CN111822053B - Chiral polysulfonate diamine-metal catalyst and synthesis and application thereof - Google Patents
Chiral polysulfonate diamine-metal catalyst and synthesis and application thereof Download PDFInfo
- Publication number
- CN111822053B CN111822053B CN202010708803.8A CN202010708803A CN111822053B CN 111822053 B CN111822053 B CN 111822053B CN 202010708803 A CN202010708803 A CN 202010708803A CN 111822053 B CN111822053 B CN 111822053B
- Authority
- CN
- China
- Prior art keywords
- formula
- diamine
- chiral
- polysulfonate
- reaction
- 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.)
- Active
Links
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/1691—Coordination polymers, e.g. metal-organic frameworks [MOF]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G75/00—Macromolecular compounds obtained by reactions forming a linkage containing sulfur with or without nitrogen, oxygen, or carbon in the main chain of the macromolecule
- C08G75/24—Polysulfonates
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
- B01J2231/32—Addition reactions to C=C or C-C triple bonds
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/84—Metals of the iron group
- B01J2531/847—Nickel
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Abstract
The invention provides a chiral polysulfonate diamine-metal catalyst and synthesis and application thereof, wherein the catalyst has a structure shown as a formula (I-1) or (I-2), and L is one of chlorine, bromine, iodine or acetate; x is one of structures shown in a formula (II-1), a formula (II-2), a formula (II-3), a formula (II-4) or a formula (II-5). The catalyst can be obtained by polymerizing a silyl ether substituted chiral diamine monomer and a bis-fluorosulfonate ester connecting unit and then coordinating with metal nickel salt. The catalyst can catalyze the asymmetric conjugate addition reaction of malonate and beta-substituted nitroethylene, and good yield and enantioselectivity are obtained. The catalyst can be recycled for multiple times, effectively reduces the use cost of the catalyst, reduces the residue of metallic nickel in the product, and has outstanding technical advantages and good application prospects for the industrial production of chiral gamma-aminobutyric acid medicines.
Description
Technical Field
The invention relates to a novel chiral polysulfonate diamine-metal catalyst, a synthetic method thereof and application thereof in catalyzing asymmetric conjugate addition reaction, belonging to the fields of catalysis technology and drug synthesis.
Background
The chiral gamma-aminobutyric acid drugs have various varieties, rich and variable pharmacological activity and wide clinical application, and have very important market positions. At present, the production of the medicaments generally adopts the traditional chiral resolution technology, the waste of raw materials is serious, the production cost is high, and the problem of environmental pollution is prominent.
In recent years, various chiral gamma-aminobutyric acid drugs can be prepared through the following steps by preparing a key chiral intermediate through the asymmetric conjugate addition reaction of malonate and beta-substituted nitroethylene. The route does not need chemical resolution, has cheap and easily obtained raw materials, low production cost and little environmental pollution, and has very high industrial application value. The choice of chiral catalyst in this reaction is key to achieving high yields and high enantioselectivities.
At present, chiral thiourea-tertiary amine catalysts and quinoline-derived squarylamine catalysts are the most commonly used catalysts for catalyzing the reaction of malonate and beta-substituted nitroethylene, but the catalysts have the defects of high preparation cost and unsatisfactory substrate universality. By adopting the chiral diamine-nickel complex as the catalyst, the yield and enantioselectivity of the reaction are improved, the substrate universality is good, the catalyst is easy to prepare, the production cost is low, and the problem of metallic nickel residue exists. To solve this problem, Li and Kobayashi et al use mesoporous silica gel to immobilize the catalyst, allowing the catalyst to be recycled (adv. Synth. Catal.2012,354, 3265; Angew. chem. int. Ed.2019,58,13313). Bellemin-Laponnaz et al use bis-diamine ligands to form coordination polymers with Ni, achieving immobilization and recycling of the catalyst (Adv. Synth. Catal.2016,358, 1982). Although the chiral diamine-nickel catalyst immobilized by the methods can obtain better yield and enantioselectivity in the conjugate addition reaction of malonate and beta-substituted nitroethylene, the synthesis of the immobilized precursor is difficult, the production cost is higher, and the method is not practically applied to the industrial production of chiral gamma-aminobutyrate medicines at present.
Disclosure of Invention
The invention aims to provide a chiral polysulfonate diamine-metal catalyst, a synthesis method thereof and application thereof in catalyzing asymmetric conjugate addition reaction of a 1, 3-dicarbonyl compound and beta-substituted nitroethylene. The catalyst can catalyze the reaction to obtain good yield and enantioselectivity, and can be recycled for many times. Effectively reduces the use cost of the catalyst, reduces the residue of metallic nickel in the product, and has good application prospect for the industrial production of chiral gamma-aminobutyric acid medicaments.
The purpose of the invention is realized by the following technical scheme:
a chiral polysulfonate diamine-metal catalyst having the structure shown in formula (I-1) or formula (I-2):
in the formulas (I-1) and (I-2), L is one of chlorine, bromine, iodine or acetate;
x is one of structures shown in a formula (II-1), a formula (II-2), a formula (II-3), a formula (II-4) or a formula (II-5);
preferably, L is bromine and X is a structure of formula (II-3).
n is an integer of 2 to 1000.
The synthesis method of the chiral polysulfonate diamine-metal catalyst comprises the following steps:
mixing silyl ether diamine shown in a formula (III-1) or a formula (III-2) with bis-fluorosulfonate shown in a formula (IV), adding alkali, and reacting in a solvent to generate polysulfonate diamine shown in a formula (V-1) or a formula (V-2); the polysulfonic diamine shown as the formula (V-1) or the formula (V-2) and NiL 2 Reacting to generate chiral polysulfonate diamine-metal catalyst shown in formula (I-1) or formula (I-2).
Wherein X is one of the structures shown in the formula (II-1), the formula (II-2), the formula (II-3), the formula (II-4) or the formula (II-5);
the alkali is sodium hydroxide, potassium hydroxide, triethylamine, N-diisopropylethylamine, triethylene Diamine (DABCO), N-methylmorpholine or 1, 8-diazabicycloundecen-7-ene (DBU);
the solvent is N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, dioxane, dichloromethane or chloroform;
the reaction of the siloxane diamine shown in the formula (III-1) or the formula (III-2) and the bis-fluorosulfonate shown in the formula (IV) is preferably carried out at 50-200 ℃ until the reactants are completely cured;
the polysulfonate diamine shown as the formula (V-1) or the formula (V-2) and NiL 2 Preferably at 50-200 ℃ for 5-20 h.
The chiral polysulfonate diamine-metal catalyst shown in the formula (I-1) or the formula (I-2) can be used for catalyzing the asymmetric conjugate addition reaction of a 1, 3-dicarbonyl compound and beta-substituted nitroethylene, and comprises the following reaction steps:
adding a chiral polysulfonate diamine-metal catalyst, a 1, 3-dicarbonyl compound and beta-substituted nitroethylene into a solvent, and stirring for reaction to obtain a conjugated addition product with good yield and enantioselectivity;
the chiral polysulfonate diamine-metal catalyst can be recovered by a centrifugation or filtration method and continuously applied to catalyzing a second reaction;
the solvent can be toluene, dichloromethane, trichloromethane, tetrahydrofuran, tert-butyl methyl ether, ethyl acetate, acetonitrile, dimethyl sulfoxide and N, N-dimethylformamide;
the 1, 3-dicarbonyl compound can be methyl malonate, ethyl malonate, isopropyl malonate, tert-butyl malonate, acetylacetone and ethyl acetoacetate;
the beta-substituted nitroethylene has a structure shown in a formula (VI),
wherein R is C3-C8 straight or branched chain alkyl, mono-or di-substituted phenyl and heteroaryl, and the substituents are fluorine, chlorine, bromine, methyl, ethyl, propyl, cyclopropyl, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, trifluoromethyl, cyano, acetyl or acetoxy; the heteroaryl is pyridyl, pyrimidyl, furyl, thienyl, benzofuryl, benzothienyl, indolyl or quinolyl.
Compared with the prior art, the invention has the following advantages and effects:
the invention provides a chiral polysulfonate diamine-metal catalyst which can be obtained by polymerizing a chiral silyl ether diamine monomer and a bis-fluorosulfonate ester connecting unit and then coordinating with a metal nickel salt. The catalyst can catalyze the asymmetric conjugate addition reaction of malonate and beta-substituted nitroethylene, and good yield and enantioselectivity are obtained. The catalyst can be recycled for multiple times, the use cost of the catalyst is effectively reduced, the residue of the metal nickel in the product is reduced, and the catalyst has outstanding technical advantages and good application prospects for industrial production of chiral gamma-aminobutyric acid medicines.
Detailed Description
The present invention is further described below with reference to examples, but the embodiments of the present invention are not limited thereto.
Example 1(1S,2S) -N 1 ,N 2 Synthesis of (4-tert-butyldimethylsilyloxy-benzyl) cyclohexane-1, 2-diamine
A500 mL round bottom flask was charged with (1S,2S) -cyclohexanediamine (11.4g,0.1mol), 4-tert-butyldimethylsiloxybenzaldehyde (52.0g,0.22mol) and anhydrous methanol (250 mL). After stirring at room temperature for 16 hours, sodium borohydride (8.3g,0.22mol) was added and the reaction was continued for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure. The crude product was purified by column chromatography (eluent: dichloromethane/methanol ═ 30: 1) to give (1S,2S) -N 1 ,N 2 Bis (4-tert-butyldimethylsilyloxy-benzyl) cyclohexane-1, 2-diamine (35.5g, 64% yield). Nuclear magnetic hydrogen spectrum (400MHz, CDCl) 3 )δ7.15(d,J＝8.0Hz,4H),6.77(d,J＝8.0Hz,4H),3.82(d,J＝12.8Hz,2H),3.56(d,J＝12.8Hz,2H),2.26(d,J＝9.2Hz,2H),2.13(d,J＝12.4Hz,2H),1.71(d,J＝8.0Hz,2H),1.33–1.16(m,4H),0.98(s,18H),0.18(s,12H).
Example Synthesis of 21, 4-bis-fluorosulfonyloxybenzene
A500 mL reaction flask was charged with 1, 4-benzenediol (11.0g,0.1mol), triethylamine (35mL,0.25mol), and dichloromethane (250mL), and sulfuryl fluoride gas was bubbled through. The above mixture was reacted at room temperature for 24 hours. After completion of the reaction, the solvent was spin-dried under reduced pressure, ethyl acetate was added to dissolve the solvent (300mL), the solution was washed with hydrochloric acid (6M,300mL), saturated sodium bicarbonate solution (300mL) and saturated brine (300mL) in this order, and dried over anhydrous sodium sulfateThe solvent was dried by spinning and recrystallized from a dichloromethane/n-hexane mixture to obtain 1, 4-difluorosulfonyloxybenzene (25.2g, 92% yield) as a white powder. Nuclear magnetic hydrogen spectrum (400MHz, CDCl) 3 )δ7.43(s,4H).
Example Synthesis of 32, 7-bis-fluorosulfonyloxynaphthalene
A500 mL reaction flask was charged with 2, 7-naphthalenediol (16.0g,0.1mol), triethylamine (35mL,0.25mol), and methylene chloride (250mL), and then with sulfuryl fluoride gas. The above mixture was reacted at room temperature for 24 hours. After the reaction, the solvent was dried under reduced pressure, ethyl acetate was added to dissolve the solvent (300mL), the solution was washed with hydrochloric acid (300mL,0.6M), saturated sodium bicarbonate solution (300mL) and saturated brine (300mL), anhydrous sodium sulfate was added to dry the solvent, and the solvent was dried by rotary evaporation and recrystallized from a dichloromethane/n-hexane mixed solvent to obtain 2, 7-difluorosulfonyloxynaphthalene (30.5g, yield 94%) as a white powder. Nuclear magnetic hydrogen spectrum (400MHz, CDCl) 3 )δ7.98(d,J＝9.2Hz,2H),7.82(d,J＝2.0Hz,2H),7.51–7.46(m,2H).
Example 4 Synthesis of (1S,2S) -Polyhydroquinone sulfonate diamine
(1S,2S) -N was added to a 250mL reaction flask 1 ,N 2 Bis (4-tert-Butyldimethylsilanyloxy-benzyl) cyclohexane-1, 2-diamine (55.0g,0.1mol), 1, 4-bis-fluorosulfonyloxybenzene (27.0g,0.1mol) and DBU (3mL,20.0mmol), the reaction was stirred at 150 ℃ and the reaction gradually solidified. After cooling to room temperature, DMF (100mL) was added and the reaction was carried out at 150 ℃ for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, poured into methanol (500mL), and a white solid was precipitated, filtered, and dried in a vacuum oven at 80 ℃ to obtain (1S,2S) -poly (hydroquinone) sulfonate diamine (50.0g, yield 82%). Infrared ray of 2931.3,2856.4,1659.1,1648.3,1611.4,1514.0,1492.1,1400.0,1214.8,1138.6,1016.1,872.1,575.6,502.9cm -1 (ii) a YuanElement analysis (%): C55.44, H4.98, N5.21, S10.01; GPC (polystyrene as standard): PD ═ 2.4; mn 4527Da.
EXAMPLE 5 Synthesis of (1S,2S) -poly-2, 7-naphthalenediol sulfonate diamine
(1S,2S) -N was added to a 250mL reaction flask 1 ,N 2 Bis (4-tert-Butyldimethylsilanyloxy-benzyl) cyclohexane-1, 2-diamine (55.0g,0.1mol), 2, 7-bis-fluorosulfonyloxynaphthalene (32.0g,0.1mol), DBU (3mL,20.0mmol), and the reaction was stirred at 150 ℃ to gradually solidify the reaction product. After cooling to room temperature, DMF (100mL) was added and the reaction was carried out at 150 ℃ for 2 hours. After the reaction is finished, cooling to room temperature, pouring the reaction solution into methanol (500mL), separating out a white solid, filtering, and drying in a vacuum drying oven at 80 ℃ to obtain (1S,2S) -poly-2, 7-naphthalenediol sulfonate diamine (53.0g, yield 86%); infrared ray of 2929.2,2856.5,1632.4,1500.0,1398.7,1365.8,1210.7,1190.2,1142.7,1117.9,873.7,839.7,743.0,624.0,534.7,472.7cm -1 (ii) a Elemental analysis (percent) C59.73, H5.11, N4.63, S9.37; GPC (polystyrene as standard): PD ═ 2.4; mn is 4745Da.
Example 6 Synthesis of (1S,2S) -Polyhydroquinone sulfonate diamine-Nickel dibromide
Nickel dibromide (11.0g,50.0mmol), (1S,2S) -poly (hydroquinone) sulfonate diamine (28.0g,50.0mmol) and DMF (150mL) were added to a 250mL reaction flask, the reaction was stirred at 150 ℃ for 16 h, and cooled to room temperature. The reaction was diluted with ethyl acetate (300mL) and n-hexane (500.0mL) was added to precipitate a brick-red solid. Filtration and drying in a vacuum oven at 80 ℃ gave (1S,2S) -poly (hydroquinone sulphonate diamine) -nickel dibromide (37.0g, 94% yield); infrared ray of 3316.6,2931.7,2858.1,1660.9,1597.0,1493.1,1403.6,1216.0,1181.2,1141.3,876.0,583.1,502.2cm -1 (ii) a Elemental analysis (Percent) C44.05, H4.38, N4.78, S8.86; ICP analysis: each gram of polymer contained 78.53mg of nickel.
EXAMPLE 7 Synthesis of (1S,2S) -poly-2, 7-naphthalenediol sulfonate diamine-nickel dibromide
Nickel dibromide (11.0g,50.0mmol), (1S,2S) -poly-2, 7-naphthalenediol sulfonate diamine (31.0g,50.0mmol) and DMF (150mL) were charged in a 250mL reaction flask, stirred at 150 ℃ for 16 hours, and cooled to room temperature. The reaction was diluted by pouring into ethyl acetate (300mL) and then n-hexane (500mL) was added to precipitate a brick-red solid. Filtering, drying in a vacuum drying oven at 80 ℃ to obtain (1S,2S) -poly-2, 7-naphthalenediol sulfonic acid ester diamine-nickel dibromide (39.0g, the yield is 95%); infrared ray of 3258.1,2932.0,2858.7,1659.5,1500.86,1398.6,1211.3,1189.9,1142.8,1118.2,873.6,842.1,757.3,744.2,638.9,623.2,582.8,535.2,472.6cm -1 (ii) a Elemental analysis (%): C50.08, H4.85, N5.37, S8.61; ICP analysis: each gram of polymer contained 63.86mg of nickel.
Example 8(1S,2S) -Polyhydroquinone sulfonate diamine-Nickel dibromide catalyzed conjugate addition
Beta-phenylnitroethylene (29.8g,0.2mol), diethyl malonate (48.0g,0.3mol), (1S,2S) -poly (p-benzenediol sulphonate diamine) -nickel dibromide (10 g, obtained in example 6) and methylene chloride (1L) were charged into a 5L reaction flask, and the reaction system was reacted at room temperature for 24 hours under protection of argon. After the reaction was completed, the solvent was dried under reduced pressure, and the crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate 15: 1) to obtain (R) -diethyl 2- (2-nitro-1-phenylethyl) malonate (56.5g, yield 95%, ee 92%). Nuclear magnetic hydrogen spectrum (400MHz, CDCl) 3 ) δ 7.40-7.18 (m,5H), 5.00-4.82 (m,2H), 4.32-4.16 (m,3H),4.03(q, J ═ 7.2Hz,2H),3.84(d, J ═ 9.2Hz,1H), 1.34-1.22 (m,3H), 1.13-1.00 (m, 3H); nuclear magnetic carbon spectrum (100 MH)z,CDCl 3 ) δ 167.45,166.81,136.26,128.92,128.34,128.02,77.65,62.14,61.87,55.01,42.98,13.96, 13.73; chiral HPLC analysis (Chiral pak AD-H, i-PrOH: n-hexane: 20:80, flow rate 1.0mL/min, wavelength 220nm), t R (main) 7.287min, t R 14.013min, 92% ee.
Example 9 Synthesis of the chiral drug, fenisobutyrin
The diethyl (R) -2- (2-nitro-1-phenylethyl) malonate (12.4g,40mmol), raney nickel (8.0g) and ethanol (40mL) obtained in example 8 were charged into a hydrogenation reaction vessel, which was then replaced with hydrogen three times and reacted at 3 atmospheres for 18 hours. The reaction solution was filtered through celite, washed with ethanol, the solvent was removed from the filtrate under reduced pressure, and the crude product was purified by column chromatography (eluent: dichloromethane/methanol ═ 5: 1) to give ethyl (4R) -2-oxo-4-phenylpyrroline-3-carboxylate (8.96g, yield 96%).
In a 50mL reaction flask were added (4R) -2-oxo-4-phenylpyrroline-3-carboxylic acid ethyl ester (7.0g,30mmol) and HCl (6M,100mL), reacted at 90 ℃ for 18 hours, cooled and extracted with ethyl acetate (200 mL. times.3), and the aqueous phase was concentrated to give the pale yellow product, fenicol, which was 6.15g, 95% yield. Nuclear magnetic hydrogen spectrum (500MHz, D) 2 O) δ 7.38-7.33 (m,2H), 7.32-7.26 (m,3H), 3.39-3.26 (m,2H), 3.21-3.13 (m,1H), 2.84-2.74 (m,1H),2.69(dd, J ═ 16.0,9.0Hz, 1H); nuclear magnetic carbon Spectroscopy (125MHz, D) 2 O)δ175.44,138.30,129.36,128.31,127.86,43.79,39.92,38.17.
Example 10 Synthesis of (1S,2S) -poly-2, 7-naphthalenediol sulfonate diamine-nickel dibromide for chiral drug baclofen
A5L reaction flask was charged with beta-p-chlorophenyl nitroethylene (36.7g,0.2mol), diethyl malonate (48.0g,0.3mol), (1S,2S) -poly-2, 7-naphthalenediol sulfonate diamine-nickel dibromide (for example)Prepared in example 7, 10g) and dichloromethane (1L), the reaction system is stirred at room temperature for 24 hours under the protection of argon. After the reaction was completed, the solvent was dried under reduced pressure, and the crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate 15: 1) to obtain (R) -diethyl 2- (2-nitro-1- (4-chloro) phenethyl) malonate (60.5g, yield 88%, ee 88%). Nuclear magnetic hydrogen spectrum (400MHz, CDCl) 3 ) δ 7.34-7.28 (m,2H), 7.23-7.16 (m,2H), 4.95-4.79 (m,2H), 4.30-4.16 (m,3H),4.04(q, J ═ 7.2Hz,2H),3.78(d, J ═ 9.2Hz,1H), 1.32-1.23 (m,3H),1.09(m, 3H); nuclear magnetic carbon spectrum (100MHz, CDCl) 3 ) δ 167.26,166.65,134.75,134.36,129.46,129.18,77.42,62.31,62.08,54.76,42.35,13.99, 13.81; chiral HPLC analysis (Chiral pak AD-H, i-PrOH: n-hexane ═ 20:80, flow rate ═ 1.0mL/min, detection wavelength ═ 220nm), t R (main) 7.670min, t R 14.604min, 88% ee.
To a hydrogenation reactor, (R) -2- (2-nitro-1- (4-chloro) phenethyl) malonic acid diethyl ester (13.8g,40mmol), Raney's nickel (8.0g) and ethanol (40mL) were added, and the reaction was carried out three times by replacement with hydrogen and at 3 atmospheres for 18 hours. The reaction solution was filtered through celite, washed with ethanol, the solvent was removed from the filtrate under reduced pressure, and the crude product was purified by column chromatography (eluent: dichloromethane/methanol ═ 5: 1) to give ethyl (4R) -2-oxo-4- (4-chlorophenyl) pyrroline-3-carboxylate (9.43g, yield 93%).
A250 mL reaction flask was charged with (4R) -2-oxo-4- (4-chlorophenyl) pyrroline-3-carboxylic acid ethyl ester (8.03g,30mmol) and HCl (6M,100mL), reacted at 90 ℃ for 18 hours, cooled, extracted with ethyl acetate (200 mL. times.3), and the aqueous phase was concentrated to give the product baclofen (7.12g, 95% yield). Nuclear magnetic hydrogen spectrum (400MHz, D) 2 O) δ 7.34(d, J ═ 8.4Hz,2H),7.24(d, J ═ 8.4Hz,2H), 3.37-3.24 (m,2H),3.14(m,1H),2.76(dd, J ═ 16.0,6.0Hz,1H),2.64(dd, J ═ 16.4,8.8Hz, 1H); nuclear magnetic carbon spectrum (100MHz, D) 2 O)δ175.23,136.91,133.36,130.02,129.38,129.27,129.22,43.54,39.36,38.09.
Example 11 Synthesis of (1S,2S) -Poly-2, 7-Naphthalenediol sulfonate diamine-Nickel dibromide for chiral drug rolipram
Beta- (3-cyclopentyloxy-4-methoxy) phenylnitroethylene (52.7g,0.2mol), diethyl malonate (48.0g,0.3mol), (1S,2S) -poly-2, 7-naphthalenediol sulfonate diamine-nickel dibromide (10.0g) and dichloromethane (1L) were charged in a 5L reaction flask, and the reaction system was reacted at room temperature for 24 hours under argon atmosphere. After the reaction was completed, the solvent was dried under reduced pressure, and the crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate 15: 1) to obtain (R) -diethyl 2- (2-nitro-1- (3-cyclopentyloxy-4-methoxy) phenethyl) malonate (77.4g, yield 91%, ee 91%). Nuclear magnetic hydrogen spectrum (400MHz, CDCl) 3 ) δ 6.83-6.68 (m,3H), 4.92-4.78 (m,2H), 4.77-4.70 (m,1H), 4.30-4.10 (m,3H),4.03(dd, J ═ 7.2,6.8Hz,2H), 3.87-3.73 (m,4H), 2.02-1.76 (m,6H), 1.66-1.56 (m,2H),1.27(t, J ═ 7.2Hz,3H), 1.11-1.02 (m, 3H); nuclear magnetic carbon spectrum (100MHz, CDCl) 3 ) Delta 167.58,166.92,149.89,147.69,128.31,120.13,114.81,111.96,80.45,78.00,62.14,61.89,55.97,55.07,42.66,32.76,24.08,14.00,13.85 Chiral HPLC analysis (Chiral pak AD-H, i-PrOH: n-hexane: 20:80, flow rate 1.0mL/min, wavelength 220nm), t R (main) 6.014min, t R 10.936min, 91% ee.
To the hydrogenation reactor were added (R) -diethyl 2- (2-nitro-1- (3-cyclopentyloxy-4-methoxy) phenethyl) malonate (15.8g,40mmol), 10% Pd/C (4.26g) and xylene (40mL), which was replaced with hydrogen three times, and reacted at 135 ℃ under 10 atmospheres for 18 hours. After the reaction was completed, methanol (30mL) was added, and filtered, and the obtained crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate 5: 1) to obtain the product rolipram (10.5g, yield 95%). Nuclear magnetic hydrogen spectrum (500MHz, CDCl) 3 ) δ 7.22(s,1H),6.80(d, J ═ 8.5,1H), 6.77-6.73 (m,2H),4.74(m,1H),3.80(s,3H),3.73(t, J ═ 9.0,1H), 3.63-3.54 (m,1H),3.36(dd, J ═ 9.5,8.0,1H),2.68(dd, J ═ 17.0,9.0,1H),2.45(dd, J ═ 17.0, 9.01H), 1.95-1.74 (m,6H), 1.65-1.52 (m, 2H); nuclear magnetic carbon spectrum (125MHz, CDCl) 3 )δ178.0,149.0,147.7,134.5,118.6,113.7,112.0,80.4,56.0,49.8,39.8,38.2,32.6,23.9.
EXAMPLE 12 Recycling of polysulfonate diamine-Nickel catalyst
Beta-phenylnitroethylene (74.6mg,0.5mmol), diethyl malonate (120.0mg,0.75mmol), (1S,2S) -poly-2, 7-naphthalenediol sulphonate diamine-nickel dibromide (prepared in example 7, 50.0mg) and dichloromethane (2.5mL) were charged into a 15mL centrifuge tube, and the reaction system was reacted at room temperature for 24 hours under protection of argon. After the reaction was completed, the stirrer was taken out, and n-hexane (2.5mL) was added to complete the precipitation of the catalyst. The centrifuge tube is placed in a centrifuge, the centrifuge tube is centrifuged for 3 minutes at the rotating speed of 1000r/min, and after the centrifugation is finished, the supernatant is sucked into a 50mL round-bottom flask. The above centrifugation was repeated 2 times using n-hexane (3.0mL) as a solvent. The combined supernatants were spin-dried under reduced pressure and the crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate 15: 1) to give diethyl (R) -2- (2-nitro-1-phenylethyl) malonate.
The centrifuged catalyst can be used for the second reaction, and the reaction operation is repeated, so that the catalyst can be recycled for 10 times. The yield and ee value of each reaction are shown in Table 1.
TABLE 1 Recycling of (1S,2S) -poly-2, 7-naphthalenediol sulfonate diamine-nickel dibromide
| Number of cycles | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 |
| Yield/%) | 89.1 | 89.7 | 91.2 | 92.2 | 96.8 | 98.4 | 94.9 | 89.6 | 88.4 | 87.1 |
| ee value/%) | 92 | 92 | 92 | 91 | 91 | 91 | 90 | 90 | 90 | 90 |
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such modifications are intended to be included in the scope of the present invention.
Claims (10)
1. A chiral polysulfonate diamine-metal catalyst for asymmetric conjugate addition reactions characterized by having the structure as shown in formula (I-1) or formula (I-2):
in the structural formulas of the formula (I-1) and the formula (I-2), L is one of chlorine, bromine, iodine or acetate;
x is one of structures shown in a formula (II-1), a formula (II-2), a formula (II-3), a formula (II-4) or a formula (II-5);
n is an integer and takes a value of 2-1000.
2. The chiral polysulfonate diamine-metal catalyst for asymmetric conjugate addition reaction of claim 1 wherein: in the structural formulas of the formula (I-1) and the formula (I-2), L is bromine, and X is the structure shown in the formula (II-3).
3. The method for synthesizing a chiral polysulfonate diamine-metal catalyst for asymmetric conjugate addition reaction as claimed in claim 1 or 2, comprising the steps of:
mixing silyl ether diamine shown in a formula (III-1) or a formula (III-2) with bis-fluorosulfonate shown in a formula (IV), adding alkali, and reacting in a solvent to generate polysulfonate diamine shown in a formula (V-1) or a formula (V-2); the polysulfonic acid ester diamine shown as the formula (V-1) or the formula (V-2) and NiL 2 Reacting to generate chiral polysulfonate diamine-metal catalyst shown in formula (I-1) or formula (I-2);
4. the method of synthesis according to claim 3, characterized in that: the alkali is sodium hydroxide, potassium fluoride, triethylamine, N-diisopropylethylamine, triethylene diamine, N-methylmorpholine or 1, 8-diazabicycloundec-7-ene.
5. The method of synthesis according to claim 3, characterized in that: the solvent is N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, dioxane, dichloromethane, chloroform, ethanol or methanol.
6. The method of synthesis according to claim 3, characterized in that:
the reaction of the siloxane diamine shown in the formula (III-1) or the formula (III-2) and the bis-fluorosulfonate shown in the formula (IV) is carried out at 50-200 ℃ until the reactants are completely cured;
the polysulfonate diamine shown as the formula (V-1) or the formula (V-2) and NiL 2 The reaction of (2) is carried out for 5 to 20 hours at a temperature of between 50 and 200 ℃.
7. Use of a chiral polysulfonate diamine-metal catalyst as described in claim 1 or 2 for catalyzing the asymmetric conjugate addition of 1, 3-dicarbonyl compounds to β -substituted nitroethylene.
8. Use according to claim 7, characterized in that: the 1, 3-dicarbonyl compound is methyl malonate, ethyl malonate, isopropyl malonate, tert-butyl malonate, acetylacetone or acetoacetate.
9. Use according to claim 7, characterized in that: the beta-substituted nitroethylene has a structure shown in a formula (VI), wherein R is C3-C8 straight chain or branched chain alkyl, monosubstituted or disubstituted phenyl and heteroaryl;
10. use according to claim 9, characterized in that:
the heteroaryl is pyridyl, pyrimidyl, furyl, thienyl, benzofuryl, benzothienyl, indolyl or quinolyl;
the substituents on the phenyl and heteroaryl groups are fluoro, chloro, bromo, methyl, ethyl, propyl, cyclopropyl, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, trifluoromethyl, cyano, acetyl or acetoxy.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010708803.8A CN111822053B (en) | 2020-07-22 | 2020-07-22 | Chiral polysulfonate diamine-metal catalyst and synthesis and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010708803.8A CN111822053B (en) | 2020-07-22 | 2020-07-22 | Chiral polysulfonate diamine-metal catalyst and synthesis and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111822053A CN111822053A (en) | 2020-10-27 |
| CN111822053B true CN111822053B (en) | 2022-09-30 |
Family
ID=72924686
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010708803.8A Active CN111822053B (en) | 2020-07-22 | 2020-07-22 | Chiral polysulfonate diamine-metal catalyst and synthesis and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111822053B (en) |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10029601A1 (en) * | 2000-06-15 | 2001-12-20 | Degussa | Soluble optically active polymer-enlarged catalysts comprise transition metal N,N'-bis(o-hydroxybenzylidene)-1,3-propanediamine complexes |
| CN101569864B (en) * | 2008-04-29 | 2011-08-03 | 中山大学 | Chiral sulfonamide organic micromolecule catalyst and application thereof |
| CN101362100A (en) * | 2008-09-12 | 2009-02-11 | 复旦大学 | Chiral amine-(sulphur)urea double functional catalyst and synthesis method and use thereof |
| CN101879458B (en) * | 2010-06-12 | 2012-04-11 | 杭州师范大学 | Preparation method of polysiloxane-loaded chiral diamine derivative catalyst |
| CN101940947B (en) * | 2010-07-05 | 2011-12-21 | 沈阳化工大学 | Method for preparing polystyrene resin-immobilized Salon-Co (III) catalyst |
| CN103951821B (en) * | 2014-04-08 | 2016-08-03 | 湖北大学 | Polyglycol supported double (S)-2-(4 '-oxygen benzyl)-N-methyl ethane-1,2-diamidogen and its production and use |
| US11274182B2 (en) * | 2017-05-11 | 2022-03-15 | Kaneka Corporation | Poly(amic acid), poly(amic acid) solution, polyimide, polyimide film, layered product, flexible device, and production method for polyimide film |
| CN111040165A (en) * | 2019-12-26 | 2020-04-21 | 白银图微新材料科技有限公司 | Polysulfonate polymer and polymerization method thereof |
-
2020
- 2020-07-22 CN CN202010708803.8A patent/CN111822053B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN111822053A (en) | 2020-10-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101531725B (en) | Alpha-nickel diimine compound olefin polymerization catalyst and preparation method thereof, and method for preparing branched polyethylene | |
| CN108383739B (en) | Aromatic amine with hydroxyl, alpha-diimine compound and application thereof in olefin polymerization | |
| CN109053818B (en) | Preparation of fluorinated nickel (II) complexes containing ortho-diphenylmethyl-substituted alpha-diimines for ethylene polymerization | |
| CN113402350B (en) | Biaryl compound and preparation method and application thereof | |
| US20140330018A1 (en) | Metathesis catalysts and methods thereof | |
| CN111960964B (en) | Fluorine substituted alpha-diimine ligand, nickel catalyst, preparation method and application thereof | |
| CN109957049B (en) | Asymmetric (alpha-diimine) nickel olefin catalyst and preparation method and application thereof | |
| CN111822053B (en) | Chiral polysulfonate diamine-metal catalyst and synthesis and application thereof | |
| CN111925356B (en) | Synthesis method and application of chiral quinoline-imidazoline ligand | |
| CN109956979B (en) | Heat-resistant asymmetric alpha-diimine nickel olefin catalyst and preparation method and application thereof | |
| CN112210056B (en) | Porous covalent organic framework material and synthesis method and application thereof | |
| CN116655529A (en) | Method for synthesizing 3-aryl quinoline compound by nickel catalysis | |
| CN105820174A (en) | Polysubstituted thienoindole derivative and preparation method thereof | |
| CN113072517B (en) | Synthetic method of five-membered oxygen heterocyclic compound | |
| JP2004531577A (en) | Preparation of cyclohexanol derivatives | |
| CN113666826B (en) | Aryl or heteroaryl methoxylation reaction method | |
| WO2023134011A1 (en) | Binuclear schiff base cobalt complex, and preparation method therefor and use thereof | |
| CN114478245A (en) | Asymmetric synthesis method of chiral gamma-alkynyl-alpha-keto acid ester compound | |
| CN114989178A (en) | Spiro [ beta-lactam-3, 3' -oxindole ] derivative and preparation method and application thereof | |
| CN111454222B (en) | Synthesis method of 2,4- (1H, 3H) -quinazolinedione and derivatives thereof | |
| CN114907197A (en) | Preparation method of bis-aziridinyl photocrosslinking probe intermediate and derivative | |
| CN111499538B (en) | Preparation method of (2S, 3R) -2-acylaminomethyl-3-hydroxybutyrate | |
| CN113620990A (en) | Thiourea type nitrogen phosphine ligand and preparation method and application thereof | |
| CN112851715A (en) | Complex for catalyzing polymerization of 4-methyl-1-pentene and preparation method thereof | |
| CN111471065A (en) | Method for metal-catalyzed boronation of terminal olefin 1, 1-aryl |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |