CN112321514B - Chiral barbituric acid compound and preparation method thereof - Google Patents
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Abstract
The invention discloses a chiral barbituric acid compound and a preparation method thereof, wherein the chiral barbituric acid compound is light with a structure shown in a formula (1)A chemically active compound comprising a levorotatory or dextrorotatory isomer thereof having the same general chemical formula:
in the formula: represents a chiral carbon atom; substituent R1And R3Each independently selected from alkyl; substituent R2Selected from alkyl or allyl; x is selected from O or S. The invention uses racemic propargyl carbonate and malonate compound as initial raw materials, uses bis- (1, 5-cyclooctadiene) nickel metal as a catalyst, uses a chiral phosphine reagent as a ligand and uses Lewis acid as a cocatalyst, and prepares the chiral barbituric acid compound in a precise and rapid manner with high yield, high enantioselectivity and approximate gram-scale through asymmetric propargyl reaction and subsequent reduction and condensation reaction under the assistance of alkali, thereby having biomedical practicability and industrial application prospect.
Description
Technical Field
The invention belongs to the technical field of asymmetric organic synthesis, and particularly relates to a chiral barbituric acid compound and a preparation method thereof.
Background
The barbituric acid compounds have the drug effects of anesthesia, hypnosis, sedation, convulsion resistance and the like in medicinal chemistry, are very important drug molecules and play very important roles in modern medicine. It is well known that enantiomers of racemic drugs often alter pharmacokinetics and pharmacodynamics. As early as 1981, professor Naylor has demonstrated that the configuration of barbituric acids is crucial for their biological activity, enantiomers of barbituric acid and its racemates exhibit different pharmacological properties, whereas chiral barbituric acid among them exhibits superior efficacy (Carroll, f.i., Philip, a., Naylor, d.m., Christensen, H.D. & gold, w.c.j.med.chem.1981,24,1241). However, due to the lack of efficient enantioselective synthesis of chiral barbituric acids, only racemic mixtures of chiral barbituric acid compounds can be used as medicaments. Also because of their interesting biological properties, challenging structural complexity, asymmetric synthesis of chiral barbiturates has attracted widespread commercial and scientific interest. Listed below are some of the barbituric acid compounds that have been reported so far:
the currently reported preparation method of the barbituric acid compound is only limited to synthesis of racemic barbituric acid derivatives, and the development of the preparation method for synthesizing the barbituric acid derivative with high stereochemical purity is of particular medical value in order to further expand the wide application of the chiral barbituric acid compound in the biological and medical fields. Therefore, there is an urgent need to develop a general strategy for the stereoselective rapid preparation of large amounts of structurally diverse barbituric acid compounds starting from a simple and readily available racemic molecular skeleton.
Disclosure of Invention
The invention aims to provide a chiral barbituric acid compound and a preparation method thereof. The chiral barbituric acid compound can show good biological activity in the fields of biology, medicine and the like, so that the application of the barbituric acid compound in biomedicine is further expanded.
The chiral barbituric acid compound is an optically active compound with a structure shown in the following formula (1), and comprises a levorotatory body or a dextrorotatory body with the same chemical general formula:
in the formula: represents a chiral carbon atom; substituent R1And R3Each independently selected from alkyl; substituent R2Selected from alkyl or allyl; x is selected from O or S.
The preparation method of the chiral barbituric acid compound comprises the following steps:
step 1: under the argon atmosphere, mixing a bis- (1, 5-cyclooctadiene) nickel metal catalyst and a chiral phosphine ligand in an organic solvent, pre-stirring for 15 minutes, then under the protection of argon, adding racemic propargyl carbonate A, malonate derivative B, alkali and Lewis acid into a mixed system, reacting for 12-96 hours at room temperature to 50 ℃, and determining a reaction end point by using a thin-layer chromatography dot plate; diluting the reaction system with ethyl acetate or dichloromethane, adding water for extraction, extracting a water phase with ethyl acetate for 3 times, combining organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure, mixing petroleum ether/ethyl acetate according to a volume ratio of 10-30: 1 to serve as an eluent, and separating by column chromatography to obtain an asymmetric propargylated product C;
step 2: under the air environment, dissolving the asymmetric propargylated product C in an organic solvent, slowly adding palladium/carbon at room temperature, and reacting for 6-12 hours at room temperature to 70 ℃ under the hydrogen atmosphere of one atmosphere; after the reaction is finished, adding ethyl acetate into the reaction system for dilution, filtering through diatomite, concentrating the filtrate under reduced pressure until the filtrate is dry, and then mixing petroleum ether/ethyl acetate according to the volume ratio of 10-30: 1 as an eluent to obtain a compound E through column chromatography separation;
and step 3: dissolving the asymmetric propargylated product C or the compound E and urea or thiourea in an organic solvent in an air environment, slowly adding alkali at 0 ℃, and reacting for 5-12 hours at 0-room temperature; after the reaction is finished, adding ethyl acetate into the reaction system for dilution, adding 6M hydrochloric acid at the temperature of 0 ℃, acidifying and extracting, washing the separated organic phase with saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, and then recrystallizing to obtain the chiral barbituric acid compound D or F.
In the step 1, the molar ratio of the bis- (1, 5-cyclooctadiene) nickel metal catalyst, the chiral phosphine ligand and the malonate derivative B is 0.1:0.12: 1; the molar equivalent ratio of the malonate derivative B to the racemic propargyl carbonate A is 1: 1-3; the molar ratio of the malonate derivative B to the base is 1: 1-3; the amount of the Lewis acid added was 0.2 equivalent to that of the malonate derivative B.
In the step 2, the addition amount of palladium/carbon is 0.1-0.5 time equivalent of the asymmetric propargylated product C.
In the step 3, the molar ratio of the asymmetric propargylated product C or the compound E to urea or thiourea is 1: 2-5; the addition amount of the alkali is 1-3 times equivalent of the asymmetric propargylated product C or the compound E.
The preparation route of the chiral barbituric acid compound is as follows:
in the formula: represents a chiral carbon atom; substituent R1、R3And R4Each independently selected from alkyl; substituent R2Selected from alkyl or allyl; r5Selected from methyl, ethyl, tert-butyl or benzyl; x is selected from O or S.
In the preparation process, the alkali is cesium carbonate, potassium tert-butoxide, sodium methoxide, sodium ethoxide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide or sodium hydride.
In the preparation process, the organic solvent is dichloromethane, acetonitrile, tetrahydrofuran, toluene, methanol, ethanol, ethyl acetate, 1, 2-dichloroethane, N-dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide.
In the preparation process, the chiral phosphine ligand is (R or S) -1,1' -binaphthyl-2, 2' -bisdiphenylphosphine, (R or S) -5,5' -bis (diphenylphosphoryl) -4,4' -di-1, 3-biphenyl, (R or S) -2,2' -bis [ di (4-methylphenyl phosphine) ] -1,1' -binaphthyl or (R or S) -5,5' -bis (diphenylphosphoryl) -tetrafluoro-di-1, 3-benzodioxole.
In the preparation process, the Lewis acid is copper trifluoromethanesulfonate, zinc trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate or scandium trifluoromethanesulfonate.
The invention provides a method for synthesizing a chiral barbituric acid compound through key steps of an asymmetric propargylation reaction. The invention uses racemic propargyl carbonate and malonate compounds as initial raw materials, uses bis- (1, 5-cyclooctadiene) nickel metal as a catalyst, uses a chiral phosphine reagent as a ligand and uses Lewis acid as a cocatalyst, and prepares a chiral barbituric acid compound in a precise and rapid manner with high yield, high enantioselectivity and near gram-scale for the first time through asymmetric propargylation reaction and subsequent reduction and condensation reaction under the assistance of alkali. The invention not only successfully develops the synthetic method of the chiral barbituric acid compound, and the chiral barbituric acid compound with high yield and high optical purity can be easily prepared, but also has wide medical prospect, lays a foundation for further expanding wider medical application of barbituric acid drug molecules, and has biomedical practicability and industrial application prospect.
Drawings
FIG. 1 is a schematic diagram of the preparation route of example 1.
FIG. 2 is a schematic diagram of the preparation route of example 2.
FIG. 3 is a schematic diagram of the preparation route of example 3.
Detailed Description
Example 1: preparation of (-) -thiohexital
1. To a dry 100mL Schlenk reaction tube under a glove box nitrogen atmosphere were added bis- (1, 5-cyclooctadiene) nickel (96.3mg, 0.35mmol, 10 mol%) and (R) -5,5 '-bis (diphenylphosphoryl) -4,4' -di-1, 3-biphenyl (256mg, 0.42mmol, 12 mol%), and 40mL of toluene was added and stirred for 15 minutes; then 7.0mmol 1x (1.4g, 2.0 equiv.), 3.5mmol 2d (603mg, 1.0 equiv.), ytterbium triflate (434.2mg, 0.7mmol, 20 mol%) and potassium tert-butoxide (785.5mg, 7.0mmol, 2.0 equiv.) were added sequentially to the reaction tube under nitrogen protection and the reaction was stirred at room temperature for about 72 hours until substrate 2d was completely consumed (monitored by TLC); the reaction was subsequently diluted with ethyl acetate and extracted with water, the aqueous phase was then extracted 3 times with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then purified by column chromatography using a 20:1 mixture of petroleum ether/ethyl acetate as eluent to give asymmetric propargylated product 3(0.71g, 80% yield, 88% ee).
A colorless liquid (0.71g, 80% yield).1H NMR(500MHz,CDCl3)δ5.91–5.71(m,1H),5.17–5.01 (m,2H),3.75(s,3H),3.71(s,3H),3.19–3.07(m,1H),2.80(d,J＝7.2Hz,2H),2.22–2.09(m, 2H),1.27(d,J＝7.0Hz,3H),1.10(t,J＝7.5Hz,3H).13C NMR(125MHz,CDCl3)δ170.57, 170.19,133.29,118.78,84.79,79.29,61.51,52.32,52.23,38.72,30.89,18.03,14.33, 12.50.ATR-FTIR(cm-1):2977,2921,2850,2244,1735,1639,1376,1228,1033,921.ESI-MS: calculated[C14H20O4+H]+:253.1434,found:253.1428.[α]20 D＝-34.3(c＝1.05,CH2Cl2).The product was analyzed by HPLC to determine the enantiomeric excess:88％ee(IG,hexane/i-PrOH ＝99/1,detector:220nm,flow rate:0.3mL/min),t1(minor)＝18.2min,t2(major)＝21.0min.
2. Asymmetric propargylated product 3(707mg, 2.8mmol, 1.0 equiv.) and thiourea (426mg, 5.6mmol, 2.0 equiv.) were placed in dry dimethylsulfoxide (30mL) under air and stirred under ice bath, and 60% sodium hydride (336mg, 8.4mmol, 3.0 equiv.) was slowly added to the reaction system; the reaction was then stirred at room temperature for about 10 hours until complete consumption of substrate 3 (monitored by TLC); the reaction was then diluted with ethyl acetate (50mL) and acidified and extracted with HCl (6M) at 0 ℃, the aqueous phase was extracted 3 times with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by recrystallization to give the desired chiral thiohexital product 4(0.41g, 55% yield, 88% ee). The chiral barbituric acid compound is finally obtained by two-step reaction in 44% of comprehensive yield.
Yellow solid (0.41g, 55% yield). M.p.124-126 ℃.1H NMR(500MHz,CDCl3)δ9.68–9.48 (m,2H),5.65–5.51(m,1H),5.21–5.06(m,2H),3.19–3.04(m,1H),2.87(dd,J＝13.0,7.4Hz, 1H),2.67(dd,J＝13.0,7.3Hz,1H),2.17–2.07(m,2H),1.31(d,J＝7.1Hz,3H),1.06(t,J＝7.5 Hz,3H).13C NMR(125MHz,CDCl3)δ176.62,169.95,168.11,130.84,121.48,87.02,77.09, 59.85,37.87,36.04,16.22,13.89,12.47.ATR-FTIR(cm-1):3218,2977,2937,2242,1733,1697, 1523,1359,1247,1155,931.ESI-MS:calculated[C13H16N2O2S+H]+:265.1005,found:265.1008. [α]20 D＝-49.1(c＝0.94,CH2Cl2).The product was analyzed by HPLC to determine the enantiomeric excess:88％ee(IF,hexane/i-PrOH＝90/10,detector:300nm,flow rate:1.0mL/min), t1(major)＝16.6min,t2(minor)＝22.0min.
Example 2: preparation of (+) -pentothiobarbital
1. To a dry 100mL Schlenk reaction tube under a glove box nitrogen atmosphere were added bis- (1, 5-cyclooctadiene) nickel (110.0mg,0.4mmol,10 mol%) and (R) -5,5 '-bis (diphenylphosphoryl) -4,4' -di-1, 3-biphenyl (293mg,0.48 mmol,12 mol%), and 50mL dichloromethane was added and stirred for 15 minutes; then under nitrogen protection 6.0mmol 1z (1.1g, 1.5 equiv.), 4.0mmol 2m (640mg,1.0 equiv.), ytterbium triflate (496.2mg,0.8mmol,20 mol%) and cesium carbonate (2.6g,8.0mmol,2.0 equiv.) were added to the reaction tube in sequence and the reaction was stirred at room temperature for about 96 hours until substrate 2m was completely consumed (monitored by TLC); the reaction was subsequently diluted with dichloromethane and extracted with water, the aqueous phase was then extracted 3 times with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then purified by column chromatography using a 20:1 mixture of petroleum ether/ethyl acetate as eluent to give the desired asymmetric propargylated product 5(0.59g, 65% yield, 90% ee).
A colorless liquid (0.59g, 65% yield).1H NMR(500MHz,CDCl3)δ3.74(s,3H),3.72(s,3H),3.18 –3.08(m,1H),2.12–2.03(m,2H),1.77(d,J＝2.4Hz,3H),1.24(d,J＝7.0Hz,3H),0.90(t,J＝ 7.5Hz,3H).13C NMR(125MHz,CDCl3)δ171.14,170.75,79.19,78.25,61.69,52.29,52.14, 30.73,27.40,18.09,9.42,3.68.ATR-FTIR(cm-1):2981,2952,2923,2246,1735,1434,1382,1240, 1136,916.ESI-MS:calculated[C12H18O4+H]+:227.1278,found:227.1284.[α]20 D＝-11.5(c＝ 0.17,CH2Cl2).The product was analyzed by HPLC to determine the enantiomeric excess:90％ee (IC,hexane/i-PrOH＝99/1,detector:211nm,flow rate:0.3mL/min),t1(minor)＝32.4min, t2(major)＝35.2min.
2. Dissolving asymmetric propargylated product 5(678.9mg, 3.0mmol) in methanol solvent under air, slowly adding 10% palladium on carbon at room temperature, and reacting at room temperature for 12 hours under one atmosphere of hydrogen; after the reaction, ethyl acetate was added to the reaction system to dilute, and the mixture was filtered through celite, and the filtrate was concentrated to dryness under reduced pressure, and then the desired compound 6(0.59g, 86% yield) was obtained by column chromatography purification using a mixture of petroleum ether/ethyl acetate at a volume ratio of 20:1 as an eluent.
A colorless liquid (0.59g, 86% yield).1H NMR(500MHz,CDCl3)δ3.75–3.65(m,6H),2.12–2.02(m,1H),1.93(q,J＝7.5Hz,2H),1.49–1.38(m,2H),1.26–1.17(m,1H),1.00–0.94(m, 1H),0.93–0.80(m,9H).13C NMR(125MHz,CDCl3)δ172.01,171.84,62.99,51.89,51.87, 37.02,35.07,27.20,21.36,15.08,14.25,9.50.ATR-FTIR(cm-1):2954,2875,1735,1434,1386, 1236,1133,914,804.ESI-MS:calculated[C12H22O4+H]+:231.1591,found:231.1592.[α]20 D＝ 10.2(c＝0.79,CH2Cl2).
3. Asymmetric propargylated reduction product 6(1150mg,5.0mmol, 1.0 equiv.) and thiourea (761 mg,10mmol,2.0 equiv.) were placed in dry N-methylpyrrolidone (50mL) under an air atmosphere and stirred under ice bath, and 60% sodium hydride (600mg,15mmol,3.0 equiv.) was slowly added to the reaction system; the reaction was then stirred at room temperature for about 10 hours until complete consumption of substrate 6 (monitored by TLC). The reaction was then diluted with ethyl acetate (80mL) and acidified and extracted with HCl (6M) at 0 ℃, the aqueous phase was extracted 3 times with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by recrystallization to give the desired chiral pentathiobarbital product 7 (0.81g, 67% yield, 90% ee). The chiral barbituric acid compound is finally obtained by a three-step reaction in a comprehensive yield of 37%.
Yellow solid (0.81g, 67% yield). M.p.142-144 ℃.1H NMR(500MHz,CDCl3)δ9.09(brs, 2H),2.20–2.04(m,3H),1.50–1.36(m,2H),1.23–1.12(m,2H),1.04(d,J＝6.9Hz,3H),0.90– 0.83(m,6H).13C NMR(125MHz,CDCl3)δ176.12,170.53,170.16,61.39,43.08,34.02,28.76, 20.83,14.47,14.06,9.95.ATR-FTIR(cm-1):3259,2985,2931,2873,1735,1672,1542,1427, 1365,1222,1172,840.ESI-MS:calculated[C11H18N2O2S+H]+:243.1162,found:243.1164. [α]20 D＝11.2(c＝0.90,CH2Cl2).The product was analyzed by HPLC to determine the enantiomeric excess:90％ee(IF,hexane/i-PrOH＝90/10,detector:300nm,flow rate:1.0mL/min),t1(major)＝ 13.7min,t2(minor)＝15.9min.
Example 3: preparation of (+) -pentobarbital
The procedure for the synthesis of asymmetric propargylated product 5 and reduced product 6 is the same as in example 2. Asymmetric propargylated reduction product 6(1150mg,5.0mmol, 1.0 equiv.) and urea (601mg,10mmol,2.0 equiv.) were placed in dry dimethylsulfoxide (50mL) under air and stirred under ice bath, and 60% sodium hydride (600mg,15mmol,3.0 equiv.) was slowly added to the reaction system; the reaction was then stirred at room temperature for about 10 hours until complete consumption of substrate 6 (monitored by TLC). The reaction was then diluted with ethyl acetate (80mL) and acidified and extracted with HCl (6M) at 0 ℃, the aqueous phase was extracted 3 times with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by recrystallization to give the desired chiral pentobarbital product 8(0.79g, 70% yield, 90% ee). The chiral barbituric acid compound is finally obtained in 39% of comprehensive yield through three-step reaction in the route.
Yellow solid (0.79g, 70% yield). M.p.107-108 ℃.1H NMR(500MHz,CDCl3)δ8.90(brs, 2H),2.20–2.03(m,3H),1.50–1.38(m,2H),1.23–1.11(m,2H),1.04(d,J＝6.9Hz,3H),0.89– 0.82(m,6H).13C NMR(125MHz,CDCl3)δ172.91,172.57,149.56,61.12,42.55,34.01,28.73, 20.87,14.38,14.07,9.90.ATR-FTIR(cm-1):3234,2962,2875,1710,1427,1359,1218,1149,792. ESI-MS:calculated[C11H18N2O3+H]+:227.1390,found:227.1394.[α]20 D＝10.7(c＝0.80, CH2Cl2).The product was analyzed by HPLC to determine the enantiomeric excess:90％ee(IF, hexane/i-PrOH＝95/5,detector:211nm,flow rate:1.0mL/min),t1(major)＝40.8min,t2(minor)＝ 45.2min.
Claims (5)
1. A preparation method of a chiral barbituric acid compound is characterized by comprising the following steps:
using racemic propargyl carbonate and malonate compounds as initial raw materials, using bis- (1, 5-cyclooctadiene) nickel metal as a catalyst, using a chiral phosphine reagent as a ligand and using Lewis acid as a co-catalyst, and preparing a chiral barbituric acid compound through an asymmetric propargylation reaction and subsequent reduction and condensation reactions under the assistance of alkali; the preparation route is as follows:
1)
2)
in the formula: represents a chiral carbon atom; substituent R1And R3Each independently selected from alkyl; substituent R2Selected from alkyl or allyl; x is selected from O or S;
the method specifically comprises the following steps:
step 1: under the argon atmosphere, mixing a bis- (1, 5-cyclooctadiene) nickel metal catalyst and a chiral phosphine ligand in an organic solvent, pre-stirring for 15 minutes, then under the protection of argon, adding racemic propargyl carbonate A, malonate derivative B, alkali and Lewis acid into a mixed system, reacting for 12-96 hours at room temperature to 50 ℃, and determining a reaction end point by using a thin-layer chromatography dot plate; diluting the reaction system with ethyl acetate or dichloromethane, adding water for extraction, extracting a water phase with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, decompressing and concentrating, and separating by column chromatography to obtain an asymmetric propargylated product C;
step 2: under the air environment, dissolving the asymmetric propargylated product C in an organic solvent, slowly adding palladium/carbon at room temperature, and reacting for 6-12 hours at room temperature to 70 ℃ under the hydrogen atmosphere of one atmosphere; after the reaction is finished, adding ethyl acetate into the reaction system for dilution, filtering through diatomite, concentrating the filtrate under reduced pressure until the filtrate is dry, and then separating through column chromatography to obtain a compound E;
and step 3: dissolving the asymmetric propargylated product C or the compound E and urea or thiourea in an organic solvent in an air environment, slowly adding alkali at 0 ℃, and reacting for 5-12 hours at 0-room temperature; after the reaction is finished, adding ethyl acetate into the reaction system for dilution, adding hydrochloric acid at 0 ℃ for acidification and extraction, washing the separated organic phase with saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, and then recrystallizing to obtain a chiral barbituric acid compound D or F;
the alkali is cesium carbonate, potassium tert-butoxide, sodium methoxide, sodium ethoxide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide or sodium hydride;
the chiral phosphine ligand is (R or S) -1,1' -binaphthyl-2, 2' -bis-diphenylphosphine, (R or S) -5,5' -bis (diphenylphosphoryl) -4,4' -di-1, 3-biphenyl, (R or S) -2,2' -bis [ di (4-methylphenyl phosphine) ] -1,1' -binaphthyl or (R or S) -5,5' -bis (diphenylphosphoryl) -tetrafluoro-di-1, 3-benzodioxolane;
the Lewis acid is copper trifluoromethanesulfonate, zinc trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate or scandium trifluoromethanesulfonate.
2. The method of claim 1, wherein:
in the step 1, the molar ratio of the bis- (1, 5-cyclooctadiene) nickel metal catalyst, the chiral phosphine ligand and the malonate derivative B is 0.1:0.12: 1; the molar equivalent ratio of the malonate derivative B to the racemic propargyl carbonate A is 1: 1-3; the molar ratio of the malonate derivative B to the base is 1: 1-3; the amount of the Lewis acid added was 0.2 equivalent to that of the malonate derivative B.
3. The method of claim 1, wherein:
in the step 2, the addition amount of palladium/carbon is 0.1-0.5 time equivalent of the asymmetric propargylated product C.
4. The method of claim 1, wherein:
in the step 3, the molar ratio of the asymmetric propargylated product C or the compound E to urea or thiourea is 1: 2-5; the addition amount of the alkali is 1-3 times equivalent of the asymmetric propargylated product C or the compound E.
5. The method of claim 1, wherein:
the organic solvent is dichloromethane, acetonitrile, tetrahydrofuran, toluene, methanol, ethanol, ethyl acetate, 1, 2-dichloroethane, N-dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide.
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