhist nun's Boot, comprises the following steps:
(1) by nitrostyrolene (2.98g, 20.0mmol), dimethyl malenate (7.92g, 60.0mmol), 9-O-pi-allyl-6 '-demethylation quinidine (0.67g, 10mol%) and N, N-diisopropylethylamine (0.52g, 20mol%) it is dissolved in THF (100mL), stir 24 hours under room temperature, react complete concentration, column chromatography (ethyl acetate/petroleum ether=1/10) purification, obtain (R)-2-(2-nitro-1-phenylethyl) dimethyl maleate (5.34g, yield 95%, ee96%).
The structural characterization data of product are as follows:
1HNMR(400MHz,CDCl3): δ 7.37 7.27 (m, 3H), 7.23 (dd, J=7.7,1.8Hz, 2H), 4.97 4.83 (m, 2H), 4.25 (td, J=8.7,5.6Hz, 1H), 3.87 (d, J=9.1Hz, 1H), 3.76 (s, 3H), 3.56 (s, 3H);13CNMR (100MHz): δ 167.9,167.3,136.2,129.1,128.5,127.9,77.5,54.8,53.1,53.0,43.0,29.8;ChiralHPLC (DaicelChiralcelOD-H) hexane/2-propanol=90/10, flowrate:1.00mL/min;λ=254nm;TR(minor)=24.0min, tR(major)=28.0min. determines that the structure of product is as follows:
(2) inside hydrogenation reaction kettle, (R)-2-(2-nitro-1-phenethyl) dimethyl maleate (2.81g is added, 10.0mmol), Raney's nickel (2.0mg) and ethanol (20mL), with hydrogen exchange three times, react 18 hours under 80 DEG C and three atmospheric pressure.Reactant liquor uses washing with alcohol after filtering with kieselguhr, obtains non-Buddhist nun's Boot (1.81g, yield 93%).
The structural characterization data of product are as follows:
[α]D 20+ 22 (c0.5, MeOH);M.P.98 99 DEG C;1HNMR(400MHz,CDCl3): 7.34-7.29 (m, 2H), 7.25-7.21 (m, 3H), 3.75 (dd, J=8.8,8.4Hz, 1H), 3.65 (q, 1H), 3.38 (dd, J=6.8,8.4Hz, 1H), 2.71 (dd, J=8.8,16.8Hz, 1H), 2.48 (dd, J=6.8,16.8Hz, 1H);13CNMR(100MHz,CDCl3): 178.0,142.1,128.8,127.1,126.7,49.6,40.3,38.0. determines that the structure of product is as follows:
Comparative example 3
A kind of method synthesizing non-Buddhist nun's Boot, comprises the following steps:
(1) by nitrostyrolene (2.98g, 20.0mmol), dimethyl malenate (7.92g, 60.0mmol) and 9-O-pi-allyl-6 '-demethylation quinidine (0.67g, 10mol%) it is dissolved in THF (100mL), stir 24 hours under room temperature, react complete concentration, column chromatography (ethyl acetate/petroleum ether=1/10) purification, obtain (R)-2-(2-nitro-1-phenylethyl) dimethyl maleate (5.28g, yield 94%, ee76%).The structural characterization data consistent with Example 8 of product.
(2) this step is with embodiment 8.
Embodiment 8 and comparative example 3 are distinctive in that have additive-free in the process preparing compound V, and the yield of both prepared compound V is close, but embodiment 8 is having additive to deposit in case, and the ee value of compound V is greatly improved.
Embodiment 9
A kind of method synthesizing rolipram, comprises the following steps:
(1) by 2-cyclopentyloxy-1-methoxyl group-4-nitroethylene base benzene (5.26g, 20.0mmol), diethyl malonate (9.60g, 60.0mmol), 9-O-pi-allyl-6 '-demethylation quinidine (0.67g, 2mmol) and N, N-diisopropylethylamine (0.52g, 2.0mmol) it is dissolved in THF (100mL), stir 24 hours under room temperature, react complete concentration, column chromatography (ethyl acetate/petroleum ether=1/10) purification, obtain 2-(1-(3-cyclopentyloxy)-4-methoxyphenyl-2-nitro-ethyl) ethyl maleate. (7.61g, yield 90%, ee90%).
The structural characterization data of product are as follows:
M.P.94.5 95.5 DEG C;[α]D 30–9.4(c1.15,CHCl3);1HNMR(CDCl3=400MHz) δ 6.81-6.72 (m, 3H), 4.90 (d, J=12.9Hz, 1H), 4.82 (d, J=12.9Hz, 1H), 4.73-4.69 (m, 1H), 4.29-4.14 (m, 3H), 4.05-4.07 (m, 2H), 3.76 (s, 3H), 3.79-3.80 (m, 1H), 2.02-1.79 (m, 5H), 1.64-1.59 (m, 3H), 1.29-1.30 (m, 3H), 0.91-0.93 (m, 3H);ESIm/z441 (M+NH4);ChiralHPLC (DaicelChiralcelAD) hexane/2-propanol=95/5, flowrate:1.00mL/min;λ=254nm;TR(minor)=20.0min, tR(major)=26.0min. determines that the structure of product is as follows:
(2) inside hydrogenation reaction kettle, 2-(1-(3-cyclopentyloxy)-4-methoxyphenyl)-2-nitro-ethyl is added) ethyl maleate. (4.23g, 10.0mmol), Raney's nickel (2.0mg) and ethanol (10mL), with hydrogen exchange three times, react 18 hours under 80 DEG C and three atmospheric pressure.Reactant liquor uses washing with alcohol after filtering with kieselguhr, obtains rolipram (2.80g, yield 93%).
The structural characterization data of product are as follows:
[α]D 27-31.0 (c1.00MeOH) for94%ee. [lit.:[α]D 25-33.9 (c1.09, MeOH) for99%eeintheR-isomer;J.Am.Chem.Soc.2002,13394.].1HNMR(400MHz,CDCl3): δ 6.76-6.84 (m, 3H);6.56 (brs, 1H), 4.75-4.78 (m, 1H), 3.83 (s, 3H), 3.77-3.73 (m, 1H), 3.66-3.58 (m, 1H), 3.38 (dd, J=7.6,8.8Hz, 1H), 2.71 (dd, J=8.8,16.8Hz, 1H), 2.47 (dd, J=8.8,16.8Hz, 1H), 1.94-1.81 (m, 6H), 1.63-1.59 (m, 2H);13CNMR(100MHz,CDCl3): δ 178.0,149.2,147.9,134.6,118.8,113.9,112.3,80.6,56.1,49.8,39.9,38.2,32.8,24.0.EI-MSm/z (%): 275 (14.69, M+), 207 (68.55), 150 (100). determine that the structure of product is as follows:
Comparative example 4
A kind of method synthesizing rolipram, comprises the following steps:
(1) by 2-cyclopentyloxy-1-methoxyl group-4-nitroethylene base benzene (5.26g, 20.0mmol), diethyl malonate (9.60g, 60.0mmol) and 9-O-pi-allyl-6 '-demethylation quinidine (0.67g, 10mol%) it is dissolved in THF (100mL), stir 24 hours under room temperature, react complete concentration, column chromatography (ethyl acetate/petroleum ether=1/10) purification, obtain 2-(1-(3-cyclopentyloxy)-4-methoxyphenyl-2-nitro-ethyl) ethyl maleate. (8.03g, yield 95%, ee76%).The structural characterization data consistent with Example 9 of product.
(2) this step is with embodiment 9.
Embodiment 9 and comparative example 4 are distinctive in that have additive-free in the process preparing compound V, and the yield of both prepared compound V is close, but embodiment 9 is having additive to deposit in case, and the ee value of compound V is greatly improved.
Above-described embodiment is the present invention preferably embodiment; but embodiments of the present invention are also not restricted to the described embodiments; the change made under other any spirit without departing from the present invention and principle, modification, replacement, combination, simplification; all should be the substitute mode of equivalence, be included within protection scope of the present invention.

Claims (5)

1. the method synthesizing γ-aminobutyric acid class chipal compounds, it is characterised in that comprise the following steps:
Under catalyst A and additive exist, nitroolefin (Compound II per I) and malonate (compounds Ⅳ) are added in solvent, nitroolefin and malonate generation conjugate addition reaction, selectively obtain compound V, compound V obtains Compound II per after there is hydro-reduction reaction, decarboxylation, amidatioon under the effect of catalyst B and hydrogen, and Compound II per acidolysis can obtain compound I;
In compound I, II, III, V, R1For phenyl, substituted-phenyl, naphthyl, thienyl, furyl, pyridine radicals, benzofuranyl, benzothienyl, quinolyl, the straight chain of C1-C6 or branched alkyl;Described substituted-phenyl is the phenyl containing 1-3 substituent group, and substituent group is selected from fluorine, chlorine, bromine, the straight chain of C1-C6 or branched alkyl, the straight chain of C1-C6 or branched alkoxy, nitro, trifluoromethyl, phenyl;
In compounds Ⅳ, V, R2For methyl, ethyl, isopropyl, n-pro-pyl, butyl, isobutyl group, the tert-butyl group;
Catalyst A has following structure formula:
Wherein R3For hydrogen, pi-allyl, benzyl, trimethyl silicon based, triethyl group is silica-based, benzoyl, acetyl group or p-toluenesulfonyl;
Described additive is N, N-diisopropylethylamine, 4-dimethylamino pyridine, N-Methylimidazole.;
Described catalyst B is Raney's nickel, palladium carbon or platinum carbon.
2. the method for synthesis γ-aminobutyric acid class chipal compounds according to claim 1, it is characterised in that: catalyst A is 6 '-demethylation quinidine, 9-O-pi-allyl-6 '-demethylation quinidine or 9-benzoyl-6 '-demethylation quinidine.
3. the method for synthesis γ-aminobutyric acid class chipal compounds according to claim 1, it is characterised in that: described solvent is ether, dipropyl ether, Di Iso Propyl Ether, oxolane, t-butyl methyl ether, dioxane, dichloromethane, dichloroethanes, chloroform, normal hexane, methanol, ethanol, isopropanol, toluene, water.
4. the method for synthesis γ-aminobutyric acid class chipal compounds according to claim 1, it is characterised in that: in described conjugate addition reaction, the mol ratio of nitroolefin and malonate is 1:1~1:5.
5. the method for synthesis γ-aminobutyric acid class chipal compounds according to claim 1, it is characterised in that: in described conjugate addition reaction, the mol ratio of catalyst A and nitroolefin is 1:2~1:20.
CN201510053178.7A 2015-02-02 2015-02-02 A kind of method synthesizing γ-aminobutyric acid class chipal compounds Expired - Fee Related CN104557583B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510053178.7A CN104557583B (en) 2015-02-02 2015-02-02 A kind of method synthesizing γ-aminobutyric acid class chipal compounds

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510053178.7A CN104557583B (en) 2015-02-02 2015-02-02 A kind of method synthesizing γ-aminobutyric acid class chipal compounds

Publications (2)

Publication Number Publication Date
CN104557583A CN104557583A (en) 2015-04-29
CN104557583B true CN104557583B (en) 2016-06-29

Family

ID=53074763

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510053178.7A Expired - Fee Related CN104557583B (en) 2015-02-02 2015-02-02 A kind of method synthesizing γ-aminobutyric acid class chipal compounds

Country Status (1)

Country Link
CN (1) CN104557583B (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112368266A (en) * 2018-06-06 2021-02-12 浙江华海药业股份有限公司 Method for preparing pregabalin
CN112608267A (en) * 2020-12-23 2021-04-06 南京艾斯特医药科技有限公司 Synthetic method of 4-phenyl-2-pyrrolidone

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101869846A (en) * 2010-06-18 2010-10-27 中国科学院上海有机化学研究所 Catalyst of first category bi-quinine or bi-quinidine, synthesis method and application
WO2013189920A1 (en) * 2012-06-19 2013-12-27 Ucb Pharma S.A. New compound based on cinchona alkaloïds for use in asymmetric michael addition

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101869846A (en) * 2010-06-18 2010-10-27 中国科学院上海有机化学研究所 Catalyst of first category bi-quinine or bi-quinidine, synthesis method and application
WO2013189920A1 (en) * 2012-06-19 2013-12-27 Ucb Pharma S.A. New compound based on cinchona alkaloïds for use in asymmetric michael addition

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Development of a Catalytic Enantioselective Conjugate Addition of 1,3-Dicarbonyl Compounds to Nitroalkenes for the Synthesis of Endothelin-A Antagonist ABT-546. Scope,Mechanism, and Further Application to the Synthesis of the Antidepressant Rolipram;David M. Barnes et al.;《J. AM. CHEM. SOC.》;20021015;第124卷;13097-13105 *

Also Published As

Publication number Publication date
CN104557583A (en) 2015-04-29

Similar Documents

Publication Publication Date Title
CN107805205B (en) Preparation method of (R) -3-aminobutanol
KR101099408B1 (en) Subsidiary urea compound and subsidiary conjugated addition using the catalyst as a method for producing a subsidiary compound by reaction
CN104557583B (en) A kind of method synthesizing γ-aminobutyric acid class chipal compounds
JP6792069B2 (en) Method for preparing 5R-benzyloxyaminopiperidine-2S-formic acid or its derivative
CN102757431B (en) A kind of novel method of synthesizing sitagliptin
CN107501112A (en) A kind of Chiral Synthesis of chiral beta amino acids and the synthetic method of medicine intermediate
CN109369432B (en) Preparation method of (S) -4-chloro-2-aminobutyrate
KR101539761B1 (en) Method for preparing compounds through a novel Michael-addition reaction using water or various acids as additives
CN105017158B (en) A kind of preparation method of cis Rosuvastatin calcium impurities
CN103923040A (en) Method of preparing furfural oxime acid
CN103787921B (en) A kind of method preparing trans 1, the 2-ring diamines of high-optical-purity
CN107235852A (en) A kind of method of synthesizing amide
CN101863815A (en) Synthesis method of cis 3-phenyl substituted s-proline derivative
CN103467350B (en) (S) preparation method of-AzeOH
CN102807516A (en) Intermediate in amisulpride and method for preparing amisulpride by using intermediate
CN106554301A (en) A kind of preparation method of BMS-477118 key intermediate
Ramanujam et al. Expeditious novel routes to enantiopure 3-amino tetrahydrofuran hydrochloride
CN110452165B (en) Preparation method of 2-methylpyridine-4-formic acid
KR100638171B1 (en) Preparation method of 2,N-dimethyl-N-3,3-diphenylpropyl-1-amino-2-propanol
CN102417497B (en) Preparation method of optically active 1-indenone-3-acetate compound
CN106674032B (en) Non-natural chirality serine new synthetic method
KR20050062944A (en) New process for preparing diisopropyl ((1-((2-amino-6-chloro-9h-purin-9-yl)methyl)cyclopropyl)oxy)-methylphosphonate
CN114315609A (en) Process for preparing cis-2-aminocyclohexanol
KR101142052B1 (en) Method of preparing zanamivir
CN112920053A (en) Preparation method of chiral alpha-methyl aromatic ethylamine

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20160629

Termination date: 20200202

CF01 Termination of patent right due to non-payment of annual fee