A process for the preparation of chiral tricyclic 3,4-dihydropyrimidine-2-thiones

Abstract

A method for preparing chiral tricyclic 3,4-dihydropyrimidine-2-thione compounds belongs to the field of synthetic chemistry. The method involves dissolving substituted benzaldehyde and thiourea in an organic solvent, then adding a chiral phosphorimide catalyst and additives, stirring at room temperature for 1-2 hours, followed by the addition of 1,3-indanedione, and reacting at 35-55°C for 30-60 hours. The resulting chiral tricyclic 3,4-dihydropyrimidine-2-thione compounds are purified. The molar ratio of substituted benzaldehyde, thiourea, chiral phosphorimide catalyst, 1,3-indanedione, and additives is 1:1-2.2:0.05-0.1:0.5-1.0:0.5-2.5, achieving a yield of 88% and an enantioselectivity of 99%. The reaction conditions are mild, and the reaction time is short, making this a highly efficient method for synthesizing chiral tricyclic 3,4-dihydropyrimidine-2-thione compounds.

Description

Technical Field

[0001] This invention belongs to the field of synthetic chemistry technology, specifically relating to a method for preparing a chiral tricyclic 3,4-dihydropyrimidine-2-thione. Background Technology

[0002] The research and application of chiral compounds play an important role in the pharmaceutical field. Organisms are mainly composed of small organic molecules such as amino acids and sugars with chiral structures, which then combine to form macromolecules such as proteins and polysaccharides. This chiral environment determines the chiral selectivity of receptors when interacting with drugs. The levorotatory and dextrorotatory forms of many drugs exhibit significant differences in their biological activity due to their different binding mechanisms with receptors or enzymes in the body. One chirality may have a therapeutic effect, while the other may be ineffective or even produce side effects. The structure of tricyclic 3,4-dihydropyrimidine-2-thione has given rise to many biologically active compounds that can act as potent antagonists of transient receptor potential A1 (TRPA1) on neuronal membranes. TRPA1 channels are widely expressed in sensory neurons and participate in physiological processes such as temperature perception, chemosensing, and pain transmission (Bioorganic & Medicinal Chemistry Letters. 2012; 22(2):797-800.). In addition, these compounds exhibit excellent antibacterial activity against Gram-positive bacteria, Bacillus subtilis, and Staphylococcus aureus (Journal of Chemical Research. 2012; 36(12):718-721). This literature also reports a method for preparing optical isomers of tricyclic 3,4-dihydropyrimidine-2-thione compounds. First, racemic products are obtained, and then supercritical fluid chromatography is used to chirally separate the products, yielding products with a single chiral configuration. However, this separation method is inefficient and costly, making it unsuitable for large-scale preparation. Therefore, developing a catalytic synthesis method for chiral tricyclic 3,4-dihydropyrimidine-2-thione is of great significance. Summary of the Invention

[0003] In order to overcome the shortcomings of the prior art, the purpose of this invention is to provide a method for preparing chiral tricyclic 3,4-dihydropyrimidine-2-thione with reasonable process design, convenient operation and high yield.

[0004] The present invention discloses a chiral tricyclic 3,4-dihydropyrimidine-2-thione compound, the structural formula of which is shown in (I).

[0005]

[0006] Ar is a mono-, di-, or tri-substituted aryl group, and may be a mono-, di-, or tri-substituted phenyl, naphthyl, pyridyl, furanyl, or thiophene group, etc.; the substituent may be fluorine, chlorine, bromine, trifluoromethyl, methyl, nitro, or methoxy, etc.

[0007] The present invention discloses a method for preparing a chiral tricyclic 3,4-dihydropyrimidine-2-thione, which involves reacting substituted benzaldehyde, 1,3-indanedione, and thiourea under the catalysis of chiral phosphorimide acid to obtain the target product, chiral tricyclic 3,4-dihydropyrimidine-2-thione. All raw materials used are commercially available. The process involves first dissolving substituted benzaldehyde and thiourea in organic solvents such as ethyl acetate, toluene, chloroform, or 1,4-dioxane, then adding a chiral phosphorimide catalyst and additives (anhydrous sodium sulfate, anhydrous magnesium sulfate, etc.), and stirring at room temperature for 1–2 hours. Next, 1,3-indanedione is added, and the reaction is carried out at 35–55°C for 30–60 hours. The mixture is then purified by column chromatography to obtain a chiral tricyclic 3,4-dihydropyrimidine-2-thione compound. The molar ratio of substituted benzaldehyde, thiourea, chiral phosphorimide catalyst, 1,3-indanedione, and additives is 1:1–2.2:0.05–0.1:0.5–1.0:0.5–2.5, and the total concentration of the raw materials in the organic solvent is 0.1–4 M.

[0008] The reaction formula is as follows:

[0009]

[0010] The structural formula of the chiral phosphorimide catalyst is shown in (II):

[0011]

[0012] The skeletal structure of chiral phosphorimides is binaphthyl (BINOL) or octahydrobinaphthyl (H8-BINOL). The chiral configuration of the binaphthyl structure can be either R or S configuration, where X... 1 With X 2 They can be the same or different, and can be phenyl, 2-naphthyl, phenyl, 9-phenanthyl, 1-pyrene, or 3,5-bis(trifluoromethyl)phenyl, etc.

[0013] This invention screened reaction conditions through extensive experiments. Initially, chiral phosphoric acid catalysts were investigated, but the reaction yielded only racemic products with very low yields. Related literature also showed that other types of catalysts did not provide good chiral control for this type of reaction. Later, chiral phosphorimide acid catalysts were used, achieving excellent chiral selectivity. Among these, the products catalyzed by 3,3'-substituted H8-BINOL-derived chiral phosphorimides exhibited superior yields and enantioselectivity. For example, using 3,3'-2-naphthyl-substituted H8-BINOL-derived phosphorimides as catalysts and p-nitrobenzaldehyde as substrate, the enantioselectivity reached a maximum of 99%. The optimal reaction temperature selected in this invention is 35–45°C for 24–48 h, achieving a yield as high as 88% and an enantioselectivity as high as 99%, demonstrating excellent technical results.

[0014] The beneficial effects of this invention are:

[0015] 1. Compared with the preparation methods in existing literature (Journal of Chemical Research.2012;36(12):718-721), the present invention can directly obtain products with single chirality without the need for complex chiral separation, which is more efficient and convenient.

[0016] 2. This invention provides an optimal method for preparing chiral tricyclic 3,4-dihydropyrimidine-2-thione compounds through extensive experimental screening. The method involves a multi-component asymmetric Biginelli reaction of substituted benzaldehyde, 1,3-indanedione, and thiourea under chiral phosphorimide catalysis. This reaction can be carried out in a conventional reaction vessel, achieving a yield of up to 88% and an enantioselectivity of up to 99%. The reaction time is short, making it a highly efficient method for synthesizing chiral tricyclic 3,4-dihydropyrimidine-2-thione compounds.

[0017] 3. The entire process design of this invention is reasonable, and the process operation is simple and efficient. By screening the optimal reaction conditions, including the type of catalyst, reaction temperature, reaction time, and additives, the reaction yield can be significantly improved, side reactions can be reduced, and production costs can be greatly reduced, which has a very good application prospect. Attached Figure Description

[0018] Figure 1 Example 1 prepared (S)-4-(3-nitrophenyl)-2-thio-1,2,3,4-tetrahydro-5H-indeno[1,2-d]pyrimidin-5-one 1 H spectrum;

[0019] Figure 2Example 1 prepared (S)-4-(3-nitrophenyl)-2-thio-1,2,3,4-tetrahydro-5H-indeno[1,2-d]pyrimidin-5-one 13 C spectrum;

[0020] Figure 3 Catalytic liquid phase diagram of (S)-4-(3-nitrophenyl)-2-thio-1,2,3,4-tetrahydro-5H-indeno[1,2-d]pyrimidin-5-one prepared in Example 1;

[0021] Figure 4 Enantiomeric liquid phase diagram of (S)-4-(3-nitrophenyl)-2-thio-1,2,3,4-tetrahydro-5H-indeno[1,2-d]pyrimidin-5-one prepared in Example 1. Detailed Implementation

[0022] The invention is illustrated by way of example in the following embodiments. The specific material ratios, process conditions, and results described are for illustrative purposes only and should not, and will not, limit the scope of the claims.

[0023] Example 1: Preparation of (S)-4-(3-nitrophenyl)-2-thio-1,2,3,4-tetrahydro-5H-indeno[1,2-d]pyrimidin-5-one

[0024]

[0025] o-Nitrobenzaldehyde (30.22 mg, 0.20 mmol) and thiourea (15.22 mg, 0.20 mmol) were dissolved in 2 mL of ethyl acetate. Then, 11.98 mg, 0.01 mmol, of a phosphorimide derived from H8-BINOL with a 3,3'-2-naphthyl substituted group (R-H8-BINOL skeleton) was added. 1 =x 2 =2-naphthyl) and anhydrous sodium sulfate (14.20 mg, 0.10 mmol), stirred at room temperature for 2 hours; then 1,3-indanedione (14.61 mg, 0.10 mmol) was added with stirring, and the reaction was carried out at 40 °C for 48 hours. After the reaction was complete, the product was purified by column chromatography (dichloromethane:ethyl acetate volume ratio = 40:1) to give a red solid (28.60 mg, 85%, 97% ee) [α]. D 25=-990 (c=0.10, EtOH). 96% ee [Daicel Chiralcel OJ-H, n-hexane / ethanol=50 / 50, 1.0 ml / min, λ=254 nm, t(major)=19.4 min, t(minor)=14.8 min] (product enantioselectivity monitoring as follows) Figure 3 and Figure 4 As shown, the absolute configuration of the product was determined by the specific rotation reported in Bioorganic & Medicinal Chemistry Letters. 2012; 22(2):797-800; 1H NMR data (e.g. Figure 1 (As shown) 1 ¹H NMR (400MHz, DMSO-d⁶) δ 11.94 (s, 1H), 10.03 (s, 1H), 8.19 (d, J = 7.4Hz, 2H), 7.83 (dd, J = 16.7, 7.4Hz, 2H), 7.70 (t, J = 7.9Hz, 1H), 7.51–7.31 (m, 3H), 5.64 (s, 1H). (CNC NMR data are shown in the original text.) Figure 2 (As shown) 13 C NMR (101MHz, DMSO) δ189.44,175.79,153.26,148.31,144.60,135.70,134.04,133.25, 132.83,131.39,130.87,123.40,122.02,121.83,121.28,104.79,53.44.HRMS(ESI)m / z calcd forC 17 H 12 N3O3S([M+H)) + ):338.0594,found:338.0581.

[0026] Example 2: Preparation of (S)-4-(4-nitrophenyl)-2-thio-1,2,3,4-tetrahydro-5H-indeno[1,2-d]pyrimidin-5-one

[0027]

[0028] p-Nitrobenzaldehyde (30.22 mg, 0.20 mmol) and thiourea (15.22 mg, 0.20 mmol) were dissolved in 2 mL of toluene. Then, 11.98 mg (0.01 mmol) of H8-BINOL-derived phosphorimide (with a 1-naphthyl substituted molecule at the 3,3' position, and a binaphthyl skeleton of R-H8-BINOL) was added. 1 =x 2=1-naphthyl) and anhydrous sodium sulfate (14.20 mg, 0.10 mmol), stirred at room temperature for 2 hours; then 1,3-indanedione (14.61 mg, 0.10 mmol) was added with stirring, and the reaction was carried out at 50 °C for 48 hours. After the reaction was complete, the product was purified by column chromatography (dichloromethane:ethyl acetate volume ratio = 40:1) to give a red solid (14.35 mg, 43%, 77% ee). [Daicel Chiralcel OJ-H, n-hexane / ethanol = 50 / 50, 1.0 ml / min, λ = 254 nm, t(major) = 19.4 min, t(minor) = 14.8 min]; 1 H NMR (400MHz, DMSO-d6) δ11.94(s,1H),10.03(s,1H),8.19(d,J=7.4Hz,2H),7.83 (dd,J=16.7,7.4Hz,2H),7.70(t,J=7.9Hz,1H),7.51–7.31(m,3H),5.64(s,1H). 13 C NMR(101MHz,DMSO-d6)δ189.44,175.79,153.26,148.31,144.60,135.70,134.04,133.25 ,132.83,131.39,130.87,123.40,122.02,121.83,121.28,104.79,53.44.HRMS(ESI)m / z calcd for C 17 H 12 N3O3S([M+H)) + ):338.0594,found:338.0581.

[0029] Example 3: Preparation of (S)-4-(3-methoxyphenyl)-2-thio-1,2,3,4-tetrahydro-5H-indeno[1,2-d]pyrimidin-5-one

[0030]

[0031] m-Methoxybenzaldehyde (27.23 mg, 0.20 mmol) and thiourea (15.22 mg, 0.20 mmol) were dissolved in 2 mL of ethyl acetate. Then, 11.98 mg, 0.01 mmol of a 3,3'-2-naphthyl-substituted H8-BINOL-derived phosphorimide (with a binaphthyl skeleton of R-H8-BINOL) was added. 1 =x 2=2-naphthyl) and anhydrous sodium sulfate (14.20 mg, 0.10 mmol), stirred at room temperature for 2 hours; then 1,3-indanedione (14.61 mg, 0.10 mmol) was added with stirring, and the reaction was carried out at 40 °C for 48 hours. After the reaction was complete, the product was purified by column chromatography (dichloromethane:ethyl acetate volume ratio = 40:1) to give a red solid (26.10 mg, 81%, 99% ee) [α]. D 25 =-1160 (c=0.10, EtOH). [Daicel Chiralcel AD, n-hexane / isopropanol=80 / 20, 1.0 ml / min, λ=254 nm, t(major)=20.8 min, t(minor)=13.4 min]; 1 H NMR (400MHz, DMSO-d6) δ11.79(s,1H),9.91(s,1H),7.82(d,J=7.2Hz,1H),7.52–7.25(m,4H),6.96–6.74(m,3H),5.34(s,1H),3.75(s,3H). 13 C NMR(101MHz,DMSO-d6)δ189.52,175.56,159.83,152.87,144.25,135.83,133.33,132.75,13 1.21,130.35,121.73,121.05,119.04,113.36,113.21,105.85,55.56,53.83.HRMS(ESI)m / z calcd for C 18 H 15 N₂O₂S([M+H)) + ):323.0849,found:323.0844.

[0032] Example 4: Preparation of (S)-4-(3-methoxyphenyl)-2-thio-1,2,3,4-tetrahydro-5H-indeno[1,2-d]pyrimidin-5-one

[0033]

[0034] m-Methoxybenzaldehyde (1.36 g, 10 mmol) and thiourea (0.76 g, 10 mmol) were dissolved in 100 mL of ethyl acetate. Then, 1.20 g (1.00 mmol) of phosphorimide derived from H8-BINOL (3,3'-2-naphthyl-substituted) was added. The binaphthyl skeleton is R-H8-BINOL. 1 =x 2=2-naphthyl) and anhydrous sodium sulfate (0.71 g, 5 mmol), stirred at room temperature for 2 hours; then 1,3-indanedione (0.73 g, 5 mmol) was added with stirring, and the reaction was carried out at 40 °C for 48 hours. After the reaction was complete, the product was purified by column chromatography (dichloromethane:ethyl acetate volume ratio = 40:1) to give a red solid (1.23 g, 76%, 99% ee) [α]. D 25 =-1160 (c=0.10, EtOH). [Daicel Chiralcel AD, n-hexane / isopropanol=80 / 20, 1.0 ml / min, λ=254 nm, t(major)=20.8 min, t(minor)=13.4 min]; 1 H NMR (400MHz, DMSO-d6) δ11.79(s,1H),9.91(s,1H),7.82(d,J=7.2Hz,1H),7.52–7.25(m,4H),6.96–6.74(m,3H),5.34(s,1H),3.75(s,3H). 13 C NMR(101MHz,DMSO-d6)δ189.52,175.56,159.83,152.87,144.25,135.83,133.33,132.75,13 1.21,130.35,121.73,121.05,119.04,113.36,113.21,105.85,55.56,53.83.HRMS(ESI)m / z calcd for C 18 H 15 N₂O₂S([M+H)) + ):323.0849,found:323.0844.

[0035] Example 5: Preparation of (S)-4-(2-nitrophenyl)-2-thio-1,2,3,4-tetrahydro-5H-indeno[1,2-d]pyrimidin-5-one

[0036]

[0037] o-Nitrobenzaldehyde (30.22 mg, 0.20 mmol) and thiourea (15.22 mg, 0.20 mmol) were dissolved in 2 mL of ethyl acetate. Then, 11.98 mg, 0.01 mmol, of a phosphorimide derived from H8-BINOL with a 3,3'-phenyl substituted structure (R-H8-BINOL skeleton) was added. 1 =x 2=phenyl) and anhydrous sodium sulfate (14.20 mg, 0.10 mmol), stirred at room temperature for 2 hours; then 1,3-indanedione (14.61 mg, 0.10 mmol) was added with stirring, and the reaction was carried out at 40 °C for 48 hours. After the reaction was complete, the product was purified by column chromatography (dichloromethane:ethyl acetate volume ratio = 40:1) to give a red solid (14.30 mg, 43%, 60% ee) [α]. D 25 =-970 (c=0.10, EtOH), [Daicel Chiralcel OJ-H column, n-hexane / EtOH=50 / 50, 1.0ml / min, λ=254nm, t(major)=28.5min, t(minor)=16.1min]; 1 H NMR (400MHz, DMSO-d6) δ11.90(s,1H),9.85(s,1H),7.99(d,J=8.3Hz,1H),7.84(d,J=7.2Hz,1H),7.76(t ,J=7.6Hz,1H),7.58(t,J=7.5Hz,2H),7.42(dt,J=34.2,7.5Hz,2H),7.29(d,J=7.0Hz,1H),6.21(s,1H). 13 C NMR(101MHz,DMSO)δ189.10,175.68,153.17,148.21,136.30,135.72,134.53,133.23, 132.77,131.36,130.96,129.86,125.14,121.72,121.25,104.49,49.68.HRMS(ESI)m / z calcd for C 17 H 12 N3O3S([M+H)) + ):338.0594,found:338.0578.

[0038] Example 6: Preparation of (S)-4-(4-nitrophenyl)-2-thio-1,2,3,4-tetrahydro-5H-indeno[1,2-d]pyrimidin-5-one

[0039]

[0040] p-Nitrobenzaldehyde (30.22 mg, 0.20 mmol) and thiourea (15.22 mg, 0.20 mmol) were dissolved in 2 mL of 1,4-dioxane. Then, 11.98 mg, 0.01 mmol, of H8-BINOL-derived phosphorimide (with a 2-naphthyl substituted at the 3,3' position, and a binaphthyl skeleton of R-H8-BINOL) was added. 1 =x 2 =2-naphthyl) and anhydrous magnesium sulfate (12.04 mg, 0.10 mmol), stirred at room temperature for 2 hours; then 1,3-indanedione (14.61 mg, 0.10 mmol) was added with stirring, and the reaction was carried out at 50 °C for 48 hours. After the reaction was complete, the product was purified by column chromatography (dichloromethane:ethyl acetate volume ratio = 40:1) to give a red solid (11.93 mg, 35%, 60% ee) [α]. D 25 =-1070 (c=0.10, EtOH). 60% ee [Daicel Chiralcel OJ-H, n-hexane / ethanol=50 / 50, 1.0 ml / min, λ=254 nm, t(major)=28.5 min, t(minor)=16.1 min] (The absolute configuration of the product was determined by the specific rotation reported in the literature Bioorganic & Medicinal Chemistry Letters. 2012; 22(2):797-800); 1 H NMR (400MHz, DMSO-d6) δ11.92(s,1H),10.01(s,1H),8.25(d,J=8.8Hz,2H),7.84(d,J=7.2Hz,1H),7. 60(d,J=8.8Hz,2H),7.46(t,J=8.0Hz,1H),7.38(t,J=7.3Hz,1H),7.33(d,J=6.9Hz,1H),5.56(s,1H). 13 C NMR(101MHz,DMSO-d6)δ189.33,175.81,153.16,149.54,147.56,135.70,133.26 ,132.82,131.39,128.67,124.42,121.80,121.27,104.79,53.58.HRMS(ESI)m / z calcd for C 17 H 12 N3O3S([M+H)) + ):338.0594,found:338.0595.

[0041] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing a chiral tricyclic 3,4-dihydropyrimidine-2-thione compound, characterized in that: The substituted benzaldehyde and thiourea were dissolved in an organic solvent, and then a chiral phosphorimide catalyst and additives were added. The mixture was stirred at room temperature for 1 to 2 hours. Then 1,3-indanedione was added, and the mixture was reacted at 35 to 55 °C for 30 to 60 hours. The mixture was purified by column chromatography to obtain a chiral tricyclic 3,4-dihydropyrimidine-2-thione compound with the structural formula shown in (I). ； Wherein, Ar is a mono-, di-, or tri-substituted phenyl, naphthyl, pyridyl, furanyl, or thiophene group; the substituent is fluorine, chlorine, bromine, trifluoromethyl, methyl, nitro, or methoxy. The structural formula of the chiral phosphorimide catalyst is shown below. ； The skeletal structure of chiral phosphorimine is binaphthalene or octahydrobinaphthalene, where X 1 With X 2 The same or different, can be phenyl, 2-naphthyl, phenyl, 9-phenanthyl or 1-pyrene or 3,5-bis(trifluoromethyl)phenyl.

2. The method for preparing a chiral tricyclic 3,4-dihydropyrimidine-2-thione compound as described in claim 1, characterized in that: The molar ratio of substituted benzaldehyde, thiourea, chiral phosphorimide catalyst, 1,3-indanedione, and additives is 1:1 ~ 2.2:0.05 ~ 0.1:0.5 ~ 1.0:0.5 ~ 2.5, and the total concentration of the raw materials in the organic solvent is 0.1 ~ 4 M.

3. The method for preparing a chiral tricyclic 3,4-dihydropyrimidine-2-thione compound as described in claim 1, characterized in that: The organic solvent is ethyl acetate, toluene, chloroform, or 1,4-dioxane.

4. The method for preparing a chiral tricyclic 3,4-dihydropyrimidine-2-thione compound as described in claim 1, characterized in that: The additive is anhydrous sodium sulfate or anhydrous magnesium sulfate.

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