Synthesis of moxidolol

Abstract

This application discloses a method for preparing mopiperol, namely 2,2,2,2-(4-(piperidin-1-yl)pyrimidino[5,4-d]pyrimidin-2,6-diyl)bis(azatriyl)tetra(ethyl-1-ol), which has good yield, high product purity, mild reaction conditions, and low cost.

Description

Technical Field

[0001] This application falls broadly in the field of medicinal chemistry, specifically relating to a method for preparing mopidazole. Background Technology

[0002] Mopidamol, also known as 2,2,2,2-(4-(piperidin-1-yl)pyrimidino[5,4-d]pyrimidin-2,6-diyl)bis(azatriyl))tetra(ethyl-1-ol), is a yellow crystalline powder, odorless, readily soluble in chloroform, dimethyl sulfoxide, and N,N-dimethylformamide, slightly soluble in acetone, insoluble in water, and has a melting point of 157-158°C.

[0003] Mopitazone is a phosphodiesterase inhibitor and a dipyridamole derivative. It possesses anticancer activity and can prevent retinal vascular defects in experimental diabetes. It has been extensively studied and applied in cardiovascular disease medications. Studies have shown that mopitazone's main pharmacological effects are vasodilation, inhibition of platelet aggregation and adhesion, and antithrombotic effects. In recent years, further research has shown that mopitazone can inhibit viral replication and has been used to treat viral upper respiratory tract infections and rotavirus enteritis. It inhibits phosphodiesterase, preventing the breakdown of cyclic adenosine monophosphate (cAMP), stabilizing mast cells, inhibiting degranulation (release of vasoactive substances), and also inhibiting the entry of dioxane nucleotides, deoxycytosine, and nucleosides into cells. Furthermore, it inhibits RNA viruses and certain DNA viruses, preventing the specific replication process of viruses.

[0004] In modern technology, the typical synthetic method for mopiridol involves preparing dipyridamole from diethanolamine and 2,6-dichloro-4,8-bis(piperidin-1-yl)pyrimidino[5,4-d]pyrimidino at high temperatures of 150-200°C, followed by reduction with Zn powder and oxidation with the participation of I2 to obtain mopiridol. However, the starting material, pyrimidino[5,4-d]pyrimidino-2,4,6,8-tetraol, has poor solubility, requiring PCl5 or other solubilizing agents, and the conditions are strict and the conversion is incomplete. Furthermore, the high temperature during the preparation of dipyridamole easily generates impurities, making purification difficult, and it is hard to achieve a chemical purity of 98% or higher. Mopiridol is an important organic compound. Therefore, developing a synthetic method with good yield, high purity, mild reaction, and low cost is an urgent problem to be solved. Summary of the Invention

[0005] The purpose of one or more embodiments of this application is to provide a preparation method for mopidadiol with good yield, high product purity, mild reaction conditions, and low cost.

[0006] One or more embodiments of this application provide a method for preparing mopidazole, which includes the following steps:

[0007] (1) 5-amino-2-methylthiopyrimidine-4-carboxylic acid is reacted with N,N'-carbonyldiimidazole to generate 5-amino-2-methylthiopyrimidine-4-carboxamide.

[0008]

[0009] (2) 5-amino-2-methylthiopyrimidine-4-carboxamide was reacted with triphosgene to generate 6-methylthiopyrimidine[5,4-D]pyrimidine-2,4-diol.

[0010]

[0011] (3) 6-Methylthiopyrimido[5,4-D]pyrimidin-2,4-diol is reacted with phosphorus pentachloride to generate 2,4-dichloro-6-methylthiopyrimido[5,4-D]pyrimidin.

[0012]

[0013] (4) 2,4-Dichloro-6-methylthiopyrimido[5,4-D]pyrimidin is reacted with N,N-diisopropylethylamine to generate 2-chloro-6-methylthio-4-piperidin-1-ylpyrimido[5,4-D]pyrimidin.

[0014]

[0015] (5) 2-Chloro-6-methylthio-4-piperidin-1-ylpyrimidino[5,4-D]pyrimidine is reacted with m-chloroperoxybenzoic acid to generate 2-chloro-6-methylsulfinyl-4-piperidinylpyrimidino[5,4-D]pyrimidine.

[0016]

[0017] (6) Reaction of 2-chloro-6-methylsulfinyl-4-piperidinylpyrimido[5,4-D]pyrimidine with diethanolamine yields 2,2,2,2-(4-(piperidin-1-yl)pyrimido[5,4-d]pyrimidin-2,6-diyl)bis(azatriyl)tetra(ethyl-1-ol)

[0018]

[0019] In one or more embodiments, in step (1), 5-amino-2-methylthiopyrimidine-4-carboxylic acid is dissolved in tetrahydrofuran, N,N'-carbonyldiimidazole is added, and the reaction mixture is then reacted at 50°C for 1-2 hours; cooled to room temperature, concentrated ammonia is slowly added, and the resulting mixture is reacted at room temperature for 14-18 hours, for example, 14, 15, 16, 17, or 18 hours.

[0020] In one or more embodiments, the reaction mixture is reacted at 50°C for 2 hours.

[0021] In one or more embodiments, the reaction mixture is reacted at 50°C for 16 hours.

[0022] In one or more embodiments, the molar ratio of 5-amino-2-methylthiopyrimidine-4-carboxylic acid to N,N'-carbonyldiimidazole is 1:2.

[0023] In one or more embodiments, in step (2), 5-amino-2-methylthiopyrimidine-4-carboxamide is dissolved in tetrahydrofuran, triphosgene is added, and then the reaction mixture is reacted at 70°C for 1-3 hours, for example, 2 hours.

[0024] In one or more embodiments, the molar ratio of 5-amino-2-methylthiopyrimidine-4-carboxamide to triphosgene is 1:0.8.

[0025] In one or more embodiments, in step (3), 6-methylthiopyrimidine[5,4-D]pyrimidine-2,4-diol is dissolved in phosphorus oxychloride, phosphorus pentachloride is added, and then the reaction mixture is reacted at 100°C for 1-3 hours, for example 2 hours.

[0026] In one or more embodiments, the molar ratio of 6-methylthiopyrimidine[5,4-D]pyrimidine-2,4-diol to phosphorus pentachloride is 1:5.

[0027] In one or more embodiments, in step (4), 2,4-dichloro-6-methylthiopyrimidine and [5,4-D]pyrimidine are dissolved in tetrahydrofuran under ice bath conditions, and N,N-diisopropylethylamine and piperidine are added. The mixture is reacted at 0°C for 15-45 minutes, for example, 20, 25, 30, 35, or 40 minutes.

[0028] In one or more embodiments, the molar ratio of 2,4-dichloro-6-methylthiopyrimidine[5,4-D]pyrimidine, N,N-diisopropylethylamine, and piperidine is 1:4:1.2.

[0029] In one or more embodiments, in step (5), 2-chloro-6-methylthio-4-piperidin-1-ylpyrimidine[5,4-D]pyrimidine is dissolved in tetrahydrofuran under ice bath conditions, and m-chloroperoxybenzoic acid is added in batches. The mixture is reacted at 0°C for 15-45 minutes, for example, 20, 25, 30, 35, or 40 minutes.

[0030] In one or more embodiments, the molar ratio of 2-chloro-6-methylthio-4-piperidin-1-ylpyrimidino[5,4-D]pyrimidinotobenzoic acid to m-chloroperoxybenzoic acid is 1:1.

[0031] In one or more embodiments, in step (6), 2-chloro-6-methylsulfinyl-4-piperidinylpyrimidine[5,4-D]pyrimidine is dissolved in diethanolamine, and the mixture is reacted at 120°C for 1-3 hours, for example 2 hours.

[0032] In one or more embodiments, mopidazole is prepared as follows:

[0033]

[0034]

[0035] In one or more embodiments, the preparation method of this application has good yield, high product purity, mild reaction conditions, and low cost. Detailed Implementation

[0036] The following embodiments are specific examples of this application and are not intended to limit the scope of protection of this application.

[0037] Example 1: Preparation of 5-amino-2-methylthiopyrimidine-4-carboxamide

[0038]

[0039] 5-Amino-2-methylthiopyrimidine-4-carboxylic acid (10.0 g, 54.05 mmol, 1.0 eq) was dissolved in tetrahydrofuran (150 ml), and N,N'-carbonyldiimidazole (17.51 ​​g, 108.10 mmol, 2.0 eq) was added. The reaction mixture was then reacted at 50 °C for 2 hours, cooled to room temperature, and concentrated ammonia (20 ml) was slowly added. The resulting mixture was reacted for another 16 hours at room temperature, and then the reaction was quenched with water. The aqueous phase was extracted with ethyl acetate (50 ml × 3), the organic phase was separated, and the solution was concentrated under reduced pressure to obtain crude 5-amino-2-methylthiopyrimidine-4-carboxamide (9.50 g, 51.63 mmol, 95.5%) as a yellow solid.

[0040] LCMS: [M+H]+=185.0, tR=1.483min

[0041] Example 2 Preparation of 6-methylthiopyrimido[5,4-D]pyrimidin-2,4-diol

[0042]

[0043] 5-Amino-2-methylthiopyrimidine-4-carboxamide (9.50 g, 51.63 mmol, 1.0 eq) was dissolved in tetrahydrofuran (100 ml), and triphosgene (12.22 g, 41.30 mmol, 0.8 eq) was added. The reaction mixture was then reacted at 70 °C for 2 hours, cooled to room temperature, and quenched with water. The aqueous phase was extracted with ethyl acetate (50 ml × 3), the organic phase was separated, and the crude product was concentrated under reduced pressure. The crude product was recrystallized from ethyl acetate and petroleum ether to give 6-methylthiopyrimidine[5,4-D]pyrimidine-2,4-diol (7.80 g, 37.14 mmol, 71.9%) as a white solid.

[0044] LCMS: [M+H]+=211.0, tR=1.280min

[0045] 1 HNMR (400MHz, DMSO-d6) δ11.72(s,1H),11.47(s,1H),8.73(s,1H),2.56(s,3H).

[0046] Example 3 Preparation of 2,4-dichloro-6-methylthiopyrimido[5,4-D]pyrimidin

[0047]

[0048] 6-Methylthiopyrimido[5,4-D]pyrimidin-2,4-diol (7.80 g, 37.14 mmol, 1.0 eq) was dissolved in phosphorus oxychloride (80 ml), and phosphorus pentachloride (38.63 g, 185.70 mmol, 5.0 eq) was added. The reaction mixture was then reacted at 100 °C for 2 hours, cooled to room temperature, and concentrated under reduced pressure to obtain a crude product. The residue was dissolved in ethyl acetate (10 ml) and slowly added dropwise to a pre-prepared ice water solution. The aqueous phase was extracted with ethyl acetate (50 ml × 3), and the organic phase was separated and concentrated under reduced pressure to obtain crude 2,4-dichloro-6-methylthiopyrimido[5,4-D]pyrimidin (6.80 g, 27.53 mmol, 74.1%) as a gray solid.

[0049] LCMS:N / A

[0050] Example 4 Preparation of 2-chloro-6-methylthio-4-piperidin-1-ylpyrimidino[5,4-D]pyrimidine

[0051]

[0052] 2,4-Dichloro-6-methylthiopyrimidino[5,4-D]pyrimidine (6.80 g, 27.53 mmol, 1.0 eq) was dissolved in tetrahydrofuran (70 ml) under ice bath conditions. N,N-diisopropylethylamine (14.21 g, 110.12 mmol, 4.0 eq) and piperidine (2.81 g, 33.04 mmol, 1.2 eq) were added. The mixture was reacted at 0 °C for 30 min. The reaction was quenched with water. The aqueous phase was extracted with ethyl acetate (30 ml × 3). The organic phase was separated and concentrated under reduced pressure to obtain the crude product. Column chromatography (petroleum ether: ethyl acetate = 3:1) gave 2-chloro-6-methylthio-4-piperidin-1-ylpyrimidino[5,4-D]pyrimidine (5.20 g, 17.57 mmol, 63.8%) as a yellow solid.

[0053] LCMS: [M+H]+=296.1, tR=2.667min

[0054] Example 5 Preparation of 2-chloro-6-methylsulfinyl-4-piperidinylpyrimido[5,4-D]pyrimidine

[0055]

[0056] 2-Chloro-6-methylthio-4-piperidin-1-ylpyrimidino[5,4-D]pyrimidine (5.20 g, 17.57 mmol, 1.0 eq) was dissolved in tetrahydrofuran (60 ml) under ice bath conditions. Then, m-chloroperoxybenzoic acid (3.04 g, 17.57 mmol, 1.0 eq) was added in portions. The mixture was reacted at 0 °C for 30 min. After the reaction was monitored by TLC, the reaction was quenched with sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (30 ml × 3). The organic phase was separated and concentrated under reduced pressure to obtain the crude product. Column chromatography (dichloromethane:methanol = 15:1) yielded 2-chloro-6-methylsulfinyl-4-piperidinylpyrimidino[5,4-D]pyrimidine (4.20 g, 13.50 mmol, 76.8%) as a yellow solid.

[0057] LCMS: [M+H]+=312.0, tR=1.995min

[0058] 1 HNMR(400MHz,DMSO-d6)δ9.47(s,1H),4.69-4.66(m,2H),4.04-4.01(m,2H),3.46(s,3H),1.72-1.72(m,6H).

[0059] Example 6 Preparation of 2,2,2,2-(4-(piperidin-1-yl)pyrimido[5,4-d]pyrimidin-2,6-diyl)bis(azatriyl))tetra(ethyl-1-ol) (Notebook 048-084):

[0060]

[0061] 2-Chloro-6-methylsulfinyl-4-piperidinylpyrimidino[5,4-D]pyrimidine (4.20 g, 13.50 mmol, 1.0 eq) was dissolved in diethanolamine (50 mL). The mixture was reacted at 120 °C for 2 hours. After the reaction was completed by LCMS monitoring, dimethyl sulfoxide (5 mL) was added to rapidly dissolve the pyrimidine. The solution was then purified using a reverse-phase formic acid system under the following conditions: 220 mesh reverse-phase column, flow rate 100 mL / min, gradient elution of 5%–30% for 20 min. The product was collected at 27%, then concentrated to obtain a crude product; it was then purified by a reverse-phase ammonia system under the following conditions: 200 mesh reverse-phase column, flow rate 100 ml / min, gradient 5%-40% for 20 min, and the product 2,2,2,2-(4-(piperidin-1-yl)pyrimidino[5,4-d]pyrimidin-2,6-diyl)bis(azatriyl))tetra(ethyl-1-ol) (3.20 g, 7.60 mmol, 56.3%) was collected at 34% as a yellow solid.

[0062] LCMS: [M+H]+=422.2, tR=1.621min

[0063] 1 HNMR (400MHz, DMSO-d6) δ8.64(s,1H),4.74-4.72(m,1H),4.19(s,1H),3.65-3.31(m,16H),1.67-1.62(m,6H).

Claims

1. A method for preparing mopidamine, comprising the following steps: (1) 5-amino-2-methylthiopyrimidine-4-carboxylic acid and N,N' -The reaction of carbonyl diimidazole produces 5-amino-2-methylthiopyrimidine-4-formamide. ； (2) 5-amino-2-methylthiopyrimidine-4-carboxamide is reacted with triphosgene to generate 6-methylthiopyrimidine[5,4-D]pyrimidine-2,4-diol. ； (3) 6-Methylthiopyrimido[5,4-D]pyrimidin-2,4-diol is reacted with phosphorus pentachloride to generate 2,4-dichloro-6-methylthiopyrimido[5,4-D]pyrimidin. ； (4) 2,4-Dichloro-6-methylthiopyrimidine[5,4-D]pyrimidine is reacted with N,N-diisopropylethylamine and piperidine to generate 2-chloro-6-methylthio-4-piperidin-1-ylpyrimidine[5,4-D]pyrimidine. ； (5) 2-Chloro-6-methylthio-4-piperidin-1-ylpyrimidino[5,4-D]pyrimidine is reacted with m-chloroperoxybenzoic acid to generate 2-chloro-6-methylsulfinyl-4-piperidinylpyrimidino[5,4-D]pyrimidine. ； (6) Reaction of 2-chloro-6-methylsulfinyl-4-piperidinylpyrimido[5,4-D]pyrimidine with diethanolamine to generate 2,2,2,2-(4-(piperidin-1-yl)pyrimido[5,4-d]pyrimidin-2,6-diyl)bis(azatriyl)tetra(ethyl-1-ol) ； In step (1), 5-amino-2-methylthiopyrimidine-4-carboxylic acid is dissolved in tetrahydrofuran and added... N,N' -Carbonyl diimidazole, then the reaction mixture was heated to 50 o React at C for 1-2 hours; cool to room temperature, slowly add concentrated ammonia, and continue to react the resulting mixture at room temperature for 14-18 hours. In step (2), 5-amino-2-methylthiopyrimidine-4-carboxamide is dissolved in tetrahydrofuran, triphosgene is added, and then the reaction mixture is heated at 70°C. o React at C for 2 hours; In step (3), 6-methylthiopyrimidine[5,4-D]pyrimidine-2,4-diol is dissolved in phosphorus oxychloride, phosphorus pentachloride is added, and then the reaction mixture is heated to 100 °C. o React at C for 1-3 hours; In step (4), 2,4-dichloro-6-methylthiopyrimidine[5,4-D]pyrimidine is dissolved in tetrahydrofuran under ice bath conditions, and then added... N,N -Diisopropylethylamine and piperidine, the mixture in 0 o React at C for 15-45 minutes; In step (5), 2-chloro-6-methylthio-4-piperidin-1-ylpyrimidine[5,4-D]pyrimidine is dissolved in tetrahydrofuran under ice bath conditions, and m-chloroperoxybenzoic acid is added in portions. The mixture is then heated to 0°C. o React at C for 15-45 minutes; In step (6), 2-chloro-6-methylsulfinyl-4-piperidinylpyrimidine[5,4-D]pyrimidine is dissolved in diethanolamine, and the mixture is heated at 120 °C. o React at C for 1-3 hours.

2. The preparation method according to claim 1, wherein in step (1), 5-amino-2-methylthiopyrimidine-4-carboxylic acid is dissolved in tetrahydrofuran, and then added... N,N' -Carbonyl diimidazole, then the reaction mixture was heated to 50 o React at C for 2 hours; cool to room temperature, slowly add concentrated ammonia, and continue to react the resulting mixture at room temperature for 16 hours.

3. The preparation method according to claim 1, wherein in step (1), the 5-amino-2-methylthiopyrimidine-4-carboxylic acid and N,N' The molar ratio of -carbonyldiimidazole is 1:

2.

4. The preparation method according to claim 1, wherein in step (2), 5-amino-2-methylthiopyrimidine-4-carboxamide is dissolved in tetrahydrofuran, triphosgene is added, and then the reaction mixture is heated to 70 °C. o React at C for 2 hours.

5. The preparation method according to claim 1, wherein in step (2), the molar ratio of 5-amino-2-methylthiopyrimidine-4-carboxamide to triphosgene is 1:0.

8.

6. The preparation method according to claim 1, wherein in step (3), 6-methylthiopyrimidine[5,4-D]pyrimidine-2,4-diol is dissolved in phosphorus oxychloride, phosphorus pentachloride is added, and then the reaction mixture is heated to 100... o React at C for 2 hours.

7. The preparation method according to claim 1, wherein in step (3), the molar ratio of 6-methylthiopyrimidine[5,4-D]pyrimidine-2,4-diol to phosphorus pentachloride is 1:

5.

8. The preparation method according to claim 1, wherein in step (4), 2,4-dichloro-6-methylthiopyrimidine[5,4-D]pyrimidine is dissolved in tetrahydrofuran under ice bath conditions, and then added... N,N -Diisopropylethylamine and piperidine, the mixture in 0 o React at C for 30 minutes.

9. The preparation method according to claim 1, wherein in step (4), the 2,4-dichloro-6-methylthiopyrimidine[5,4-D]pyrimidine, N,N The molar ratio of diisopropylethylamine to piperidine is 1:4:1.

2.

10. The preparation method according to claim 1, wherein in step (5), 2-chloro-6-methylthio-4-piperidin-1-ylpyrimidine[5,4-D]pyrimidine is dissolved in tetrahydrofuran under ice bath conditions, and m-chloroperoxybenzoic acid is added in batches, the mixture being heated to 0°C. o React at C for 30 minutes.

11. The preparation method according to claim 1, wherein in step (5), the molar ratio of 2-chloro-6-methylthio-4-piperidin-1-ylpyrimidino[5,4-D]pyrimidine to m-chloroperoxybenzoic acid is 1:

1.

12. The preparation method according to claim 1, wherein in step (6), 2-chloro-6-methylsulfinyl-4-piperidinylpyrimidine[5,4-D]pyrimidine is dissolved in diethanolamine, and the mixture is heated at 120 °C. o React at C for 2 hours.

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