CN110776470A - Method for synthesizing chiral 3, 4-dihydro quinazolinone through iridium-catalyzed asymmetric hydrogenation of quinazolinone compound - Google Patents
Method for synthesizing chiral 3, 4-dihydro quinazolinone through iridium-catalyzed asymmetric hydrogenation of quinazolinone compound Download PDFInfo
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- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
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- C07D239/72—Quinazolines; Hydrogenated quinazolines
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Abstract
The invention provides a method for synthesizing chiral 3, 4-dihydro-quinazolinone by iridium-catalyzed asymmetric hydrogenation of quinazolinone compound,
in the formula: r is C
1‑6Alkyl or aryl containing a substituent; r' is hydrogen, C
1At least one of alkyl, alkoxy and chlorine; the substituents are F, Cl, CF
3At least one of Ph, Me and MeO. The method has wide substrate range, realizes the synthesis diversity of chiral 3, 4-dihydro quinazolinone, and simultaneously, the enantiomeric excess of the chiral 3, 4-dihydro quinazolinone can reach 98%. The method has the advantages of simple, convenient, practical and feasible operation, high yield, environment friendliness, commercial availability of the catalyst, mild reaction conditions and practical application value.
Description
Technical Field
The invention relates to a method for synthesizing 3, 4-dihydro quinazolinone by catalyzing quinazolinone compound asymmetric hydrogenation with iridium catalytic system with high enantioselectivity, belonging to the field of chemical synthesis of chiral amine compounds.
Background
The chiral 3, 4-dihydro quinazolinone compound has broad spectrum biological activity, and thus has important application in the field of medicinal chemistry (formula 1). For example, the second generation aids non-nucleoside reverse transcriptase inhibitors DPC 083 and DPC 961 exhibit encouraging biological activity in the treatment of aids; the calcium sodium ion exchange inhibitor SM-15811 has good drug effect in treating ischemic heart disease.
Asymmetric addition of nucleophiles to quinazolinones is currently the most prominent method for the synthesis of chiral 3, 4-dihydroquinazolinones (reference one: (a) Yuan, h.n.; Wang, s.; Nie, j.; Meng, w.; Yao, q.; Ma, j.a. angelw.chem.int.ed.2013, 52,3869.(b) Xie, h.; Zhang, y.; Zhang, s.; Chen x.; Wang, w.angelw.chem.int.2011, 50,11773.(c) Jiang, b.; Si, y.g. angelw.chem.int.2012.2004, 43,216.(d) Zhang, f.g.; Zhu, x.y.; Li, s. Nie, j. ma. 48,11552). The chiral 3, 4-dihydro quinazolinone compound and the derivative thereof synthesized by the asymmetric hydrogenation method have excellent atom economy, but the related reports are relatively rare at present. 2013, the Zhou group used Pd (OCOCOCF)
3)
2The asymmetric hydrogenation of quinazolinone was achieved with maximum enantioselectivity of 98% using (S) -SynPhos catalyst. However, the substrate range is limited to trifluoromethyl, difluoromethyl substituted quinazolinone compounds (reference II: Duan, Y.; Zhu, X. -Y.; Ma, J. -A.; Zhou, Y. -G.tetrahedron Lett.2013,54,6161.). It is still very meaningful to further develop asymmetric hydrogenation of quinazolinone compounds to achieve diverse synthesis of chiral dihydroquinazolinones to meet the extensive demands of scientific research.
Disclosure of Invention
The invention aims to provide a method for synthesizing a chiral 3, 4-dihydro quinazolinone compound by catalyzing asymmetric hydrogenation quinazolinone compound by iridium, and in order to realize the aim, the technical scheme adopted by the invention is as follows:
provides a method for synthesizing 3, 4-dihydro quinazolinone by iridium-catalyzed asymmetric hydrogenation of quinazolinone compound,
in the formula:
r is C
1-6Including linear, branched and cyclic alkyl groups or substituted aryl groups, such as: methyl, ethyl, propyl, isopropyl, cyclohexyl, etc., preferably methyl, isopropyl, cyclohexyl;
r' is hydrogen, C
1Including straight or branched chain alkoxy groups of 1 to 3 carbon atoms, such as: methoxy, ethoxy, isopropoxy, preferably methoxy.
The asymmetric hydrogenation synthesis method specifically comprises two stages of catalyst preparation and substrate hydrogenation;
(1) catalyst preparation
Mixing an iridium metal precursor, a chiral diphosphine ligand and an organic solvent, and stirring at room temperature for 10-20 minutes to obtain a catalyst;
(2) hydrogenation reaction
Adding the obtained catalyst, additive and organic solvent into a quinazolinone substrate under the protection of nitrogen, transferring into a high-pressure kettle, charging hydrogen gas at 100-1000 psi, and stirring at 25-80 ℃ for 12-24 hours to generate a product.
The organic solvent is at least one of toluene, tetrahydrofuran, dichloromethane, ethyl acetate, 1, 4-dioxane and methanol.
The iridium metal precursor is selected from methoxy (cyclooctadiene) iridium dimer, bis (cyclooctene) iridium chloride dimer, 1, 5-cyclooctadieneiridium chloride dimer.
The ligand is selected from (R) -DifluorPhos, (R) -MeOBIPHep, (R) -SegPhos, (R) -SynPhos, (R) -BINAP, (S, S) -MeDuPhos.
The method comprises the following feeding proportions: the molar ratio of the metal precursor of iridium, the chiral diphosphine ligand, the additive and the substrate is as follows: 0.01-0.05:0.022-0.110:0.05-0.10:1.
The additive is trichloroisocyanuric acid, N-bromosuccinimide, bromochlorohydantoin, iodine and N-iodosuccinimide.
The asymmetric hydrogenation reaction is carried out at a reaction pressure of 100-1200psi, preferably 200-800 psi, and a reaction temperature of 0-100 deg.C, preferably 25-80 deg.C.
When the hydroxyl group with an isomerization functional group is introduced into the aromatic compound, the aromaticity can be reduced to a certain extent, so that the activity of a substrate is improved, and the substrate is easier to be hydrogenated.
The invention adopts a transition metal iridium catalytic system to catalyze the asymmetric hydrogenation reaction of the quinazolinone compound, realizes the effective synthesis of chiral 3, 4-dihydro quinazolinone, and has the following beneficial effects:
1. the reaction selectivity is good, and the enantiomeric excess value of the product can be up to 98% ee;
2. chiral 3, 4-dihydro quinazolinone compounds can be well obtained;
3. the catalyst is convenient to prepare, and the reaction operation is simple, convenient and practical;
4. the hydrogenation reaction condition is mild, and the atom economy is high.
Detailed Description
The present invention will be described in detail by way of examples, which are given as alternatives, but are not limited thereto.
The method for asymmetric hydrogenation reaction comprises two stages of catalyst preparation and substrate hydrogenation
(1) Preparing a catalyst: adding an iridium metal precursor and a chiral diphosphine ligand into an organic solvent, and stirring at room temperature for 10-20 minutes to obtain the catalyst.
(2) And (3) hydrogenation reaction, namely adding the catalyst, the additive and the organic solvent into a substrate under the protection of nitrogen, sealing the substrate into a high-pressure kettle, introducing hydrogen, and stirring the mixture for 12 to 24 hours at a temperature of between 25 and 80 ℃ to generate a product.
The specific conditions of the hydrogenation reaction are as follows: under the protection of nitrogen, adding the catalyst, the additive and the organic solvent into an ampoule of a quinazolinone substrate, moving the ampoule into a reaction kettle, introducing hydrogen, reacting for 12-24 hours at a certain temperature, releasing the hydrogen, decompressing, concentrating, removing the solvent, and performing column chromatography separation to obtain a target product.
The catalyst is a complex of iridium metal precursor and diphosphine ligand, and the iridium metal precursor and the diphosphine ligand are commercially available without any treatment.
Examples 1 to 13
Optimization of 4-substituted quinazolinone hydrogenation reaction conditions
Adding 1, 5-cyclooctadiene iridium chloride dimer (0.5-5 mol% of the dosage of a substrate) and chiral diphosphine ligand (1.1-11 mol% of the dosage of the substrate) into a reaction bottle, replacing with nitrogen, adding an organic solvent (1.0-4.0mL), and stirring at room temperature for 10 minutes; then transferring the solution into a reaction bottle which is pre-filled with a substrate 1a (0.1mmol) and an additive (5 mol% -30 mol% of the substrate amount) by using an organic solvent (1.0-2.0 mL), moving the reaction bottle into a reaction kettle, introducing hydrogen (400psi-800psi), and reacting for 24 hours at 25-80 ℃; releasing hydrogen, removing the solvent, directly performing column chromatography separation to obtain a target product, and changing the types of the organic solvent, the additive and the chiral diphosphine ligand in the reaction process to obtain 13 different embodiments, wherein the changed types are shown in Table 1. The equations and ligand structures are as follows:
note: in the formula [ Ir (COD) Cl]
2Is 1, 5-cyclooctadiene iridium chloride dimer, chiral ligand, Additive and Solvent.
The yield was the conversion, the enantiomeric excess of the product was determined by chiral liquid chromatography and is detailed in table 1.
TABLE 1 asymmetric hydrogenation condition optimization of 4-phenylquinazolinone 1a
a
Examples 14 to 28
Iridium catalyzed asymmetric hydrogenation of 4-substituted quinazolinones
1, 5-cyclooctadiene iridium chloride dimer (1.0 mol% based on the amount of the substrate) and (R) -SegPhos (2.2 mol% based on the amount of the substrate) were charged into a reaction flask, and tetrahydrofuran (1.0 mL) was added after nitrogen substitution, followed by stirring at room temperature for 10 minutes; transferring the solution into an ampoule with tetrahydrofuran (2.0mL) in which a substrate 1(0.3mmol) and bromochlorohydantoin (10 mol%) are placed in advance, moving the ampoule into a reaction kettle, introducing hydrogen (600psi), and reacting at 25 ℃ for 24 hours; releasing hydrogen, removing solvent, separating by column chromatography to obtain pure product, and changing the kind of substrate during reaction to obtain 15 different examples, wherein the changed kinds are shown in Table 2. The reaction formula is as follows:
note: in the formula [ Ir (COD) Cl]
2Is 1, 5-cyclooctadiene iridium chloride dimer, (R) -SegPhos is chiral ligand, BCDMH is bromochlorohydantoin, THF is tetrahydrofuran.
The yields were isolated and the enantiomeric excess of the product was determined by chiral liquid chromatography, see table 2.
TABLE 2 Iridium catalyzed asymmetric hydrogenation synthesis of 3, 4-dihydroquinazolinone 2
a
(S)-(-)-4-Phenyl-3,4-dihydroquinazolin-2(1H)-one(2a):white solid,91％yield,the known compound,98％ee,[α]
20 D＝-110.4(c 0.92,MeOH),R
f＝0.31(dichloromethane /methanol＝15/1)；
1H NMR(400MHz,CDCl
3)δ7.41–7.26(m,5H),7.17–7.07(m,1H), 6.92–6.67(m,3H),5.64(s,1H)；
13C NMR(100MHz,CD
3OD)δ155.4,144.2,136.0,128.4, 127.9,127.5,126.7,126.5,122.0,121.5,114.0,57.8；Enantiomericexcess was determined by HPLC(OD-H column,Hexanes/i-PrOH＝90/10,detector:254nm,flow rate:1.0 mL/min,30℃),t
1＝16.0min(maj),t
2＝24.4min.
(-)-4-o-Tolyl-3,4-dihydroquinazolin-2(1H)-one(2b):white solid,mp:117-118℃,97％ yield,the new compound,92％ee,[α]
20 D＝-74.2(c 0.26,MeOH),R
f＝0.35(dichloro methane/methanol＝15/1)；
1H NMR(400MHz,DMSO)δ9.24(s,1H),7.33–7.02(m,6H), 6.87–6.81(m,1H),6.80–6.73(m,1H),6.70(d,J＝7.2Hz,1H),5.81(d,J＝1.8Hz,1H),2.39(s,3H)；
13C NMR(100MHz,DMSO)δ153.7,143.0,137.8,135.5,131.2,128.6,128.3,127.9,126.9,126.8,121.7,121.6,114.3,54.7,19.5；Enantiomeric excess wasdetermined by HPLC(OD-H column,Hexanes/i-PrOH＝90/10,detector:254nm,flowrate:1.0mL/min, 30℃),t
1＝12.6min(maj),t
2＝14.6min；HRMS(ESI)m/z Calculated forC
15H
15N
2O [M+H]
+239.1179,found 239.1177.
(-)-4-m-Tolyl-3,4-dihydroquinazolin-2(1H)-one(2c):white solid,mp:210-211℃,90％ yield,the new compound,96％ee,[α]
20 D＝-78.3(c 0.66,MeOH),R
f＝0.35(dichloro methane/methanol＝15/1)；
1H NMR(400MHz,DMSO)δ9.21(s,1H),7.38(s,1H),7.20(t, J＝7.6Hz,1H),7.13–6.93(m,5H),6.80(t,J＝6.8Hz,2H),5.47(s,1H),2.26(s,3H)；
13C NMR(100MHz,DMSO)δ154.2,145.5,138.1,137.4,128.9,128.4,128.3,127.2,123.9, 122.1,121.5,114.3,57.2,21.6；Enantiomeric excess was determined by HPLC(OD-H column,Hexanes/i-PrOH＝90/10,detector:254nm,flow rate:1.0mL/min,30℃),t
1＝16.8 min(maj),t
2＝19.6min；HRMS(ESI)m/z Calculated for C
15H
15N
2O[M+H]
+239.1179, found 239.1177.
(-)-4-p-Tolyl-3,4-dihydroquinazolin-2(1H)-one(2d):white solid,97％yield,the known compound,95％ee,[α]
20 D＝-135.8(c 0.33,MeOH),R
f＝0.30(dichloromethane/methanol ＝15/1)；
1H NMR(400MHz,CDCl
3)δ8.96(s,1H),7.28–7.19(m,2H),7.18–7.04(m,3H), 6.93–6.61(m,3H),5.93(s,1H),5.60(s,1H),2.31(s,3H)；
13C NMR(100MHz,CDCl
3)δ 155.2,140.1,138.0,136.0,129.6,128.3,127.1,126.9,122.3,121.5,114.6,58.3,21.1； Enantiomeric excess was determined by chiral HPLC(OD-Hcolumn,Hexanes/i-PrOH＝ 90/10,detector:254nm,flow rate:1.0mL/min,30℃),t
1＝18.5min(maj),t
2＝22.6min.
(-)-4-(3,5-Dimethylphenyl)-3,4-dihydroquinazolin-2(1H)-one(2e):whitesolid,mp: 200-201℃,91％yield,the new compound,96％ee,[α]
20 D＝-140.8(c 0.24,MeOH),R
f＝ 0.35(dichloromethane/methanol＝15:1)；
1H NMR(400MHz,CDCl
3)δ7.81(s,1H), 7.17–7.13(m,1H),6.96(s,3H),6.89–6.82(m,2H),6.76(d,J＝7.8Hz,1H),5.58(s,1H), 5.27(s,1H),2.30(s,6H)；
13C NMR(100MHz,CDCl
3)δ154.3,142.7,138.7,135.7,130.0, 128.4,127.1,125.0,122.4,121.4,114.3,58.8,21.3；Enantiomeric excess wasdetermined by HPLC(OD-H column,Hexanes/i-PrOH＝90/10,detector:254nm,flowrate:1.0mL/min, 30℃),t
1＝13.1min(maj),t
2＝16.8min；HRMS(ESI)m/z Calculated forC
16H
17N
2O [M+H]
+253.1335,found 253.1337.
(-)-4-(3-Methoxyphenyl)-3,4-dihydroquinazolin-2(1H)-one(2f):whitesolid,mp: 175-176℃,88％yield,the new compound,95％ee,[α]
20 D＝-70.4(c 0.82,MeOH),R
f＝ 0.40(neat ethyl acetate)；
1H NMR(400MHz,DMSO)δ9.26(s,1H),7.44(s,1H),7.24(t,J ＝7.8Hz,1H),7.10(dd,J＝16.2,7.8Hz,2H),6.84(dd,J＝17.6,9.2Hz,5H),5.50(s,1H), 3.72(s,3H)；
13C NMR(100MHz,DMSO)δ159.8,154.2,147.0,137.4,130.2,128.3,127.2, 122.0,121.6,118.8,114.4,112.8,112.7,57.0,55.5；Enantiomeric excess wasdetermined by HPLC(IC column,Hexanes/i-PrOH＝80/20,detector:230nm,flow rate:0.80mL/min,30 ℃),t
1＝15.7min,t
2＝25.8min(maj)；HRMS(ESI)m/z Calculated forC
15H
15N
2O
2[M+H]
+255.1128,found 255.1126.
(-)-4-(4-Methoxyphenyl)-3,4-dihydroquinazolin-2(1H)-one(2g):whitesolid,mp: 236-237℃,98％yield,the new compound,91％ee,[α]
20 D＝-85.6(c 0.55,MeOH),R
f＝0.40(dichloromethane/methanol＝15/1)；
1H NMR(400MHz,DMSO)δ9.24(s,1H),7.38 (s,1H),7.21(d,J＝8.6Hz,2H),7.11(t,J＝7.6Hz,1H),7.00(d,J＝7.5Hz,1H),6.89(d,J ＝8.6Hz,2H),6.82(t,J＝7.4Hz,2H),5.48(d,J＝1.5Hz,1H),3.72(s,3H)；
13C NMR(100MHz,DMSO)δ159.0,154.2,137.6,137.4,128.2,128.0,127.2,122.5,121.5,114.3,56.6,55.6；Enantiomeric excess was determined by HPLC(OD-3 column,Hexanes/i-PrOH ＝90/10,detector:254nm,flow rate:1.0mL/min,30℃),t
1＝24.0min,t
2＝25.7min(maj)； HRMS(ESI)m/z Calculated for C
15H
15N
2O
2[M+H]
+255.1128,found 255.1133.
(-)-4-(3,5-Dimethoxyphenyl)-3,4-dihydroquinazolin-2(1H)-one(2h):whitesolid,mp: 115-116℃,91％yield,the new compound,95％ee,[α]
20 D＝-85.5(c 0.60,MeOH),R
f＝ 0.30(dichloromethane/methanol＝15/1)；
1H NMR(400MHz,DMSO)δ9.19(s,1H),7.36 (s,1H),7.17–6.99(m,2H),6.79(dd,J＝14.6,7.6Hz,2H),6.42(d,J＝1.8Hz,2H),6.36(s, 1H),5.40(d,J＝1.9Hz,1H),3.67(s,6H)；
13C NMR(100MHz,DMSO)δ160.5,153.7, 147.2,136.9,127.8,126.7,121.3,121.0,113.8,104.5,98.4,56.6,55.1；Enantiomeric excess was determined by HPLC(IA column,Hexanes/i-PrOH＝75/25,detector:254nm,flow rate: 0.90mL/min,30℃),t
1＝12.0min(maj),t
2＝21.0min；HRMS(ESI)m/z Calculated for C
16H
17N
2O
3[M+H]
+285.1234,found 285.1236.
(-)-4-(4-Chlorophenyl)-3,4-dihydroquinazolin-2(1H)-one(2i):whitesolid,yield:97％, the known compound,98％ee,[α]
20 D＝-168.9(c 0.54,MeOH),R
f＝0.42(dichloro- methane/methanol＝15/1)；
1H NMR(400MHz,DMSO)δ9.27(s,1H),7.47(s,1H),7.40(d, J＝8.5Hz,2H),7.31(d,J＝8.4Hz,2H),7.12(t,J＝7.6Hz,1H),7.05(d,J＝7.4Hz,1H), 6.83(t,J＝7.5Hz,2H),5.56(s,1H)；
13C NMR(100MHz,DMSO)δ154.1,144.4,137.4, 132.4,129.0,128.6,128.5,127.2,121.7,121.6,114.5,56.4；Enantiomericexcess was determined by HPLC(OD-3 column,Hexanes/i-PrOH＝90/10,detector:254nm,flow rate: 0.90mL/min,30℃),t
1＝19.3min,t
2＝20.1min(maj).
(-)-4-(4-Fluorophenyl)-3,4-dihydroquinazolin-2(1H)-one(2j):whitesolid,95％yield, the known compound[1781596-98-2],97％ee,[α]
20 D＝-88.3(c 0.30,MeOH),R
f＝0.38 (dichloromethane/methanol＝15/1)；
1H NMR(400MHz,DMSO)δ9.32(s,1H),7.50(s, 1H),7.39–7.28(m,2H),7.21–7.05(m,3H),7.04(d,J＝7.2Hz,1H),6.99–6.72(m,2H), 5.58(d,J＝2.4Hz,1H)；
13C NMR(100MHz,DMSO)δ161.9(d,J
CF＝243.2Hz),154.2,141.7(d,J＝3.0Hz),137.4,128.8(d,J
CF＝8.3Hz),128.4,127.2,121.9,121.7,115.7(d,J
CF＝21.4Hz),114.5,56.4；
19F NMR(376MHz,DMSO)δ-115.36；Enantiomeric excess wasdetermined by HPLC(OD-3 column,Hexanes/i-PrOH＝90/10,detector:254nm,flowrate:1.0mL/min,30℃),t
1＝15.4min,t
2＝16.6min(maj).
(-)-4-(Diphenyl-4-yl)-3,4-dihydroquinazolin-2(1H)-one(2k):whitesolid,mp:227-228 ℃,97％yield,the new compound,94％ee,[α]
20 D＝-136.2(c 0.08,MeOH)；R
f＝0.45 (dichloromethane/methanol＝15/1)；
1H NMR(400MHz,DMSO)δ9.27(s,1H),7.62(d,J ＝8.0Hz,4H),7.54–7.27(m,6H),7.12(t,J＝8.4Hz,2H),6.84(t,J＝7.4Hz,2H),5.58(d, J＝2.5Hz,1H)；
13C NMR(100MHz,DMSO)δ154.2,144.6,140.3,139.7,137.5,129.4, 128.4,127.9,127.4,127.3,127.1,122.0,121.6,114.4,56.8；Enantiomericexcess was determined by HPLC(IC column,Hexanes/i-PrOH＝80/20,detector:254nm,flow rate: 0.80mL/min,30℃),t
1＝15.6min,t
2＝16.6min(maj)；HRMS(ESI)m/zCalculated for C
20H
17N
2O[M+H]
+301.1335,found 301.1335.
(-)-6-Methyl-4-phenyl-3,4-dihydroquinazolin-2(1H)-one(2l):whitesolid,95％yield, the known compound,97％ee,,[α]
20 D＝-31.1(c 0.46,MeOH),R
f＝0.25(dichloro- methane/methanol＝30/1)；
1H NMR(400MHz,DMSO)δ9.18(s,1H),7.52–7.10(m,6H), 6.92(d,J＝7.8Hz,1H),6.85(s,1H),6.73(d,J＝8.0Hz,1H),5.47(s,1H),2.14(s,3H)；
13C NMR(100MHz,DMSO)δ154.3,145.6,135.0,130.3,129.0,128.8,127.8,127.5, 126.7,121.9,114.3,57.3,20.8；Enantiomeric excess was determined by HPLC(OD-H column,Hexanes/i-PrOH＝95/05,detector:254nm,flow rate:0.70mL/min,30℃),t
1＝ 44.7min(maj),t
2＝51.8min.
(-)-6-Chloro-4-phenyl-3,4-dihydroquinazolin-2(1H)-one(2m):whitesolid,97％yield, the known compound,96％ee,[α]
20 D＝-12.2(c 0.49,MeOH),R
f＝0.23(dichloro methane/methanol＝25/1)；
1H NMR(400MHz,DMSO)δ9.40(s,1H),7.54(s,1H),7.45–7.21(m,5H),7.21–7.02(m,2H),6.83(d,J＝8.4Hz,1H),5.55(d,J＝2.6Hz,1H)；
13CNMR(100MHz,DMSO)δ153.9,144.9,136.5,129.2,128.2,128.0,126.8,126.6, 125.1,124.1,116.1,56.7；Enantiomeric excess was determined by HPLC(OD-H column,Hexanes/i-PrOH＝90/10,detector:254nm,flow rate:0.70mL/min,30℃),t
1＝21.4min(maj),t
2＝24.0min.
(-)-6,7-Dimethoxy-4-phenyl-3,4-dihydroquinazolin-2(1H)-one(2n):whitesolid,mp: 110-111℃,85％yield,the new compound,93％ee,[α]
20 D＝-53.5(c 0.54,MeOH),R
f＝ 0.35(dichloro-methane/methanol＝25/1)；
1H NMR(400MHz,DMSO)δ8.97(s,1H), 7.38–7.27(m,5H),7.27–7.17(m,1H),6.69(s,1H),6.48(s,1H),5.42(d,J＝2.6Hz,1H), 3.68(d,J＝4.0Hz,3H),3.60(s,3H)；
13C NMR(100MHz,DMSO)δ154.2,149.2,145.7,143.9,131.2,129.0,127.6,126.6,113.0,111.6,99.3,57.0,56.6,55.9；Enantiomericexcess was determined by HPLC(IC column,Hexanes/i-PrOH＝72/28,detector:254nm,flowrate: 0.80mL/min,30℃),t
1＝15.7min(maj),t
2＝17.2min；HRMS(ESI)m/zCalculated for C
16H
16N
2O
3[M+H]
+285.1234,found 285.1235.
(+)-4-Cyclohexyl-3,4-dihydroquinazolin-2(1H)-one(2o):white solid,mp:130-131℃, 91％yield,the new compound,96％ee,[α]
20 D＝+14.3(c 0.40,MeOH),R
f＝0.33(dichloro- methane/methanol＝15/1)；
1H NMR(400MHz,DMSO)δ8.97(s,1H),7.14–7.07(m,1H), 6.99(dd,J＝25.3,8.6Hz,2H),6.89–6.80(m,1H),6.80–6.70(m,1H),4.10(t,J＝3.8Hz, 1H),1.74–1.61(m,2H),1.60–1.47(m,3H),1.46–1.33(m,1H),1.21–0.86(m,5H)；
13C NMR(100MHz,DMSO)δ154.8,138.6,127.9,127.2,121.0,120.8,113.8,58.6,46.8,28.6, 27.1,26.4,26.2,26.1；Enantiomeric excess was determined by HPLC(ICcolumn, Hexanes/i-PrOH＝92/08,detector:254nm,flow rate:1.0mL/min,30℃),t
1＝21.1min (maj),t
2＝22.5min；HRMS(ESI)m/z Calculated for C
14H
19N
2O[M+H]
+231.1492,found 231.1492.
(+)-4-Isopropyl-3,4-dihydroquinazolin-2(1H)-one(2p):white solid,92％yield,the known compound,86％ee,[α]
20 D＝+20.2(c 0.56,MeOH),R
f＝0.40(dichloromethane/methanol＝15/1)；
1H NMR(400MHz,CDCl
3)δ8.09(s,1H),7.19–7.12(m,1H), 7.03(d,J＝7.4Hz,1H),6.95(t,J＝7.4Hz,1H),6.73(d,J＝7.8Hz,1H),5.61(s,1H),4.36 (t,J＝3.4Hz,1H),2.16–1.85(m,1H),0.99(d,J＝7.0Hz,3H),0.87(d,J＝6.8Hz,3H)；
13C NMR(100MHz,CDCl
3)δ155.5,136.7,128.1,126.6,121.9,120.3,114.2,60.0,36.7, 18.5,16.0；Enantiomeric excess was determined by HPLC(IC column,Hexanes/i-PrOH＝90/10,detector:254nm,flow rate:1.0mL/min,30℃),t
1＝13.2min(maj),t
2＝14.4min。
Claims (6)
1. A method for synthesizing 3, 4-dihydro quinazolinone by asymmetric hydrogenation is characterized in that: the 3, 4-dihydro-quinazolinone is prepared by iridium-catalyzed quinazolinone compound
In the formula:
r is C
1-6Or aryl containing substituents of F, Cl, CF
3At least one of Ph, Me and MeO;
r' is hydrogen, C
1At least one of alkyl, alkoxy and chlorine.
2. The method of asymmetric hydrogenation synthesis according to claim 1, characterized by comprising two stages of catalyst preparation and substrate hydrogenation;
(1) catalyst preparation
Mixing an iridium metal precursor, a chiral diphosphine ligand and an organic solvent, and stirring at normal temperature for 10-20 minutes to obtain a catalyst;
(2) hydrogenation reaction
Adding a catalyst, an additive and an organic solvent into a quinazolinone substrate under the protection of nitrogen, transferring the quinazolinone substrate into a high-pressure kettle, filling hydrogen under the pressure of 100-1000 psi, and stirring at 25-80 ℃ for 12-24 hours to generate a product;
the additive is trichloroisocyanuric acid, N-bromosuccinimide, bromochlorohydantoin, iodine or N-iodosuccinimide.
3. The method of asymmetric hydrogenation synthesis according to claim 2, wherein: the organic solvent is at least one of toluene, tetrahydrofuran, dichloromethane, ethyl acetate, 1, 4-dioxane and methanol.
4. The method of any of claims 1-2, wherein: the iridium metal precursor is selected from methoxy (cyclooctadiene) iridium dimer, bis (cyclooctene) iridium chloride dimer, 1, 5-cyclooctadieneiridium chloride dimer.
5. The method of any of claims 1-2, wherein: the chiral diphosphine ligand is selected from (R) -Difluorophohos, (R) -MeOBIPHep, (R) -SegPhos, (R) -SynPhos, (R) -BINAP, (S, S) -MeDuPhos.
6. The method of any of claims 1-2, wherein: the method comprises the following feeding proportions: the molar ratio of the metal precursor of iridium, the chiral diphosphine ligand, the additive and the substrate is as follows: 0.01-0.05:0.022-0.110:0.05-0.10:1.
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| CN106995413A (en) * | 2016-01-25 | 2017-08-01 | 中国科学院大连化学物理研究所 | A kind of method of iridium catalytic hydrogenation asymmetric syntheses bridged piperazine derivatives |
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| CN104710406A (en) * | 2013-12-13 | 2015-06-17 | 中国科学院大连化学物理研究所 | Method for synthesizing chiral cyclic amine through catalyzing asymmetric hydrogenation of quinolin-3-amine by iridium |
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| CN111548329A (en) * | 2020-05-27 | 2020-08-18 | 浙江乐普药业股份有限公司 | Preparation method of brivaracetam |
| CN111548329B (en) * | 2020-05-27 | 2022-06-17 | 浙江乐普药业股份有限公司 | Preparation method of brivaracetam |
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