Preparation method of polysubstituted 1, 3 thiazolidine compound

Abstract

The polysubstituted 1, 3 thiazolidine compound has wide pharmaceutical activity, also belongs to an important synthetic intermediate in the field of organic preparation, can be used for synthesizing various natural products and bioactive molecules with biological activity, and has very high organic synthesis application value. The invention relates to a simple method for preparing a polysubstituted 1, 3-thiazolidine compound, which comprises the following steps: taking an arylglycine derivative and an episulfide ethane derivative as raw materials, taking an organic micromolecule photosensitizer, lewis acid and haloid acid which are cheap and easy to obtain as catalysts, and reacting for 10-20 hours at room temperature and under visible light irradiation to obtain the polysubstituted 1, 3-thiazolidine compound. And separating and purifying to obtain a series of polysubstituted 1, 3 thiazolidine compounds. Compared with the prior art, the method has the advantages of simple steps, cheap and easily available raw materials and catalysts, mild reaction conditions, simple reaction operation and the like, and is suitable for large-scale preparation of the polysubstituted 1, 3-thiazolidine compound.

Description

Technical Field

[0001] The invention belongs to the technical field of synthesis and preparation of organic compounds, and in particular relates to a preparation method of a polysubstituted 1,3-thiazolidine compound. Background Art

[0002] Polysubstituted 1,3-thiazolidine is a very important five-membered nitrogen heterocyclic compound. This class of compounds has a variety of drug activities such as protecting the liver, anti-cancer, anti-diabetes and anti-aging. In addition, polysubstituted 1,3-thiazolidine is also an important skeleton of many natural products and bioactive molecules (such as Rapamycin analogue, PDE4 inhibitor, etc.), and can be used as an organic synthesis intermediate to participate in the synthesis of complex natural products and active drug molecules.

[0003] The reported methods for synthesizing 1,3-thiazolidine compounds are mainly condensation reactions between cysteine ​​and glyoxylic acid derivatives. However, this strategy usually has the disadvantages of harsh reaction conditions (excessive base is required), single product structure, and poor diastereoselectivity. This limits the applicability of the reported methods.

[0004] Here, the present invention provides a novel method for synthesizing polysubstituted 1,3-thiazolidine compounds by a visible light-catalyzed oxidative dehydrogenation form [2+3] cyclization reaction between a glycine derivative and an episulfide compound. The method uses cheap, abundant, green visible light as an energy source and oxygen in the air as a green oxidant. In addition, the method has the advantages of cheap and readily available raw materials, mild reaction conditions, simple operation, rich product types, and excellent diastereoselectivity. A series of polysubstituted 1,3-thiazolidine compounds can be efficiently prepared with a yield of 85%-96%. Summary of the invention

[0005] The present invention aims to provide a method for synthesizing polysubstituted 1,3-thiazolidine compounds with mild reaction conditions, greenness, high efficiency, simple operation and low cost.

[0006] The reaction equation is shown below.

[0007]

[0008] Where R 1 The substituents may be alkyl, alkoxy, aryl and halogen; R 2 The substituent may be an alkoxy group, an aryl group, a substituted amino group, etc.; R 3 The substituent may be a substituted aryl group, an alkyl group, an alkoxy group, or the like.

[0009] The preparation process mainly includes the following steps: adding glycine derivatives, photocatalysts, Lewis acids and appropriate amounts of solvents into a flask in sequence, stirring at room temperature for 10 to 20 hours under visible light irradiation, then adding ethylene sulfide derivatives and hydrohalic acid, and continuing to stir at room temperature for 5 hours, evaporating the solvent under reduced pressure, and obtaining polysubstituted 1,3-thiazolidine derivatives by column chromatography.

[0010] In the above steps, the photocatalyst is preferably one of rhodamine B (Rh-B), rhodamine 6G (Rh-6G), rose bengal, eosin Y, and basic blue B.

[0011] In the above steps, the Lewis acid is preferably Cu(OAc) 2 ·H 2 O, FeSO 4 7H 2 O、Cu(OTf) 2 、Fe(OTf) 2 、Ce(OTf) 2 One of them.

[0012] In the above steps, the hydrohalic acid is preferably one of hydroiodic acid and hydrobromic acid.

[0013] In the above steps, the visible light source is preferably one of a 26W energy-saving lamp and a 5W blue LED lamp.

[0014] In the above steps, the solvent is preferably one of dichloromethane, chloroform, toluene, 1,2-dichloroethane, acetonitrile, ethyl acetate, and a mixed solvent of 1,2-dichloroethane and acetonitrile.

[0015] In the above steps, the molar ratio of the glycine derivative, the photosensitizer, the Lewis acid, the ethylene sulfide derivative and the hydrohalic acid is 1:0.02:0.2:1.5:0.3.

[0016] In the above steps, the temperature during the reaction is preferably room temperature.

[0017] Compared with the prior art, the present invention has the following advantages:

[0018] 1. Reaction raw materials and catalysts are cheap and readily available.

[0019] 2. The reaction is carried out in a "one-pot method" with a high reaction yield (85-96%).

[0020] 3. The reaction is carried out at room temperature, in air and under visible light irradiation. The reaction conditions are mild, the operation is simple and environmentally friendly, overcoming the shortcomings of traditional methods such as limited substrate types and poor diastereoselectivity. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 13-(4-methoxyphenyl)-4-phenylthiazolidine-2-carboxylic acid ethyl ester 1 H NMR spectrum

[0022] Figure 2 3-(4-methoxyphenyl)-4-phenylthiazolidine-2-carboxylic acid ethyl ester 13 C NMR spectrum

[0023] Figure 3 The DEPT spectrum of ethyl 3-(4-methoxyphenyl)-4-phenylthiazolidine-2-carboxylate DETAILED DESCRIPTION

[0024] The following examples can help those skilled in the art to better understand the present invention, but they do not limit the present invention in any way. The raw materials used in the present invention are all known compounds, which can be purchased from the market or prepared by methods known in the art.

[0025] Example 1: Preparation of ethyl 3-(4-methoxyphenyl)-4-phenylthiazolidine-2-carboxylate In a 10 mL flask, 104.5 mg (0.5 mmol) of (4-methoxyphenyl)glycine ethyl ester was dissolved in 5.0 mL of dichloromethane, to which 4.8 mg (0.01 mmol) of Rh-6G and 27.8 mg (0.1 mmol) of FeSO were added. 4 7H 2 O, then stirred at room temperature for 12 hours under 26W energy-saving lamp. After the raw material conversion is complete, 102mg (0.75mmol) of phenyl thioethane and 25mg (0.15mmol) of hydrobromic acid are added thereto, and stirred at room temperature for 5 hours. Then the solvent is evaporated under reduced pressure, and the product is obtained by column chromatography (petroleum ether / ethyl acetate = 16:1), with a yield of 96%, >20:1dr. Pale yellow liquid. 1 H NMR (400 MHz, CDCl 3 )δ7.35-7.26(m,5H),6.71(d,J=9.1Hz,2H),6.46(d,J=9.2Hz,2H),5.38(s,1H),5.27(dd,J=7.2,1.6Hz,1H),4. 30-4.17(m,2H),3.98(dd,J=11.2,7.2Hz,1H),3.68(s,3H),2.90(dd,J=11.2,1.5Hz,1H),1.28(t,J=7.1Hz,3H); 13 C NMR (101 MHz, CDCl 3)δ171.9,152.3,142.6,138.8,128.7,127.6,126.5,115.0,114.9,66.0,64.1,61.7,55.7,39.3,14.3.HRMS(ESI)calcd for C 19 H 22 NO 3 S(M+H + )344.1315, found 344.1316.

[0026] Example 2: Preparation of (3-(4-methoxyphenyl)-4-phenylthiazolidine-2-carbonyl)glycine ethyl ester In a 10 mL flask, 133 mg (0.5 mmol) of (4-methoxyphenyl) glycylglycine ethyl ester was dissolved in 5.0 mL of 1,2-dichloroethane, to which 4.8 mg (0.01 mmol) of Rh-6G and 27.8 mg (0.1 mmol) of FeSO were added. 4 7H 2 O, then stirred at room temperature for 19 hours under 26W energy-saving lamp. After the conversion of the raw materials was complete, 102mg (0.75mmol) of phenyl thioethane and 34mg (0.15mmol) of hydroiodic acid were added thereto, and stirred at room temperature for 5 hours. Then the solvent was evaporated under reduced pressure, and the product was obtained by column chromatography (petroleum ether / ethyl acetate = 4:1), with a yield of 85%, >20:1dr. White solid. 1 H NMR (400 MHz, CDCl 3 )δ7.32-7.27(m,1H),7.25-7.21(m,1H),7.17-7.12(m,2H),6.88(dd,J=6.7,4.4Hz,1H),6.73-6.67(m,2H),6.54-6.48(m,2H),5. 47(dd,J=6.1,1.5Hz,1H),5.27(s,1H),4.26-4.15(m,3H),3.91-3.82(m,2H),2.95(dd,J=11.3,1.5Hz,1H),1.26(t,J=7.2Hz,3H); 13 C NMR (101 MHz, CDCl 3 )δ171.9,169.7,152.9,140.4,137.9,128.5,127.7,127.0,116.2,114.8,66.9,66.4,61.7,55.6,41.4,38.6,14.2.HRMS(ESI)calcd for C 21 H25 N 2 O 4 S(M+H + )401.1530, found 401.1531.

[0027] Example 3: Preparation of ethyl 3-(4-methylphenyl)-4-phenylthiazolidine-2-carboxylate In a 10 mL flask, 125 mg (0.5 mmol) of (4-methylphenyl)glycine ethyl ester was dissolved in 5.0 mL of toluene, and 10.2 mg (0.01 mmol) of Rose Bengal and 20 mg (0.1 mmol) of Cu(OAc) were added. 2 ·H 2 O, then stirred at room temperature for 12 hours under 26W energy-saving lamp. After the conversion of the raw materials was complete, 102mg (0.75mmol) of phenyl thioethane and 34mg (0.15mmol) of hydroiodic acid were added thereto, and stirred at room temperature for 5 hours. Then the solvent was evaporated under reduced pressure, and the product was obtained by column chromatography (petroleum ether / ethyl acetate = 16:1), with a yield of 89%, >20:1dr. Yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ7.25-7.19(m,5H),6.90-6.82(m,2H),6.37-6.29(m,2H),5.31(s,1H),5.22(dd,J=7.2,1.1Hz,1H),4.26- 4.07(m,2H),3.93(dd,J=11.2,7.2Hz,1H),2.82(dd,J=11.2,1.2Hz,1H),2.11(s,3H),1.22(t,J=7.2Hz,3H); 13 C NMR (101 MHz, CDCl 3 )δ171.8,142.5,142.2,129.9,128.7,127.6,127.1,126.4,113.7,65.8,63.7,61.7,39.3,20.3,14.3.HRMS(ESI)calcd for C 19 H 22 NO 2 S(M+H + )328.1366, found 328.1365.

[0028] Example 4: Preparation of ethyl 3-(3-fluoro-4-methylphenyl)-4-phenylthiazolidine-2-carboxylate In a 10 mL flask, 106 mg (0.5 mmol) of (3-fluoro-4-methylphenyl)glycine ethyl ester was dissolved in 5.0 mL of acetonitrile, and 6.5 mg (0.01 mmol) of eosin Y and 36.1 mg (0.1 mmol) of Cu(OTf) were added. 2 , then stirred at room temperature for 20 hours under 5W blue LED light. After the conversion of the raw materials was complete, 102 mg (0.75 mmol) of phenyl thioethane and 34 mg (0.15 mmol) of hydroiodic acid were added thereto, and stirred at room temperature for 5 hours. Then the solvent was evaporated under reduced pressure, and the product was obtained by column chromatography (petroleum ether / ethyl acetate = 16:1) with a yield of 88% and >20:1dr. Light brown solid. 1 H NMR (400 MHz, CDCl 3 )δ7.37-7.26(m,5H),6.90(t,J=8.5Hz,1H),6.21-6.11(m,2H),5.34(s,1H),5.26(d,J=7.1Hz,1H),4.35-4.16( m,2H),4.00(dd,J=11.3,7.2Hz,1H),2.89(dd,J=11.4,1.1Hz,1H),2.09(d,J=1.8Hz,3H),1.30(t,J=7.1Hz,3H); 13 C NMR (101 MHz, CDCl 3 )δ171.4,163.1,160.7,144.1,143.9,142.0,132.0,131.9,128.8,127.8,126.4,113.8,113. 6,109.10,109.09,101.2,100.9,66.0,63.6,61.9,39.2,14.3,13.63,13.60.HRMS(ESI)calcd for C 19 H 20 FNO 2 S(M+H + ):346.1272, found 346.1274.

[0029] Example 5: Preparation of ethyl 3-(4-bromophenyl)-4-phenylthiazolidine-2-carboxylate In a 10 mL flask, 129 mg (0.5 mmol) of (4-bromophenyl) glycine ethyl ester was dissolved in 5.0 mL of a mixed solvent (1,2-dichloroethane: acetonitrile = 10:1), and 4.8 mg (0.01 mmol) of Rh-B and 35.4 mg (0.1 mmol) of Fe(OTf) were added. 2, then stirred at room temperature for 20 hours under 26W white LED light. After the conversion of the raw materials was complete, 102mg (0.75mmol) of phenyl thioethane and 34mg (0.15mmol) of hydroiodic acid were added thereto, and stirred at room temperature for 5 hours. Then the solvent was evaporated under reduced pressure, and the product was obtained by column chromatography (petroleum ether / ethyl acetate = 16:1), with a yield of 91%, >20:1dr. White solid. 1 HNMR (400MHz, CDCl 3 )δ7.33-7.24(m,5H),7.20(d,J=9.0Hz,2H),6.38(d,J=9.0Hz,2H),5.76(s,1H),4.96(dd,J=7.2,2.6Hz, 1H), 4.80 (dd, J=8.0, 7.2Hz, 1H), 4.25-4.17 (m, 2H), 4.05 (dd, J=8.1, 2.7Hz, 1H), 1.26 (t, J=7.1Hz, 3H); 13 C NMR (100 MHz, CDCl 3 )δ169.4,141.5,140.7,131.9,128.9,127.8,126.1,115.3,110.5,88.2,75.7,61.6,60.9,14.1.HRMS-ESI:calcd for C 18 H 18 BrNO 3 (M+Na + )398.0362, found 398.0372.

[0030] Example 6: Preparation of ethyl 4-(4-methoxyphenyl)-3-(4-chlorophenyl)thiazolidine-2-carboxylate In a 10 mL flask, 104.5 mg (0.5 mmol) of (4-methoxyphenyl)glycine ethyl ester was dissolved in 5.0 mL of chloroform, and 5.1 mg (0.01 mmol) of basic blue B and 27.8 mg (0.1 mmol) of FeSO were added. 4 7H 2 O, then stirred at room temperature for 20 hours under 26W white LED light. After the raw material conversion is complete, 128mg (0.75mmol) 4-chloro-phenyl thioethane and 25mg (0.15mmol) hydrobromic acid are added thereto, and stirred at room temperature for 5 hours. Then the solvent is evaporated under reduced pressure, and the product is obtained by column chromatography (petroleum ether / ethyl acetate = 16:1), with a yield of 87%, >20:1dr. Pale yellow liquid. 1 H NMR (400 MHz, CDCl3 )δ7.56(d,J=8.4Hz,2H),7.28(d,J=8.5Hz,2H),6.75-6.68(m,2H),6.52-6.44(m,2H),5.12(s,1H),5.00(dd,J=10.0,5.6Hz, 1H), 4.34 (q, J = 7.1Hz, 2H), 3.69 (s, 3H), 3.43 (dd, J = 11.7, 10.0Hz, 1H), 3.33 (dd, J = 11.7, 5.6Hz, 1H), 1.37 (t, J = 7.1Hz, 3H); 13 C NMR (101 MHz, CDCl 3 )δ172.4,153.0,140.1,139.8,133.5,129.2,128.2,116.0,114.6,69.1,67.3,62.0,55.7,40.1,14.3.HRMS(ESI)calcd for C 19 H 21 ClNO 3 S(M+H + )378.0925, found 378.0922.

[0031] Example 7: Preparation of N-cyclohexyl-3-(4-methoxyphenyl)-4-(phenyl)thiazolidine-2-carboxamide In a 10 mL flask, 131 mg (0.5 mmol) of N-cyclohexyl-2-((4-methoxyphenyl)amino)acetamide was dissolved in 5.0 mL of ethyl acetate, and 4.8 mg (0.01 mmol) of Rh-B and 36.1 mg (0.1 mmol) of Cu(OTf) were added thereto. 2 , then stirred at room temperature for 16 hours under 5W blue LED light. After the raw material conversion is complete, 102mg (0.75mmol) of phenyl thioethane and 25mg (0.15mmol) of hydrobromic acid are added thereto, and stirred at room temperature for 5 hours. Then the solvent is evaporated under reduced pressure, and the product is obtained by column chromatography (petroleum ether / ethyl acetate = 16:1), with a yield of 92%, >20:1dr. Light brown liquid. 1 H NMR (400 MHz, CDCl 3)δ7.30-7.22(m,3H),7.16-7.10(m,2H),6.72-6.66(m,2H),6.52-6.46(m,2H),6. 17(d,J=8.7Hz,1H),5.44(d,J=5.9Hz,1H),5.19(s,1H),3.83-3.73(m,2H),3.68( s,3H),2.93(dd,J=11.3,1.3Hz,1H),1.91(dd,J=12.6,4.3Hz,1H),1.83-1.72(m, 1H),1.72-1.52(m,3H),1.43-1.27(m,2H),1.19-1.04(m,2H),1.03-0.84(m,1H); 13 C NMR (101 MHz, CDCl 3 )δ170.5,152.8,140.4,138.0,128.5,127.7,126.9,116.2,114.8,66.8,66.7,55.6,48.3,38.5,33.1,32.8,25.5,24.9,24.7.HRMS(ESI)calcd for C 23 H 29 N 2 O 2 S(M+H + )397.1944, found 397.1949.

[0032] Example 8: Preparation of ethyl 3-(4-methoxyphenyl)thiazolidine-2-carboxylate In a 10 mL flask, 104.5 mg (0.5 mmol) of (4-methoxyphenyl)glycine ethyl ester was dissolved in 5.0 mL of 1,2-dichloroethane, and 10.2 mg (0.01 mmol) of Rose Bengal and 20 mg (0.1 mmol) of Cu(OAc) were added. 2 ·H 2 O, then stirred at room temperature for 20 hours under 26W white LED light. After the raw material conversion is complete, 45mg (0.75mmol) of ethylene sulfide and 25mg (0.15mmol) of hydrobromic acid are added thereto, and stirred at room temperature for 5 hours. Then the solvent is evaporated under reduced pressure, and the product is obtained by column chromatography (petroleum ether / ethyl acetate = 16:1), with a yield of 93%. Light yellow liquid. 1 H NMR (400 MHz, CDCl 3)δ6.86-6.79(m,2H),6.74-6.67(m,2H),5.13(s,1H),4.26-4.14(m,2H),3.85-3.75(m,2H),3.75(s,3H),3.61-3.30(m,1H),3.10-3.04(m,1H),1.27(t,J=7.1Hz,3H); 13 C NMR(101MHz,CDCl 3 )δ171.8,153.4,141.0,116.1,114.9,64.9,61.6,55.8,53.7,30.6,14.2.HRMS(ESI)calcdfor C 19 H 22 NO 4 S(M+H + )268.1002,found 268.1000.

Claims

1. A method for preparing a polysubstituted 1,3-thiazolidine compound, characterized in that The specific steps are: add the glycine derivative shown in Ⅰ, the photocatalyst, the Lewis acid and the appropriate amount of solvent to a flask in sequence, stir at room temperature for 10-20 hours under visible light irradiation, then add the thioethane derivative shown in II and the hydrohalic acid, stir at room temperature for 5 hours, evaporate the solvent under reduced pressure, and obtain a polysubstituted 1,3 thiazolidine derivative by column chromatography. The preparation process is shown in the figure below: Where R 1 The substituents may be alkyl, alkoxy, aryl and halogen; R 2 The substituent may be an alkoxy group, an aryl group, a substituted amino group, etc.; R 3 The substituent may be a substituted aryl group, an alkyl group, an alkoxy group, or the like.

2. The method for preparing a polysubstituted 1,3-thiazolidine compound according to claim 1, characterized in that: The photocatalyst is one of rhodamine B (Rh-B), rhodamine 6G (Rh-6G), rose bengal, eosin Y, and basic blue B.

3. The method for preparing a polysubstituted 1,3-thiazolidine compound according to claim 1, characterized in that: The Lewis acid is one of Cu(OAc)2·H2O, FeSO4·7H2O, Cu(OTf)2, Fe(OTf)2, and Ce(OTf)2.

4. The method for preparing a polysubstituted 1,3-thiazolidine compound according to claim 1, characterized in that: The hydrohalic acid is one of hydroiodic acid and hydrobromic acid.

5. The method for preparing a polysubstituted 1,3-thiazolidine compound according to claim 1, characterized in that: The visible light source is one of a 26W energy-saving lamp and a 5W blue LED lamp.

6. The method for preparing a polysubstituted 1,3-thiazolidine compound according to claim 1, characterized in that: The solvent is one of dichloromethane, chloroform, toluene, 1,2-dichloroethane, acetonitrile, ethyl acetate, and a mixed solvent of 1,2-dichloroethane and acetonitrile.

7. The method for preparing a polysubstituted 1,3-thiazolidine compound according to claim 1, characterized in that: The molar ratio of the glycine derivative, the photosensitizer, the Lewis acid, the ethylene sulfide derivative and the hydrohalic acid is 1:0.02:0.2:1.5:0.3.

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