Synthesis method of chiral beta-aminoketone derivative

Abstract

The invention discloses a synthesis method of a chiral beta-aminoketone derivative, which comprises the following specific synthesis process: dissolving an alpha-vinyl ketone compound, an aromatic amine compound and a chiral primary amine catalyst in a low-polarity organic solvent, and reacting at 20-80 DEG C to obtain the chiral beta-aminoketone compound, a reaction equation in the preparation process is as follows: chiral primary amine is used as a catalyst, the asymmetric protonation reaction of Aza-Michael addition of an organic catalytic alpha-vinyl ketone compound and an aromatic amine compound is realized for the first time, and a brand-new synthesis method is provided for preparing a beta-aminoketone derivative with optical activity.

Description

Technical Field

[0001] This invention belongs to the field of asymmetric protonation reaction technology of chiral primary amine catalyzed β-amino ketone derivatives, and specifically relates to a method for synthesizing chiral β-amino ketone derivatives. Background Technology

[0002] β-aminoketone derivatives play an important role in medicinal chemistry and organic chemistry as important components of active drug molecules and organic synthesis intermediates. Examples include phenbutazone, which can be used in anti-tumor research; cispentylmycin, which treats fungal infections; levodopa, which treats Parkinson's disease; and paclitaxel, an anticancer drug.

[0003] The most atom-economical method for synthesizing β-aminoketone derivatives is the direct Aza-Michael addition reaction of aromatic amines to α,β-unsaturated carbonyl compounds. Current reports on asymmetric reactions of this type are limited, primarily employing chiral metal complex catalysis. One literature report (Org. Lett.:2004, 6:1861-1864) describes a palladium-catalyzed asymmetric Aza-Michael / Protonation reaction of aromatic amine trifluoromethanesulfonates to α,β-unsaturated imide substrates, yielding excellent product yields (97% ee). Another literature report (Chem. Lett.:2019, 48:783) describes a Lewis acid complex surfactant Cu(OSO2C9H) 19 )2 can achieve good enantioselectivity (82% ee). However, these methods all require the use of expensive and toxic metals as catalysts, and there are currently no reports on organocatalyzed reactions of this type. Summary of the Invention

[0004] The technical problem solved by this invention is to provide a method for synthesizing chiral β-amino ketone derivatives. This method efficiently prepares chiral β-amino ketone derivatives through an asymmetric protonation reaction involving organocatalytic α-vinyl ketone compounds and aromatic amine compounds via Aza-Michael addition.

[0005] To solve the above-mentioned technical problems, the present invention adopts the following technical solution: a method for synthesizing chiral β-amino ketone derivatives, the specific synthesis process of which is as follows: α-vinyl ketone compounds, aromatic amine compounds, and a chiral primary amine catalyst are dissolved in a low-polarity organic solvent and reacted at 20–80°C to obtain chiral β-amino ketone compounds. The chemical reaction equations in the preparation process are as follows:

[0006]

[0007] Where R1 is a phenyl or a substituted phenyl group, and the substituent on the substituted phenyl group is C. 1-6 Alkyl group, R2 is C1-6 Alkyl group, where Ar is a phenyl group, a substituted phenyl group, or a naphthyl group, and the substituent on the substituted phenyl group is C. 1-6 Alkyl, methoxy, fluorine, chlorine, or bromine, wherein the chiral primary amine catalyst comprises:

[0008]

[0009] Furthermore, the reaction temperature is preferably room temperature.

[0010] Furthermore, the low-polarity organic solvent is one or more of 1,2-dichloroethane, chloroform, trichloroethane, acetonitrile, or ethanol.

[0011] Furthermore, the molar ratio of the α-vinyl ketone compound, the aromatic amine compound, and the chiral primary amine catalyst is 1.5–3:1:0.1.

[0012] Furthermore, the molar ratio of the α-vinyl ketone compound, the aromatic amine compound, and the chiral primary amine catalyst is 2:1:0.1.

[0013] A method for synthesizing a chiral β-amino ketone derivative, the specific synthetic steps of which are as follows: 0.01 mmol of chiral primary amine catalyst, 0.2 mmol of α-substituted vinyl ketone, and 1 mL of 1,2-dichloroethane solvent are added sequentially to a 5 mL graduated test tube and stirred at room temperature. Subsequently, 0.1 mmol of an aromatic amine compound is dissolved in 1 mL of 1,2-dichloroethane solvent and added to the reaction system. The reaction is stirred continuously. After the reaction is completed by TLC monitoring, the chiral β-amino ketone compound is directly separated by column chromatography.

[0014] Compared with the prior art, the present invention has the following advantages and beneficial effects: The effectiveness of the present invention is reflected in the fact that, by using a chiral primary amine catalyst, the asymmetric protonation reaction of organocatalyzed α-vinyl ketone compounds and aromatic amine compounds via Aza-Michael addition is realized for the first time to prepare chiral β-amino ketone derivatives. This avoids the use of expensive and toxic metal catalysts in the current synthesis of chiral β-amino ketone derivatives. At the same time, the synthesis method of the present invention can obtain good yield and moderate enantioselectivity. Detailed Implementation

[0015] The following examples further illustrate the above-mentioned content of the present invention in detail, but it should not be construed as limiting the scope of the subject matter of the present invention to the following examples. All technologies implemented based on the above-mentioned content of the present invention are within the protection scope of the present invention.

[0016] Examples 1-3 follow the same method, all based on the following synthetic route, but the chiral primary amine catalysts used are 1a-1c from Table 1, and the results are shown in Table 1.

[0017]

[0018] Table 1. Preparation of chiral β-amino ketone derivatives using different chiral primary amine catalysts 4a

[0019]

[0020] Examples 4-8 follow the same method as Example 1, all based on the following synthetic route, but the solvents used are 1,2-dichloroethane, chloroform, acetonitrile, and ethanol, respectively. The results are shown in Table 2.

[0021]

[0022] Table 2. Preparation of chiral β-amino ketone derivatives using different solvents 4a

[0023]

[0024] Examples 9 and 10 follow the same method as Example 4, with the reaction carried out based on the following synthetic route, but the reaction temperatures were 40°C and 60°C, respectively. The results are shown in Table 3.

[0025]

[0026] Table 3. Preparation of chiral β-aminoketone derivatives using different temperatures 4a

[0027]

[0028] Example 4

[0029] Preparation of compound 4a:

[0030]

[0031] In a 5 mL graduated test tube, chiral primary amine catalyst 1a (0.01 mmol), α-substituted vinyl ketone 2a (0.2 mmol), and reaction solvent 1,2-dichloroethane (1 mL) were added sequentially and stirred at room temperature for 10 min. Then, aromatic amine compound 3a (0.1 mmol) was dissolved in 1,2-dichloroethane (1 mL) and added to the reaction system. The reaction was continued with stirring for 24 h. After the reaction was completed, TLC monitoring showed that product 4a was obtained by direct column chromatography, yielding 21.5 mg, 90% yield, and enantiomeric excess: 62%. [α] D 25 =13.7 (c=1.08, CHCl3); 1H NMR (400MHz, CDCl3) δ8.04–7.89(m,2H),7.59(t,J=7.4Hz,1H),7.48(t,J=7.7Hz,2H),7.19(dd,J=8.3,7.5Hz,2H),6.72(t,J=7.3Hz,1H), 6.62(d,J=7.8Hz,2H),4.06(s,1H),3.95–3.76(m,1H),3.63(dd,J=13.4,7.7Hz,1H),3.34(dd,J=13.4,5.2Hz,1H),1.29(d,J=3.4Hz,3H). 13 C NMR (101MHz, CDCl3) δ203.5,147.8,136.4,133.2,129.3,128.7,128.4,117.5,112.9,46.6,40.3,16.0.IR(KBr,cm -1 ):3405,3054,3023,2968,2850,1507,1448,1434,1377,1322,1253,1210,1181,1155,1074,1028,1001,974.HRMS(ESI)calcd for C 16 H 18 NO + 240.1383, found240.1373; HPLC analysis: Daicel Chiralpak AD-H, hexane / iso-propanol=80:20, flowrate=1.0mL / min, λ=230nm, retention time 7.10min (minor) and 7.54min (major).

[0032] Example 11

[0033] Preparation of compound 4b:

[0034]

[0035] In a 5 mL graduated test tube, chiral primary amine catalyst 1a (0.01 mmol), α-substituted vinyl ketone 2a (0.2 mmol), and reaction solvent 1,2-dichloroethane (1 mL) were added sequentially and stirred at room temperature for 10 min. Then, aromatic amine compound 3b (0.1 mmol) was dissolved in 1,2-dichloroethane (1 mL) and added to the reaction system. The reaction was continued with stirring for 24 h. After the reaction was completed, TLC monitoring showed that product 4b was obtained by direct column chromatography, yielding 25.1 mg, 87% yield, and enantiomeric excess of 64%. [α] D 25 =14.1 (c=1.25, CHCl3); 1 H NMR (400MHz, CDCl3) δ7.99–7.93(m,2H),7.71–7.54(m,4H),7.47(t,J=7.7Hz,2H),7.42–7.34(m,1H),7.25–7.18(m,1H),6.8 9–6.78(m,2H),4.41–4.02(m,1H),4.03–3.89(m,1H),3.79–3.66(m,1H),3.47(dd,J=13.4,5.1Hz,1H),1.35(d,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ203.5,145.5,136.4,135.2,133.3,129.1,128.7,128.4, 127.6,127.5,126.4,125.9,122.0,118.1,104.2,46.5,40.1,16.1.IR(KBr,cm -1 ):3405,3054,2969,2928,2851,1676,1602,1579,1523,1486,1448,1399,136 1,1258,1226,1211,1189,1158,1146,1127,1100,1076,975; HRMS(ESI)calcd forC 20 H 20 NO + 290.1539, found 290.1529; HPLC analysis: Daicel Chiralpak AD-H, hexane / iso-propanol=80:20, flow rate=1.0mL / min, λ=254nm, retention time 6.17min (minor) and 6.67min (major).

[0036] Example 12

[0037] Preparation of compound 4c:

[0038]

[0039] In a 5 mL graduated test tube, chiral primary amine catalyst 1a (0.01 mmol), α-substituted vinyl ketone 2a (0.2 mmol), and reaction solvent 1,2-dichloroethane (1 mL) were added sequentially and stirred at room temperature for 10 min. Then, aromatic amine compound 3c (0.1 mmol) was dissolved in 1,2-dichloroethane (1 mL) and added to the reaction system. The reaction was continued with stirring for 24 h. After the reaction was completed, TLC monitoring showed that product 4c was obtained by direct column chromatography, yielding 27.5 mg, 93% yield, and enantiomeric excess: 26%. [α] D 25 =3.7 (c=1.38, CHCl3); 1 H NMR (400MHz, CDCl3) δ8.03–7.90(m,2H),7.59(dd,J=10.5,4.3Hz,1H),7.48(t,J=7.6Hz,2H),7.25–7.15(m,2H),6.71–6.48 (m,2H),3.94(s,1H),3.94–3.80(m,1H),3.60(dt,J=39.6,19.8Hz,1H),3.32(dd,J=13.2,5.4Hz,1H),1.31(d,J=2.9Hz,9H). 13 C NMR (101MHz, CDCl3) δ203.5,145.4,140.4,136.4,133.2,128.7,128.4,126.1,112.7,46.9,40.5,33.9,31.5,16.0.IR(KBr,cm -1 ):3400,3061,2963,2868,1679,1615,1597,1579,1460,1364,1195,1095,1038,974; HRMS(ESI)calcd forC 20 H 26 NO +296.2009, found 296.1997; HPLC analysis: Daicel Chiralpak AD-H, hexane / iso-propanol=80:20, flow rate=1.0mL / min, λ=210nm, retention time 14.72min (minor) and 18.45min (major).

[0040] Example 13

[0041] Preparation of compound 4d:

[0042]

[0043] In a 5 mL graduated test tube, chiral primary amine catalyst 1a (0.01 mmol), α-substituted vinyl ketone 2a (0.2 mmol), and reaction solvent 1,2-dichloroethane (1 mL) were added sequentially and stirred at room temperature for 10 min. Then, aromatic amine compound 3d (0.1 mmol) was dissolved in 1,2-dichloroethane (1 mL) and added to the above reaction system. The reaction was continued with stirring for 18 h. After the reaction was completed, TLC monitoring showed that product 4d (24.5 mg, 91% yield, enantiomeric excess: 28%) was obtained by direct column chromatography. [α] D 25 =3.2 (c=1.23, CHCl3); 1 H NMR (400MHz, CDCl3) δ8.16–7.84(m,2H),7.58(t,J=7.4Hz,1H),7.48(t,J=7.7Hz,2H),6.88–6.70(m,2H),6.68–6.47(m, 2H),3.92–3.80(m,1H),3.77(s,3H),3.58(dd,J=13.1,7.6Hz,1H),3.28(dd,J=13.1,5.3Hz,1H),1.29(d,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ203.6,152.2,142.0,136.4,133.2,128.7,128.3,115.0,114.4,55.8,47.8,40.4,16.0.IR(KBr,cm -1 ):3395,2932,2833,1676,1596,1448,1377,1235,1209,1180,1038,1002,974; HRMS(ESI)calcd for C 17 H20 NO2 + 270.1489, found 270.1475; HPLC analysis: Daicel Chiralpak OD-H, hexane / iso-propanol=80:20, flow rate=1.0mL / min, λ=230nm, retention time 8.08min (minor) and 8.58min (major).

[0044] Example 14

[0045] Preparation of compound 4e:

[0046]

[0047] In a 5 mL graduated test tube, chiral primary amine catalyst 1a (0.01 mmol), α-substituted vinyl ketone 2a (0.2 mmol), and reaction solvent 1,2-dichloroethane (1 mL) were added sequentially and stirred at room temperature for 10 min. Then, aromatic amine compound 3e (0.1 mmol) was dissolved in 1,2-dichloroethane (1 mL) and added to the reaction system. The reaction was continued with stirring for 28 h. After the reaction was completed, TLC monitoring showed that the product 4e was obtained by direct column chromatography, yielding 21.6 mg, 84% yield, and enantiomeric excess: 56%. [α] D 25 =12.1 (c=1.08, CHCl3); 1 H NMR (400MHz, CDCl3) δ7.98–7.89(m,2H),7.59(t,J=7.4Hz,1H),7.48(t,J=7.7Hz,2H),6.94–6.84(m,2H),6.59–6.50(m, 2H),3.92(s,J=12.8Hz,1H),3.94–3.72(m,1H),3.63–3.41(m,1H),3.29(dd,J=13.2,5.0Hz,1H),1.29(d,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ203.5,157.0,154.7,144.2,136.3,133.3,128.7,128.3,115.8,115.6,113.8,113.7,47.3,40.3,16.0.IR(KBr,cm -1):3400,3061,2971,2930,2854,1676,1613,1596,1579,1448,1378,1321,1248,1211,1183,1116,1002,974; HRMS(ESI)calcd for C 16 H 17 FNO + 258.1289, found 258.1279; HPLC analysis: Daicel Chiralpak AD-H, hexane / iso-propanol=80:20, flow rate=1.0mL / min, λ=254nm, retention time 7.82min (minor) and 9.20min (major).

[0048] Example 15

[0049] Preparation of compound 4f:

[0050]

[0051] In a 5 mL graduated test tube, chiral primary amine catalyst 1a (0.01 mmol), α-substituted vinyl ketone 2a (0.2 mmol), and reaction solvent 1,2-dichloroethane (1 mL) were added sequentially and stirred at room temperature for 10 min. Then, aromatic amine compound 3f (0.1 mmol) was dissolved in 1,2-dichloroethane (1 mL) and added to the reaction system. The reaction was continued with stirring for 26 h. After the reaction was completed, TLC monitoring showed that product 4f was obtained by direct column chromatography, yielding 22.1 mg, 81% yield, and enantiomeric excess of 63%. [α] D 25 =15.3 (c=1.10, CHCl3); 1 H NMR (400MHz, CDCl3) δ8.08–7.82(m,2H),7.66–7.52(m,1H),7.48(t,J=7.7Hz,2H),7.16–7.00(m,2H),6.62–6.47(m,2 H),4.05(s,1H),3.90–3.74(m,1H),3.60(dd,J=13.4,7.9Hz,1H),3.31(dd,J=13.4,5.0Hz,1H),1.29(d,J=7.1Hz,3H). 13C NMR (101MHz, CDCl3) δ203.3,146.4,136.3,133.3,129.1,128.8,128.3,122.0,113.9,46.6,40.2,16.0.IR(KBr,cm -1 ):3403,3060,2972,2931,2874,1676,1598,1579,1448,1402,1378,1320,1293,1248,1210,1178,1091,1002,974.HRMS(ESI)calcd for C 16 H 17 ClNO + 274.0993, found 274.0984; HPLC analysis: Daicel Chiralpak OJ-H, hexane / iso-propanol=80:20, flow rate=1.0mL / min, λ=254nm, retention time 20.32min (minor) and 21.40min (major).

[0052] Example 16

[0053] Preparation of 4g of compound:

[0054]

[0055] In a 5 mL graduated test tube, chiral primary amine catalyst 1a (0.01 mmol), α-substituted vinyl ketone 2a (0.2 mmol), and reaction solvent 1,2-dichloroethane (1 mL) were added sequentially and stirred at room temperature for 10 min. Then, 3 g (0.1 mmol) of an aromatic amine compound was dissolved in 1,2-dichloroethane (1 mL) and added to the reaction system. The reaction was continued with stirring for 24 h. After the reaction was completed, TLC monitoring showed that the product was directly separated by column chromatography to obtain 4 g of product (21.1 mg, 71% yield, enantiomeric excess: 68%). [α] D 25 =16.4 (c=1.05, CHCl3). 1H NMR(400MHz, CDCl3)δ7.92(dd,J=11.1,9.7Hz,2H),7.90–7.79(m,2H),7.63–7.53(m,1H),7.48(t,J=7.7Hz,2H),6.62–6.51 (m,2H),4.53(s,1H),3.92–3.83(m,4H),3.67(dd,J=13.6,8.0Hz,1H),3.41(dd,J=13.6,4.8Hz,1H),1.31(d,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ203.1,167.2,151.6,136.1,133.4,131.6,128.8,128.3,118.5,111.4,51.5,45.7,40.2,16.1.IR(KBr,cm -1 ):3391,2931,1680,1605,1579,1527,1448,1435,1380,1338,1313,1279,1211,1176,1113,1002,974.HRMS(ESI)calcd for C 18 H 20 NO3 + 298.1438, found 298.1429; HPLC analysis: Daicel Chiralpak OJ-H, hexane / iso-propanol=80:20, flow rate=1.0mL / min, λ=254nm, retention time 29.81min (minor) and 32.54min (major).

[0056] Example 17

[0057] Preparation of compound 4h:

[0058]

[0059] In a 5 mL graduated test tube, chiral primary amine catalyst 1a (0.01 mmol), α-substituted vinyl ketone 2b (0.2 mmol), and reaction solvent 1,2-dichloroethane (1 mL) were added sequentially and stirred at room temperature for 10 min. Then, aromatic amine compound 3a (0.1 mmol) was dissolved in 1,2-dichloroethane (1 mL) and added to the reaction system. The reaction was continued with stirring for 24 h. After the reaction was completed, the product was directly separated by column chromatography at 4 h, 23.5 mg, 93% yield, and enantiomeric excess: 57%; [α] D 25 =10.3 (c=1.19, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.86(d,J=8.2Hz,2H),7.28(d,J=7.9Hz,2H),7.22–7.12(m,2H),6.76–6.65(m,1H),6.62(dd,J=8.6,0.9Hz,2H),3.96(d ,J=41.4Hz,1H),3.87(pd,J=7.1,5.4Hz,1H),3.62(dd,J=13.3,7.6Hz,1H),3.33(dd,J=13.3,5.2Hz,1H),2.43(s,3H),1.29(d,J=7.1Hz,3H). 13 CNMR(101MHz, CDCl3)δ203.1,147.9,144.1,133.9,129.4,129.3,128.5,117.4,112.8,46.6,40.2,21.6,16.1.IR(KBr,cm -1 ):3404,3052,2970,2929,2873,1672,1572,1506,1458,1433,1408,1377,1321,1252,1221,1182,1154,1070,1034,973.HRMS(ESI)calcd for C 17 H 20 NO + 254.1539, found 254.1529. HPLC analysis: Daicel Chiralpak OD-H, hexane / iso-propanol=80:20, flow rate=1.0mL / min, λ=254nm, retention time 6.16min (major) and 7.55min (minor).

[0060] The above embodiments describe the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are only illustrative of the principles of the present invention. Various changes and modifications can be made to the present invention without departing from the scope of the principles of the present invention, and all such changes and modifications fall within the protection scope of the present invention.

Claims

1. A method for synthesizing a chiral β-aminoketone derivative, characterized in that... The specific synthesis process is as follows: α-vinyl ketone compounds, aromatic amine compounds, and a chiral primary amine catalyst are dissolved in a low-polarity organic solvent and reacted at 20–80 °C to obtain chiral β-amino ketone compounds. The chemical reaction equations for the preparation process are as follows: Where R1 is a phenyl or a substituted phenyl group, and the substituent on the substituted phenyl group is C. 1-6 Alkyl group, R2 is C 1-6 Alkyl group, where Ar is a phenyl group, a substituted phenyl group, or a naphthyl group, and the substituent on the substituted phenyl group is C. 1-6 Alkyl, methoxy, fluorine, chlorine, or bromine, wherein the chiral primary amine catalyst comprises:

2. The method for synthesizing the chiral β-aminoketone derivative according to claim 1, characterized in that: The preferred reaction temperature is room temperature.

3. The method for synthesizing chiral β-aminoketone derivatives according to claim 1, characterized in that: The low-polarity organic solvent is one or more of 1,2-dichloroethane, chloroform, trichloroethane, acetonitrile, or ethanol.

4. The method for synthesizing the chiral β-aminoketone derivative according to claim 1, characterized in that: The molar ratio of the α-vinyl ketone compound, the aromatic amine compound, and the chiral primary amine catalyst is 1.5–3:1:0.

1.

5. The method for synthesizing chiral β-aminoketone derivatives according to claim 1, characterized in that: The molar ratio of the α-vinyl ketone compound, the aromatic amine compound, and the chiral primary amine catalyst is 2:1:0.

1.

6. The method for synthesizing chiral β-aminoketone derivatives according to claim 1, characterized in that... The specific synthesis steps are as follows: 0.01 mmol of chiral primary amine catalyst, 0.2 mmol of α-substituted vinyl ketone and 1 mL of 1,2-dichloroethane solvent were added sequentially to a 5 mL graduated test tube and stirred at room temperature. Then, 0.1 mmol of aromatic amine compound was dissolved in 1 mL of 1,2-dichloroethane solvent and added to the reaction system. The reaction was stirred and continued. After the reaction was completed by TLC monitoring, the chiral β-amino ketone compound was directly separated by column chromatography.

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