CN110903189A - Synthesis method of chiral 2-aryl propionate - Google Patents
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Abstract
The invention belongs to the technical field of chemical synthesis, relates to a synthesis method of chiral 2-aryl propionate, and particularly relates to enantioselective synthesis of 2-aryl propionate. The invention relates to a copper salt, a chiral phosphine ligand, a hydrosilicon compound (calculated as SiH), R1Adding OH and 2-aryl acrylate into a reaction bottle according to a certain proportion, reacting in a reaction solvent at-50-40 ℃ for 0.25-6h, and after the reaction is finished, hydrolyzing, separating liquid, extracting, washing, drying and carrying out column chromatography to obtain the target compound. Compared with the prior art, the invention adopts a Cu catalytic system to reduce the 2-aryl acrylate, and the catalyst Cu compound has low price, thereby breaking through the limitations of hydrogen high-pressure reduction and noble metal catalysts. The product is treated with simple waterThe chiral 2-aryl propionic acid can be obtained by decomposition reaction, wherein partial products are effective components of the existing medicines on the market, such as ibuprofen and naproxen.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and relates to enantioselective synthesis of 2-aryl propionate.
Background
2-aryl propionic acids are common analgesic and anti-inflammatory drugs. Wherein ibuprofen (ibuprofen) is OTC non-steroidal anti-inflammatory drug[1]It is widely used for treating headache, neuralgia, rheumatic arthritis, rheumatoid arthritis and other diseases. The effective component is (S) - (+) -ibuprofen, and the (R) - (-) -ibuprofen isomer is ineffective. Naproxen (Naproxen) is a PG synthetase inhibitor, has the effects of relieving inflammation, fever and pain, has certain curative effects on various acute pain analgesics, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, gout, chronic degenerative diseases of the motor system, light and moderate pain and the like, and is used for relieving migraine, tension headache, postoperative pain and pain related to various gynecological operations[2]. Clinical results showed that the biological activity of (S) - (+) -naproxen was 28 times higher than that of (R) - (-) -naproxen. The structures of (S) - (+) -ibuprofen and (S) - (+) -naproxen are shown in FIG. 1.
The synthesis of racemic ibuprofen includes Boots method and BHC method. The Boots method uses isobutyl benzene as raw material, and produces isobutyl acetophenone by Friedel-crafts reaction, and then produces ibuprofen by Darzens reaction and oxidation reaction[3]. The method has the problems of long route, poor atom economy and high raw material cost, and has high requirement on the corrosion resistance of equipment; BHC method is characterized by that it utilizes 1- (4-isobutyl phenyl) ethanone to make reduction and alcohol carbonylation reaction to synthesize ibuprofen[4]Wherein the carbonylation reaction adopts Pd (PPh)3)2Cl2Used as a catalyst. The method has good atom economy, but has the problems of high cost and toxicity of the noble metal Pd, high pressure for reaction and the like. The synthesis method and the existing problems of naproxen are similar to those of ibuprofen.
Chiral (S) - (+) -ibuprofen and (S) - (+) -naproxen are mainly obtained by resolution of racemic ibuprofen and naproxen, respectively. The compounds are prepared by adopting an asymmetric catalysis method, so that high-atom economic reaction can be realized, the generation of ineffective isomers and the influence on human bodies or environment are reduced, and the method has good industrial application prospect. The main method at present is the asymmetric hydroformylation of aryl ethylene catalyzed by transition metals Rh, Ru and Pd[5]Or by hydrogen esterification[6]Asymmetric carbonylation of 1-arylethanols[7]Or asymmetric hydrogenation of 2-arylacrylic acids[8 , 9]. However, the transition metals used in the catalysts are expensive and require high pressure, which limits their industrial application.
Reference to the literature
1.Kantor,T.G.,Ibuprofen.Annals ofinternal medicine 1979,91(6),877-82.
2.Todd,P.A.；Clissold,S.P.,Naproxen.A reappraisal of its pharmacology,and therapeutic use in rheumatic diseases andpain states.Drugs 1990,40(1),91-137.
3. In Fengli, Zhao Yu Liang, jin Zi Lin, ibuprofen synthesis of green progress organic chemistry, 2003,11,1198-
4.Sheldon,R.A.Chemtech 1994,24,38.
5.Francio,G.；Leitner,W.,Highly regio-and enantio-selective rhodium-catalysed asymmetric hydroformylation without organicsolvents.Chem.Commun.1999,(17),
1663-1664.
6.Cometti,G.；Chiusoli,G.P.J.Organomet.Chem.1982,236,C31.
7.Xie,B.H.；Xia,C.G.；Lu,S.J.；Chen,K.J.；Kou,Y.；Yin,Y.Q.,The firstasymmetric carbonylation of 1-(6'-methoxy-2'-naphthyl)ethanol to the methylester of(S)-naproxen.Tetrahedron Lett.1998,39(40),7365-7368.
8.Monteiro,A.L.；Zinn,F.K.；DeSouza,R.F.；Dupont,J.,Asymmetrichydrogenation of2-arylacrylic acids catalyzed by immobilized Ru-BINAP complexin1-n-butyl-3-methylimidazolium tetrafluoroborate molten salt.Tetrahedron-Asym.1997,8(2),177-179.
9. Zhang Shumo, Chencaiyou, chiral bisphosphine ligands and their use in asymmetric hydrogenation and related reactions, Chinese patent application No. 201510765575.7,2015.11.11.
Disclosure of Invention
Aiming at the problems, the invention uses cheap copper as a catalyst and silane as a reducing agent to reduce 2-aryl acrylate in the presence of chiral phosphine ligand to generate chiral 2-aryl propionate. The chiral 2-aryl propionic acid can be obtained by simply hydrolyzing the target compound. The method has the advantages of mild condition, simple operation, environmental protection and certain chiral selectivity. The 2- (4-methoxyphenyl) propionate and the like obtained by the method can be widely applied to the synthesis of the two medicines.
The synthesis method comprises the following steps: copper salt, chiral phosphine ligand, hydrosilicon compound (calculated as SiH), R1Adding OH and 2-aryl acrylate into a reaction bottle according to a certain proportion, reacting in a reaction solvent at-50-40 ℃ for 0.25-6h, and after the reaction is finished, hydrolyzing, separating liquid, extracting, washing, drying and carrying out column chromatography to obtain the target compound.
The asymmetric catalytic reduction of 2-aryl acrylate to synthesize 2-aryl substituted propionate has the following reaction formula:
wherein Ar ═ Ph,4-F-Ph,4-Cl-Ph,4-Br-Ph,4-I-Ph,4-MeO-Ph,4-Me2CHCH2-one of Ph,1-Nap,2- (6-MeO-2-Nap),2- (6-Me-2-Nap),2- (6-Cl-2-Nap) or 2- (6-Br-2-Nap); preferably 4-Me2CHCH2-Ph and 2- (6-MeO-2-Nap). R ═ Me, Et, CF3CF2C such as n-Pr, i-Pr, n-Bu, i-Bu, t-Bu1-C5Or phenyl, benzyl, substituted phenyl with methyl or ethyl, substituted benzyl.
The copper salt, the chiral phosphine ligand, the hydrosilicon compound (calculated as SiH), R1The molar ratio of OH to 2-aryl acrylate is (0.0005-0.03): (0.0005-0.03): (1-5): (0-4): 1.
the copper salt is as follows: CuF (PPh)3)3·2MeOH、Cu(OAc)2·H2O, CuX and sodium tert-butoxide or potassium tert-butoxide, wherein X is one of F, Cl and I. To avoid racemization due to excess potassium or sodium tert-butoxide, the ratio of CuX to potassium or sodium tert-butoxide is preferably from 2:1 to 1: 1. Theoretically, the ratio of the two is 1:1, wherein Cu (II) is reduced to Cu (I).
The silicon hydride is SiH or PhSiH3、Ph2SiH2、Ph3SiH、Ph2MeSiH、(SiHMe2)2O、Et3SiH、(MeO)3SiH、(SiHMe2)2NH。
Said R1OH is a primary, secondary or tertiary alcohol of 1-6 carbon atoms.
The chiral phosphine ligand is a phosphine compound L1-L6 with the following structure or an enantiomer thereof.
Wherein Ar' ═ Ph,3,5-Me2-Ph,3,4,5-(MeO)2-Ph，4-MeO-3,5-(t-Bu)2-Ph。
The reaction solvent is ether, aromatic hydrocarbon or alkyl halide, including ethyl ether, butyl ether, tetrahydrofuran, benzene, toluene, xylene, dichloromethane, 1, 2-dichloroethane, etc.
Compared with the prior art, the invention adopts a Cu catalytic system to reduce the 2-aryl acrylate, and the catalyst Cu compound has low price, thereby breaking through the limitations of hydrogen high-pressure reduction and noble metal catalysts. The chiral 2-aryl propionic acid can be obtained by simple hydrolysis reaction of the product, and can be used as an effective component for producing medicaments such as ibuprofen, naproxen and the like.
Drawings
FIG. 1 structures of (S) -ibuprofen and (S) -naproxen;
FIG. 2 Structure of the ligand;
FIG. 3 chiral GC spectrum of racemic methyl 2-phenylpropionate;
FIG. 4 is a chiral GC spectrum of methyl 2-phenylpropionate produced by asymmetric catalytic reaction;
FIG. 5 chiral HPLC chromatogram of racemic methyl 2- (4-isobutylphenyl) propionate;
FIG. 6 chiral HPLC chromatogram of methyl 2- (4-isobutylphenyl) propionate generated by asymmetric catalytic reaction.
FIG. 7 chiral HPLC chromatogram of methyl 2- (2-chlorophenyl) propionate generated by asymmetric catalysis;
FIG. 8 shows a chiral HPLC chromatogram of methyl 2- (4-methoxyphenyl) propionate generated by asymmetric catalytic reaction.
Detailed Description
The invention is described in more detail below with reference to specific examples, without limiting the scope of the invention. Unless otherwise specified, the experimental methods adopted by the invention are all conventional methods, and experimental equipment, materials, reagents and the like used in the experimental method can be obtained from commercial sources.
Example 1
A dry reaction flask purged with nitrogen was charged with Cu (OAc)2·H2O (2.0mg), (R, R) -L1(Ar' ═ Ph) (2.0mg), and toluene (2.0mL), and stirred at room temperature to a blue solution. To the mixture was added poly (methylhydrogensiloxane) (120. mu.L) and n-butanol (118. mu.L), and after stirring for 5min, methyl 2-phenylacrylate (0.065g) was added and further stirred for 2 h. Thereafter, saturated NH was added to the reaction mixture4Stirring the solution F (4.0mL) for 60min, separating liquid, extracting the water phase with ethyl acetate (3X 5.0mL), washing the combined organic phase with NaCl saturated solution, drying with anhydrous sodium sulfate, concentrating, and separating with a column to obtain 0.046g of methyl 2-phenylpropionate with a yield of 70%; the composition of the enantiomer is analyzed by chiral GC, ee is 8 percent, and the dominant configuration is (S) -configuration.1H NMR(500MHz,CDCl3)δ7.32–7.20(m,5H),3.66(q,J＝7.1Hz,1H),3.59(s,3H),1.43(d,J＝7.2Hz,3H).13C NMR(126MHz,CDCl3) δ 175.13,140.67,128.77,127.59,127.26,52.17,45.54,18.74. analytical conditions: chromatographic column beta-dex 225 chiral column, 30m × 0.25mm × 0.25 μm; the column temperature was 80 ℃. Retention time 51.6min (S-configuration), 52.7min (R-configuration).
Example 2
Into a dry reaction flask purged with nitrogen, Cu (OAc) was charged2·H2O (2.0mg), (R) -L2(Ar' ═ Ph) (3.0mg), and tetrahydrofuran (2.0mL) were stirred at room temperature to prepare a blue solution. Poly (methylhydrogensiloxane) (180. mu.L) and tert-butanol (140. mu.L) were added to the above system, and after stirring, methyl 2-phenylacrylate (162mg) was added, and the reaction was further stirred for 2 hours. Adding saturated NH to the reaction mixture4Cl solution (4.0 m)L), continuing stirring for 20min, separating liquid, extracting an aqueous phase by using ethyl acetate (3X 5.0mL), washing combined organic phases by using a NaCl saturated solution, drying by using anhydrous sodium sulfate, concentrating, and carrying out column separation to obtain colorless liquid 2-methyl phenylpropionate 101mg with the yield of 62%; by chiral GC analysis, the ee value is 19%, and the dominant configuration is (S) -configuration.
Example 3
Into a dry reaction flask purged with nitrogen, Cu (OAc) was charged2·H2O (2.0mg), (S) -L3(Ar' ═ Ph) (6.1mg), and toluene (2.0mL) were stirred at room temperature to prepare a blue solution. Adding Ph to the above liquid2SiH2(184. mu.L) and neopentyl butanol (132mg), stirred for 5min, then added with methyl 2-phenylacrylate (152mg), and the reaction was continued for 2h with stirring. Adding saturated NH to the reaction mixture4Cl solution (4.0mL), stirring for 20min, separating, extracting the aqueous phase with ethyl acetate (3X 5.0mL), washing the combined organic phases with saturated NaCl solution, drying over anhydrous sodium sulfate, concentrating, and separating with a column to obtain 2-phenylpropionic acid methyl ester (111mg, yield 72%), GC chiral analysis, ee 22%), with the predominant configuration being (S) -configuration.
Example 4
Into a dry reaction flask purged with nitrogen, Cu (OAc) was charged2·H2O(2.0mg)、(R)-L4(Ar'＝4-Me-3,5-(t-Bu)2-Ph) (5.6mg), toluene (2.0mL) and stirred at room temperature to a blue solution. The temperature was reduced to-25 ℃ and poly (methylhydrogensiloxane) (120. mu.L) and tert-butanol (182. mu.L) were added to the above liquid, and after stirring for 5min, methyl 2-phenylacrylate (161mg) was added. After stirring for 2h, saturated NH was then added4And (3) continuously stirring the Cl solution (4.0mL) for 30min, separating liquid, extracting the water phase by using ethyl acetate (3X 5.0mL), washing the combined organic phase by using a NaCl saturated solution, drying the combined organic phase by using anhydrous sodium sulfate, concentrating, and carrying out column separation to obtain a product (149mg, the yield is 91%, the ee is 35%, the advantageous configuration is (S) -configuration, and chiral GC spectrograms of analysis of the raceme and the methyl 2-phenylpropionate obtained by the reaction are respectively shown in a figure 3 and a figure 4.
Example 5
Into a dry reaction flask purged with nitrogen, Cu (OAc) was charged2·H2O(2.0mg)、(R)-L4(Ar'＝4-Me-3,5-(t-Bu)2-Ph) (5.6mg), xylene (2.0mL) was stirred at room temperature to a blue solution. The temperature was reduced to-30 ℃ and poly (methylhydrogensiloxane) (120. mu.L) and methanol (40. mu.L) were added to the above liquid, stirred for 5min and then added with methyl 2- (4-isobutylphenyl) -acrylate (108 mg). Stirring for 2h, and adding saturated NH4And (3) continuously stirring the Cl solution (4.0mL) for 30min, separating liquid, extracting an aqueous phase by using dimethylbenzene (3X 5.0mL), washing combined organic phases by using a NaCl saturated solution, drying the combined organic phases by using anhydrous sodium sulfate, concentrating, and separating by using a column to obtain a product (93mg, the yield is 85%, ee 53%, and the predominant configuration is (S) -configuration.1HNMR(500MHz,CDCl3)δ7.20(d,J＝7.9Hz,2H),7.10(d,J＝7.9Hz,2H),3.70(q,J＝7.1Hz,1H),3.66(s,3H),2.44(d,J＝7.2Hz,2H),1.87-1.81(m,1H),1.49(d,J＝7.2Hz,3H),0.90(d,J＝6.6Hz,6H).13CNMR(126MHz,CDCl3) Delta 175.39,140.70,137.85,129.49,127.25,52.15,45.16,45.14,30.33,22.54,18.77 chiral HPLC spectra of the racemate and the methyl 2- (4-isobutylphenyl) -propionate obtained in this reaction are shown in fig. 5 and 6, respectively.
Example 6
CuCl (10mg), KOBu were added to a dry Huliang bottle purged with nitrogen under nitrogent(11.2mg), chiral ligand L5(Ar' ═ Ph) (67mg), THF (2.0mL), stirred for 10min, then 1/10 was removed, another reaction flask was added, THF (2.0mL) was added, and the temperature was reduced to-50 ℃. Adding (MeO) to the reaction flask3SiH (127. mu.L) and tert-butanol (92. mu.L), and after stirring for 5min, methyl 2- (2-chlorophenyl) acrylate (92mg,0.50mmol) was added. Stirring for 1h, and adding saturated NH4Cl solution (4.0mL), stirring for 20min, separating the liquids, extracting the aqueous phase with ethyl acetate (3X 5.0mL), washing the combined organic phases with saturated NaCl solution, drying over anhydrous sodium sulfate, concentrating, and separating with a column to obtain the product (89mg, 90% yield, ee 47%).1H NMR(500MHz,CDCl3)δ7.37(dd,J＝7.9,1.4Hz,1H),7.31(dd,J＝7.7,1.7Hz,1H),7.28–7.23(m,1H),7.22–7.17(m,1H),4.22(q,J＝7.2Hz,1H),3.68(s,3H),1.50(d,J＝7.2Hz,3H).13C NMR(126MHz,CDCl3) δ 174.61,138.57,133.79,129.82,128.53,128.42,127.31,52.31,42.21, 17.75. The 2- (2-chlorphenyl) methyl propionate obtained by the reaction is subjected to chiral ODThe HPLC chromatogram of the-H column analysis is shown in FIG. 7.
Example 7
Into a dry reaction flask purged with nitrogen, Cu (OAc) was charged2·H2O (2.0mg), (S) -L4(Ar' ═ Ph) (5.8mg), and toluene (2.0mL), and the mixture was stirred at room temperature for 10 min. Adding Ph to the above liquid2SiH2(184. mu.L) and tert-butanol (140. mu.L), and after stirring for 5min, benzyl 2-phenylacrylate (232mg) was added and the reaction was continued for 2h with stirring. Thereafter, saturated NH was added to the reaction mixture4Stirring the Cl solution (4.0mL) for 20min, separating, extracting the aqueous phase with ethyl acetate (3X 5.0mL), washing the combined organic phases with a saturated NaCl solution, drying over anhydrous sodium sulfate, concentrating, and separating with a column to obtain 169mg of benzyl 2-phenylpropionate with a yield of 72%; by HPLC analysis, ee 22%.
Example 8
CuF (PPh) was added to a dry Huliang bottle purged with nitrogen3)32MeOH (4.6mg) and (R) -L4(Ar' ═ 4-Me-3,5- (t-Bu)2-Ph) (5.6mg) and toluene (1.0mL) were stirred at room temperature for 10min, then 0.1mL of the liquid was taken out and added to another reaction flask, the temperature was reduced to-25 ℃, poly (methylhydrosiloxane) (120. mu.L) and t-butanol (182. mu.L) were added to the latter reaction flask, and after stirring for 5min, methyl 2- (4-methoxyphenyl) acrylate (97mg) was added and stirred for 5 h. Then saturated NH was added to the reaction flask4Cl solution (4.0mL), stirring for 30min, separating the liquids, extracting the aqueous phase with ethyl acetate (3X 5.0mL), washing the combined organic phases with saturated NaCl solution, drying over anhydrous sodium sulfate, concentrating, and separating with a column to obtain methyl (4-methoxyphenyl) propionate (90mg, 92% yield, ee 38%).1H NMR(500MHz,CDCl3)δ7.22(d,J＝8.6Hz,1H),6.86(d,J＝8.7Hz,1H),3.78(s,1H),3.72–3.66(q,J＝7.2Hz,1H),3.65(s,1H),1.47(d,J＝7.2Hz,3H).13C NMR(126MHz,CDCl3) δ 175.39,158.81,132.78,128.58,114.14,55.37,52.09,44.68, 18.79. The chiral HPLC chromatogram of methyl 2- (4-methoxyphenyl) propionate obtained in this reaction is shown in FIG. 8.
The above description is only for the purpose of creating a preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can substitute or change the technical solution and the inventive concept of the present invention within the technical scope of the present invention.
Claims (3)
1. A synthetic method of chiral 2-aryl propionate is characterized in that copper salt, chiral phosphine ligand, hydrosilicon compound (calculated as SiH), R1Adding OH and 2-aryl acrylate into a reaction bottle according to a certain proportion, reacting in a reaction solvent at-50-40 ℃ for 0.25-6h, and after the reaction is finished, hydrolyzing, separating liquid, extracting, washing, drying and carrying out column chromatography to obtain a target compound; the copper salt, the chiral phosphine ligand, the hydrosilicon compound (calculated as SiH), R1The molar ratio of OH to 2-aryl acrylate is (0.0005-0.03): (0.0005-0.03): (1-5): (0-4): 1;
the 2-aryl acrylate
In (1), Ar ═ Ph,4-F-Ph,4-Cl-Ph,4-Br-Ph,4-I-Ph,4-MeO-Ph,4-Me2CHCH2-one of Ph,1-Nap,2- (6-MeO-2-Nap),2- (6-Me-2-Nap),2- (6-Cl-2-Nap) or 2- (6-Br-2-Nap);
R＝Me,Et,CF3CF2n-Pr, i-Pr, n-Bu, i-Bu, t-Bu or C1-C5Or phenyl, benzyl, substituted phenyl with methyl or ethyl, substituted benzyl;
the copper salt is as follows: CuF (PPh)3)3·2MeOH、Cu(OAc)2·H2O, CuX and sodium tert-butoxide or potassium tert-butoxide, wherein X is one of F, Cl and I;
the silicon hydride is SiH or PhSiH3、Ph2SiH2、Ph3SiH、Ph2MeSiH、(SiHMe2)2O、Et3SiH、(MeO)3SiH、(SiHMe2)2NH；
Said R1OH is a primary, secondary or tertiary alcohol of 1-6 carbon atoms;
the chiral phosphine ligand is a phosphine compound L1-L6 with the following structure or an enantiomer thereof;
wherein Ar' ═ Ph,3,5-Me2-Ph,3,4,5-(MeO)2-Ph，4-MeO-3,5-(t-Bu)2-Ph；
The reaction solvent is ether or aromatic hydrocarbon or alkyl halide.
2. The method of claim 1, wherein the ratio of CuX to potassium or sodium tert-butoxide is 2:1-1: 1.
3. The method of claim 1, wherein the reaction solvent is selected from the group consisting of ethyl ether, butyl ether, tetrahydrofuran, benzene, toluene, xylene, methylene chloride, and 1, 2-dichloroethane.
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