A 5,6-diphenylpyrazine-2-piperidine compound, a preparation method and application thereof

Abstract

The application discloses a 5,6-diphenylpyrazine-2-piperidine compound and a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. The 5,6-diphenylpyrazine-2-piperidine compound has simple structure, short synthesis route and low synthesis cost, and through in-vitro anti-platelet aggregation activity detection, it is found that the prepared 5,6-diphenylpyrazine-2-piperidine compound has excellent anti-platelet aggregation activity, and can play a more excellent thrombus prevention and treatment effect as an active ingredient of an antithrombotic drug.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to a 5,6-diphenylpyrazine-2-piperidine compound, its preparation method, and its application. Background Technology

[0002] Prostaglandin I2 (PGI2) is a member of the eicosanoid family of lipids and an antagonist of thromboxanes; reduced synthesis of PGI2 promotes thrombus formation. Activation of the PGI2 receptor (IP receptor) not only inhibits platelet-mediated aggregation but also has a strong vasodilatory effect. IP receptor agonists can treat diseases including pulmonary hypertension (PAH), arteriosclerosis obliterans, coronary artery disease, myocardial infarction, transient ischemic attack, angina pectoris, stroke, ischemia-reperfusion injury, restenosis, atrial fibrillation, intermittent claudication, Raynaud's phenomenon, varicose veins, thrombosis, diabetes, diabetic nephropathy, hypertension, hyperlipidemia, cerebral infarction, rheumatoid arthritis, and chronic obstructive pulmonary disease (COPD).

[0003] Currently marketed PGI2-type drugs generally suffer from short half-lives, poor chemical stability, and significant side effects, resulting in poor efficacy. Therefore, there is an urgent need to develop a non-endogenous PGI2-type IP receptor agonist with a long half-life, good chemical stability, higher selectivity, and fewer side effects. Summary of the Invention

[0004] In view of the above-mentioned prior art, the present invention provides a 5,6-diphenylpyrazine-2-piperidine compound, its preparation method and application, so as to obtain an antithrombotic drug with good chemical stability, higher selectivity and fewer side effects.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is to provide a 5,6-diphenylpyrazine-2-piperidine compound, the structural formula of which is shown in Formula I:

[0006]

[0007] Where n is 0, 1, or 2; R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 and R 9 Each is independently a hydrogen atom, an alkyl group, a nitrile group, a halogen atom, or a methoxy group, having no more than 4 carbon atoms.

[0008] Furthermore, the alkyl group is methyl.

[0009] Furthermore, the halogen atom is an F atom.

[0010] Furthermore, 5,6-diphenylpyrazine-2-piperidine compounds are one of the compounds having the following structural formula:

[0011]

[0012] This invention also discloses a method for preparing the above-mentioned compound, the method comprising the following steps:

[0013] S1: 5-Chloro-2,3-diphenylpyrazine, the compound shown in Formula II, and a base are co-dissolved in an organic solvent and reacted at 100–200 °C for 8–48 h to obtain the compound shown in Formula III;

[0014]

[0015] S2: The compound shown in Formula III, tert-butyl bromoacetate, and the catalyst were co-dissolved in a mixed solution under ice bath conditions. The mixture was stirred for 30–45 min, then naturally heated to room temperature and the reaction was continued for 0.5–3 h to obtain the compound shown in Formula IV. The mixed solution was prepared by mixing equal volumes of toluene and a 40 wt% KOH solution.

[0016]

[0017] S3: Dissolve the compound shown in Formula IV with LiOH or NaOH in an organic solvent under ice bath conditions, react for 2–10 h, then acidify and extract to obtain the product.

[0018] Furthermore, 5-chloro-2,3-diphenylpyrazine is prepared via the following steps:

[0019] SS1: Under an inert atmosphere, biphenyl amide, aminoacetamide and base are dissolved in an organic solvent in a molar ratio of 1:1 to 1.5:2 to 2.5, and the mixture is heated under reflux for 3 to 5 hours to obtain an intermediate as shown in Formula V.

[0020]

[0021] SS2: Under an inert atmosphere, the intermediate shown in Formula V is mixed with phosphorus oxychloride in a molar ratio of 1:5 to 10, a tail gas absorption device is added, and the mixture is heated and refluxed until the raw materials react completely to obtain the final product.

[0022] Furthermore, the molar ratio of 5-chloro-2,3-diphenylpyrazine, the compound shown in Formula II, and the base in S1 is 1:1 to 3:0 to 3, wherein the base is selected from potassium carbonate, triethylamine, or N,N-diisopropylethylamine.

[0023] Furthermore, the catalyst described in S2 is tetrabutylammonium bisulfate, and the molar ratio of the compound shown in Formula III, tert-butyl bromoacetate, and tetrabutylammonium bisulfate is 1:1 to 3:0.5 to 2.

[0024] This invention also discloses the application of the above-mentioned 5,6-diphenylpyrazine-2-piperidine compounds in the preparation of IP receptor agonists.

[0025] Furthermore, IP receptor agonists serve as the active ingredient in antithrombotic drugs.

[0026] The beneficial effects of this invention are: the 5,6-diphenylpyrazine-2-piperidine compounds of this invention have simple structures, short synthetic routes, and low synthetic costs. Furthermore, in vitro antiplatelet aggregation activity tests have shown that the prepared 5,6-diphenylpyrazine-2-piperidine compounds have excellent antiplatelet aggregation activity and can play a better role in the prevention and treatment of thrombosis as active ingredients in antithrombotic and vasodilating drugs. Detailed Implementation

[0027] The embodiments of the present invention are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Any equivalent substitutions made in the art based on the content disclosed in the present invention shall fall within the protection scope of the present invention.

[0028] The structure of the compound was determined by nuclear magnetic resonance (NMR). 1 It can be determined by ¹H NMR or liquid chromatography-mass spectrometry (LC-MS).

[0029] LC-MS; Nuclear Magnetic Resonance Spectrometer 1 H NMR) is performed using a Bruker AVANCE-600 or 400, nuclear magnetic resonance (NMR) 1 ¹H NMR shifts (δ) are given in parts per million (ppm). The solvent used for determination is CDCl₃, d⁶-DMSO, or d⁶-DMSO with added D₂O. The internal standard is tetramethylsilane (TMS). Chemical shifts are expressed in 10⁻¹⁰ ppm. -6 (ppm) is given as the unit.

[0030] The specific embodiments of the present invention will be described in detail below with reference to examples.

[0031] Example 1

[0032] 2-((1-(5,6-diphenylpyrazin-2-yl)piperidin-3-yl)oxy)acetic acid, with the following structural formula:

[0033]

[0034] It is prepared through the following steps:

[0035] Step 1: Preparation of 5,6-diphenyl-2-hydroxypyrazine

[0036]

[0037] Under nitrogen protection, bibenzoyl (21.0 g, 0.10 mol), aminoacetamide (8.9 g, 0.12 mol), and NaOH (9.6 g, 0.24 mol) were sequentially added to 1 L of methanol solvent. The mixture was heated under reflux for 4 h, and the reaction was monitored by TLC, indicating that the starting materials reacted completely. The reaction solution was cooled to 0 °C, and then 12.5 mL of 12N HCl solution was added dropwise. After stirring the reaction solution at room temperature for 30 min, 10 g of sodium bicarbonate and 130 mL of water were added. The reaction solution was filtered, and the solid was washed with a small amount of water and methanol, respectively. After vacuum drying, 22.0 g of white solid (5,6-diphenyl-2-hydroxypyrazine) was obtained, with a yield of 88.6%.

[0038] Step 2: Preparation of 5-chloro-2,3-diphenylpyrazine

[0039]

[0040] Under nitrogen protection, 19.8 g (0.8 mol) of 5,6-diphenyl-2-hydroxypyrazine was added to 200 mL of phosphorus oxychloride solvent. A tail gas absorption device was added, and the mixture was heated to reflux. The reaction was monitored by TLC until the reactants were completely reacted. The reaction mixture was cooled to room temperature and rotary evaporated under reduced pressure. The mixture was then extracted with ethyl acetate and washed successively with cooled sodium bicarbonate solution, water, and saturated brine. After drying with sodium sulfate, the mixture was filtered and rotary evaporated to obtain crude 5-chloro-2,3-diphenylpyrazine as a gray solid. The crude solid was then slurried with ethyl acetate, filtered, and dried under vacuum to obtain 18.6 g of white solid (5-chloro-2,3-diphenylpyrazine), yield: 87.5%.

[0041] Step 3: Preparation of 1-(5,6-diphenylpyrazin-2-yl)-3-piperidinol

[0042]

[0043] Under nitrogen protection, 5-chloro-2,3-diphenylpyrazine (533 mg, 2.00 mmol), potassium carbonate (414 mg, 3.00 mmol), and 3-hydroxypiperidine (303 mg, 3.00 mmol) were added to 10 mL of N-methylpyrrolidone (NMP). The mixture was heated to 120 °C and reacted for 48 h. The reaction was monitored by LC-MS until the reactants were completely reacted. The reaction mixture was cooled and ice water was added. The mixture was extracted with ethyl acetate. The organic mixed phase was washed with water and saturated brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The mixture was then purified by silica gel column chromatography. The solid was collected under reduced pressure and dried under vacuum to give 553 mg of a yellow solid (1-(5,6-diphenylpyrazin-2-yl)pyrrolidine-3-ol), yield: 83.4%, ESI-MS: m / z = 332.2 (M+H). + .

[0044] Step 4: Preparation of tert-butyl 2-((1-(5,6-diphenylpyrazin-2-yl)piperidin-3-yl)oxy)acetate

[0045]

[0046] Under ice bath conditions, 1-(5,6-diphenylpyrazin-2-yl)-3-piperidinol (497 mg, 1.50 mmol), tetrabutylammonium bisulfate (510 mg, 1.50 mmol), and tert-butyl bromoacetate (438 mg, 2.25 mmol) were added sequentially to a mixture of 2.5 mL toluene and 2.5 mL 40% KOH. The mixture was stirred vigorously for 30 min, allowed to warm naturally to room temperature, and reacted for 2 h. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic mixed phase was washed with water and saturated brine, dried over MgSO4, filtered, solvent removed under reduced pressure, purified by silica gel column chromatography, collected under reduced pressure, and dried under vacuum to give 482 mg of a yellow oil (2-((1-(5,6-diphenylpyrazin-2-yl)piperidin-3-yl)oxy)tert-butyl acetate), yield: 72.1%, ESI-MS: m / z = 446.2 (M+H). + .

[0047] Step 5: Preparation of 2-((1-(5,6-diphenylpyrazin-2-yl)piperidin-3-yl)oxy)acetic acid

[0048]

[0049] Under ice bath conditions, 2-((1-(5,6-diphenylpyrazin-2-yl)piperidin-3-yl)oxy)tert-butyl acetate (222 mg, 0.50 mmol) and LiOH (48.0 mg, 2.00 mmol) were added sequentially to 2 mL of MeOH solution. The reaction was allowed to proceed overnight. Methanol was removed under reduced pressure. 5 mL of ice water and 5 mL of ethyl acetate were added to the reaction solution, and the pH was adjusted to 5-6 with 2N HCl. The mixture was extracted with ethyl acetate, washed with water and saturated brine, dried over MgSO4, filtered, solvent removed under reduced pressure, and purified by silica gel column chromatography. The purified solution was collected under reduced pressure and dried under vacuum to give 167 mg of a pale yellow oily liquid (2-((1-(5,6-diphenylpyrazin-2-yl)piperidin-3-yl)oxy)acetic acid, yield: 85.8%, ESI-MS: m / z = 390.2 (M+H). + ; 1 H NMR (600MHz, CDCl3) δ8.32 (s, 1H), 7.40 (dd, J = 8.1, 1.4Hz, 2H), 7.34-7.23 (m, 8H),4.24-4.15(m,3H),4.02(dt,J=9.1,4.3Hz,1H),3.64-3.58(m,1H),3.48( dd,J=13.0,8.0Hz,1H),3.36(ddd,J=12.7,9.3,3.1Hz,1H),2.11-2.06(m,1H) ,1.95-1.88(m,1H),1.70(dd,J=8.8,3.7Hz,1H),1.59(dd,J=9.6,3.9Hz,1H).

[0050] Example 2

[0051] 2-((1-(5,6-diphenylpyrazin-2-yl)piperidin-4-yl)oxy)acetic acid, with the following structural formula:

[0052]

[0053] The synthesis steps were the same as in Example 1, except that 3-hydroxypiperidine in step 3 of Example 1 was replaced with 4-hydroxypiperidine, yielding a yellow oily substance 2-((1-(5,6-diphenylpyrazin-2-yl)piperidin-4-yl)oxy)acetic acid; ESI-MS: m / z = 390.2 (M+H) + ; 1H NMR (600MHz, CDCl3) δ8.23 (s, 1H), 7.44 (d, J = 6.8Hz, 2H), 7.37-7.33 (m, 2H), 7.30-7.24 (m, 6H), 4.21 ( s,2H),4.19-4.14(m,2H),3.78-3.70(m,1H),3.40-3.36(m,2H),2.07-2.01(m,2H),1.81-1.73(m,2H).

[0054] Example 3

[0055] 2-(((2R,4R)-1-(5,6-diphenylpyrazin-2-yl)-2-methylpiperidin-4-yl)oxy)acetic acid, with the following structural formula:

[0056]

[0057] Its synthesis steps 1 and 2 are the same as steps 1 and 2 in Example 1.

[0058] Step 3: Preparation of (2R)-4-hydroxy-2-methylpiperidine-1-carboxylic acid tert-butyl ester

[0059]

[0060] (R)-2-methyl-4-oxopiridine-1-carboxylic acid tert-butyl ester (852 mg, 4.00 mmol) was added to 20 mL of methanol, and sodium borohydride (168 mg, 4.40 mmol) was slowly added under ice bath conditions. The reaction was carried out at 20 °C for 3 h. The reaction was monitored by LC-MS until the starting material was completely reacted. The solvent was removed under reduced pressure, and excess sodium borohydride was quenched with ice water. The mixture was extracted with ethyl acetate, and the organic mixed phase was washed with water and saturated brine. The mixture was dried over MgSO4, filtered, collected under reduced pressure, and dried under vacuum to obtain 817 mg of a pale yellow liquid ((2R)-4-hydroxy-2-methylpiperidine-1-carboxylic acid tert-butyl ester), yield: 94.9%.

[0061] Step 4: Preparation of (2R)-2-methylpiperidin-4-ol

[0062]

[0063] Under ice bath conditions, tert-butyl (2R)-4-hydroxy-2-methylpiperidin-1-carboxylate (817 mg, 3.80 mmol) and 1 mL trifluoroacetic acid were added sequentially to 2 mL of dichloromethane. The mixture was stirred for 10 min, allowed to warm naturally to room temperature, and then stirred for 12 h. Ice water and 10% sodium hydroxide solution were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic mixed phase was dried over MgSO4, filtered, collected under reduced pressure, and dried under vacuum to give 345 mg of a yellow oily substance (2R)-2-methylpiperidin-4-ol, yield: 78.9%.

[0064] Step 5: Preparation of (2R)-1-(5,6-diphenylpyrazin-2-yl)-2-methylpiperidin-4-ol

[0065]

[0066] Under nitrogen protection, 5-chloro-2,3-diphenylpyrazine (532 mg, 2.00 mmol), N,N-diisopropylethylamine (498 mg, 3.00 mmol), and (2R)-2-methylpiperidin-4-ol (230 mg, 2.00 mmol) were added to 5 mL of N-methylpyrrolidone (NMP). The tube was sealed, and the reaction was heated to 190 °C for 48 h. The reaction was monitored by LC-MS until the reactants were completely reacted. The reaction solution was cooled, and ice water was added. The mixture was extracted with ethyl acetate, and the organic mixed phase was washed with water and saturated brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The mixture was then purified by silica gel column chromatography, collected under reduced pressure, and dried under vacuum to give 614 mg of a yellow solid ((2R)-1-(5,6-diphenylpyrazin-2-yl)-2-methylpiperidin-4-ol), yield: 88.9%, ESI-MS: m / z = 346.2 (M+H). + .

[0067] Step 6: Preparation of tert-butyl 2-(((2R)-1-(5,6-diphenylpyrazin-2-yl)-2-methylpiperidin-4-yl)oxy)acetate

[0068]

[0069] Under ice bath conditions, add 2.5 mL of toluene and 2.5 mL of 40%... To a mixture of KOH, (2R)-1-(5,6-diphenylpyrazin-2-yl)-2-methylpiperidin-4-ol (519 mg, 1.50 mmol), tetrabutylammonium hydrogen sulfate (510 mg, 1.50 mmol), and tert-butyl bromoacetate (438 mg, 2.25 mmol) were added sequentially. The mixture was stirred vigorously for 30 min, allowed to warm naturally to room temperature, and reacted for 2 h. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic mixed phase was washed with water and saturated brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The mixture was then purified by silica gel column chromatography, collected under reduced pressure, and dried under vacuum to obtain 492 mg of a yellow oily substance (2-(((2R)-1-(5,6-diphenylpyrazin-2-yl)-2-methylpiperidin-4-yl)oxy)tert-butyl acetate), yield: 71.4%, ESI-MS: m / z = 460.3 (M+H). + .

[0070] Step 7: Preparation of 2-(((2R,4R)-1-(5,6-diphenylpyrazin-2-yl)-2-methylpiperidin-4-yl)oxy)acetic acid

[0071]

[0072] Under ice bath conditions, 2-(((2R)-1-(5,6-diphenylpyrazin-2-yl)-2-methylpiperidin-4-yl)oxy)acetic acid tert-butyl ester (248 mg, 0.50 mmol) and LiOH (48.0 mg, 2.00 mmol) were added sequentially to 2 mL of MeOH solution. The reaction was allowed to proceed overnight. Methanol was removed under reduced pressure. 5 mL of ice water and 5 mL of ethyl acetate were added to the reaction solution, and the pH was adjusted to 5-6 with 2N HCl. The mixture was extracted with ethyl acetate, washed with water and saturated brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The mixture was then purified by silica gel column chromatography. Two fractions were obtained. One fraction was collected under reduced pressure and dried under vacuum to give 86 mg of a pale yellow oily liquid, 2-(((2R)-1-(5,6-diphenylpyrazin-2-yl)-2-methylpiperidin-4-yl)oxy)acetic acid. Yield: 43.0%, ESI-MS: m / z = 404.2 (M+H). + Its sodium salt NMR data: 1H NMR(400MHz,d6-DMSO-D2O)δ8.20(s,1H),7.37-7.08(m,10H),4.81(s,1H),4.33(d,J=11.9Hz,1H),3.76(s,1H),3.6 8(s,2H),2.98(t,J=12.3Hz,1H),2.07(dd,J=48.5,9.8Hz,2H),1.36(dd,J=79.0,6.0Hz,2H),1.13(d,J=6.5Hz,3H).

[0073] Example 4

[0074] 2-(((2R,4S)-1-(5,6-diphenylpyrazin-2-yl)-2-methylpiperidin-4-yl)oxy)acetic acid, with the following structural formula:

[0075]

[0076] The synthesis steps are the same as in Example 3, except for step 7. After purification by silica gel column chromatography, two components were obtained. The two components were collected under reduced pressure and dried under vacuum to obtain 80 mg of a pale yellow oily liquid, 2-(((2R,4R)-1-(5,6-diphenylpyrazin-2-yl)-2-methylpiperidin-4-yl)oxy)acetic acid; ESI-MS: m / z = 404.2 (M+H). + Its sodium salt NMR data: 1 HNMR(400MHz,d6-DMSO-D2O)δ8.18(s,1H),7.33-7.20(m,10H),4.60-4.51(m,1H),4.12(d,J=12.1Hz,1H),3.75 (s,1H),3.64(s,2H),3.29(t,J=12.0Hz,1H),1.92(d,J=13.4Hz,2H),1.76-1.56(m,2H),1.28(d,J=6.8Hz,3H).

[0077] Example 5

[0078] 2-(((2S,4S)-1-(5,6-diphenylpyrazin-2-yl)-2-methylpiperidin-4-yl)oxy)acetic acid, with the following structural formula:

[0079]

[0080] The synthesis steps are the same as in Example 3, with the following differences: First, in step 3 of Example 3, (R)-2-methyl-4-oxopiridine-1-carboxylic acid tert-butyl ester is replaced with (S)-2-methyl-4-oxopiridine-1-carboxylic acid tert-butyl ester; second, in step 7, after purification by silica gel column chromatography, two fractions are obtained. The first fraction is collected under reduced pressure and dried under vacuum to obtain a yellow oily 2-(((2S,4S)-1-(5,6-diphenylpyrazin-2-yl)-2-methylpiperidin-4-yl)oxy)acetic acid; ESI-MS: m / z = 404.2 (M+H) + Its sodium salt NMR data: 1 H NMR(400MHz,d6-DMSO-D2O)δ8.07(s,1H),7.21(dt,J=15.4,6.2Hz,11H),4.49(s,1H),4.06(d,J=11.8Hz,1H) ,3.79-3.64(m,3H),3.28(t,J=12.2Hz,1H),1.91(d,J=13.3Hz,2H),1.74-1.57(m,2H),1.23(d,J=6.7Hz,3H).

[0081] Example 6

[0082] 2-(((2S,4R)-1-(5,6-diphenylpyrazin-2-yl)-2-methylpiperidin-4-yl)oxy)acetic acid, with the following structural formula:

[0083]

[0084] The synthesis steps are the same as in Example 3, with the following differences: First, in step 3 of Example 3, (R)-2-methyl-4-oxopiridine-1-carboxylic acid tert-butyl ester is replaced with (S)-2-methyl-4-oxopiridine-1-carboxylic acid tert-butyl ester; second, in step 7, after purification by silica gel column chromatography, two fractions are obtained. The second fraction is collected under reduced pressure and dried under vacuum to obtain a yellow oily 2-(((2S,4R)-1-(5,6-diphenylpyrazin-2-yl)-2-methylpiperidin-4-yl)oxy)acetic acid; ESI-MS: m / z = 404.2 (M+H) + Its sodium salt NMR data: 1 H NMR(400MHz,d6-DMSO-D2O)δ8.16(s,1H),7.24(dd,J=16.7,10.7Hz,10H),4.79(s,1H),4.31(d,J=12.5H z,1H),3.73(s,3H),2.98(t,J=12.6Hz,1H),2.16-1.94(m,3H),1.50-1.19(m,3H),1.11(d,J=6.6Hz,3H).

[0085] Example 7

[0086] 2-((1-(5,6-diphenylpyrazin-2-yl)-3,3-dimethylpiperidin-4-yl)oxy)acetic acid, with the following structural formula:

[0087]

[0088] The synthesis steps were the same as in Example 3, except that (R)-2-methyl-4-oxopiridine-1-carboxylic acid tert-butyl ester in step 3 of Example 3 was replaced with 3,3-dimethyl-4-oxopiridine-1-carboxylic acid tert-butyl ester, yielding a yellow oily 2-((1-(5,6-diphenylpyrazin-2-yl)-3,3-dimethylpiperidin-4-yl)oxy)acetic acid; ESI-MS: m / z = 418.2 (M+H) + Its sodium salt NMR data: 1 H NMR(400MHz,d6-DMSO-D2O)δ8.27(s,1H),7.38-7.16(m,10H),4.09(d,J=13.1Hz,2H),3.71(dd,J=22.7,7.8Hz,2H),3.21 (dd,J=27.0,9.3Hz,2H),3.01(d,J=13.1Hz,1H),1.90(d,J=8.6Hz,1H),1.56(d,J=9.0Hz,1H),0.97(s,3H),0.87(s,3H).

[0089] Example 8

[0090] (S)-2-((1-(5,6-diphenylpyrazin-2-yl)-3,3-dimethylpiperidin-4-yl)oxy)acetic acid, with the following structural formula:

[0091]

[0092] The 2-((1-(5,6-diphenylpyrazin-2-yl)-3,3-dimethylpiperidin-4-yl)oxy)acetic acid obtained in Example 7 was resolved using a Daicel CHIRALPAK IG chiral column to yield 75 mg of a yellow solid (S)-2-((1-(5,6-diphenylpyrazin-2-yl)-3,3-dimethylpiperidin-4-yl)oxy)acetic acid. ESI-MS: m / z = 418.2 (M+H) + Its sodium salt NMR data: 1H NMR(400MHz,d6-DMSO-D2O)δ8.27(s,1H),7.38-7.16(m,10H),4.09(d,J=13.1Hz,2H),3.71(dd,J=22.7,7.8Hz,2H),3.21 (dd,J=27.0,9.3Hz,2H),3.01(d,J=13.1Hz,1H),1.90(d,J=8.6Hz,1H),1.56(d,J=9.0Hz,1H),0.97(s,3H),0.87(s,3H).

[0093] Example 9

[0094] (R)-2-((1-(5,6-diphenylpyrazin-2-yl)-3,3-dimethylpiperidin-4-yl)oxy)acetic acid, with the following structural formula:

[0095]

[0096] The 2-((1-(5,6-diphenylpyrazin-2-yl)-3,3-dimethylpiperidin-4-yl)oxy)acetic acid obtained in Example 7 was resolved using a Daicel CHIRALPAK IG chiral column to yield 70 mg of a yellow solid (R)-2-((1-(5,6-diphenylpyrazin-2-yl)-3,3-dimethylpiperidin-4-yl)oxy)acetic acid. ESI-MS: m / z = 418.2 (M+H) + Its sodium salt NMR data: 1 H NMR(400MHz,d6-DMSO-D2O)δ8.27(s,1H),7.38-7.16(m,10H),4.09(d,J=13.1Hz,2H),3.71(dd,J=22.7,7.8Hz,2H),3.21 (dd,J=27.0,9.3Hz,2H),3.01(d,J=13.1Hz,1H),1.90(d,J=8.6Hz,1H),1.56(d,J=9.0Hz,1H),0.97(s,3H),0.87(s,3H).

[0097] Example 10

[0098] 2-(((3S,5R)-1-(5,6-diphenylpyrazin-2-yl)-3,5-dimethylpiperidin-4-yl)oxy)acetic acid, with the following structural formula:

[0099]

[0100] Its synthesis steps 1 and 2 are the same as steps 1 and 2 in Example 1.

[0101] Step 3: Preparation of cis-1-benzyl-3,5-dimethyl-4-hydroxypiperidine

[0102]

[0103] cis-1-benzyl-3,5-dimethyl-4-oxoperididine (217 mg, 1.00 mmol) was added to 5 mL of methanol, and sodium borohydride (42 mg, 1.10 mmol) was slowly added under ice bath conditions. The reaction was carried out at 20 °C for 3 h. The reaction was monitored by TLC until the starting material was completely reacted. The solvent was removed under reduced pressure, and excess sodium borohydride was quenched with ice water. The mixture was extracted with ethyl acetate, and the organic mixed phase was washed with water and saturated brine. The mixture was dried over MgSO4, filtered, collected under reduced pressure, and dried under vacuum to give 178 mg of colorless liquid cis-1-benzyl-3,5-dimethyl-4-hydroxypiperididine, yield: 81.2%.

[0104] Step 4: Preparation of cis-3,5-dimethyl-4-hydroxypiperidine

[0105]

[0106] Under ice bath conditions, cis-1-benzyl-3,5-dimethyl-4-hydroxypiperidine (178 mg, 0.81 mmol) and 1 mL trifluoroacetic acid were added sequentially to 2 mL of dichloromethane. The mixture was stirred for 10 min, allowed to warm naturally to room temperature, and reacted for 12 h. Ice water and 10% sodium hydroxide solution were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic mixed phase was dried over MgSO4, filtered, collected under reduced pressure, and dried under vacuum to obtain 100 mg of a yellow oily substance, cis-3,5-dimethyl-4-hydroxypiperidine, with a yield of 95.6%.

[0107] The synthesis steps 5, 6, and 7 are the same as those in Example 3, except that (2R)-2-methylpiperidin-4-ol in step 5 of Example 3 is replaced with cis-3,5-dimethyl-4-hydroxypiperidine, ultimately yielding a yellow oily cis-2-((1-(5,6-diphenylpyrazin-2-yl)-3,5-dimethylpiperidin-4-yl)oxy)acetic acid; ESI-MS: m / z = 418.2 (M+H) + .

[0108] Example 11

[0109] 2-((1-(5,6-diphenylpyrazin-2-yl)-3,5-dimethylpiperidin-4-yl)oxy)acetic acid, with the following structural formula:

[0110]

[0111] The synthesis steps were the same as in Example 10, except that cis-1-benzyl-3,5-dimethyl-4-oxoperidine in step 3 of Example 10 was replaced with 1-benzyl-3,5-dimethyl-4-oxoperidine, ultimately yielding a yellow oily 2-((1-(5,6-diphenylpyrazin-2-yl)-3,5-dimethylpiperidin-4-yl)oxy)acetic acid; ESI-MS: m / z = 418.2 (M+H) + .

[0112] Example 12

[0113] 2-((1-(5,6-diphenylpyrazin-2-yl)-3,3-difluoropiperidin-4-yl)oxy)acetic acid, with the following structural formula:

[0114]

[0115] The synthesis steps were the same as in Example 3, except that (R)-2-methyl-4-oxopiridine-1-carboxylic acid tert-butyl ester in step 3 of Example 3 was replaced with 3,3-difluoro-4-oxopiridine-1-carboxylic acid tert-butyl ester, yielding a yellow oily 2-((1-(5,6-diphenylpyrazin-2-yl)-3,3-difluoropiperidin-4-yl)oxy)acetic acid; ESI-MS: m / z = 426.2 (M+H) + .

[0116] Example 13

[0117] 2-((1-(5,6-diphenylpyrazin-2-yl)-3-fluoropiperidin-4-yl)oxy)acetic acid, its structural formula is as follows:

[0118]

[0119] The synthesis steps were the same as in Example 3, except that (R)-2-methyl-4-oxopiridine-1-carboxylic acid tert-butyl ester in step 3 of Example 3 was replaced with 3-fluoro-4-oxopiridine-1-carboxylic acid tert-butyl ester, yielding a yellow oily 2-((1-(5,6-diphenylpyrazin-2-yl)-3-fluoropiperidin-4-yl)oxy)acetic acid; ESI-MS: m / z = 408.2 (M+H) + ; 1H NMR (600MHz, CDCl3) δ8.20 (d, J = 3.2Hz, 1H), 7.38-7.33 (m, 2H), 7.29-7.17 (m, 8 H),4.86-4.74(m,1H),4.68-4.55(m,1H),4.42-4.36(m,0.5H),4.25(d,J=16.6H z,2H),4.16(dd,J=12.7,5.9Hz,0.5H),4.03-3.91(m,1H),3.86-3.65(m,2H),3 .47-3.43(m,0.5H),3.40-3.28(m,0.5H),2.17-2.06(m,1H),1.89-1.69(m,1H).

[0120] Example 14

[0121] 2-(((3R,4S)-1-(5,6-diphenylpyrazin-2-yl)-3-fluoropiperidin-4-yl)oxy)acetic acid, with the following structural formula:

[0122]

[0123] The synthesis steps were the same as in Example 3, except that (R)-2-methyl-4-oxopiridine-1-carboxylic acid tert-butyl ester in step 3 of Example 3 was replaced with (3R,4S)-3-fluoro-4-oxopiridine-1-carboxylic acid tert-butyl ester, yielding a yellow oily 2-(((3R,4S)-1-(5,6-diphenylpyrazin-2-yl)-3-fluoropiperidin-4-yl)oxy)acetic acid; ESI-MS: m / z = 408.2 (M+H) + .

[0124] Example 15

[0125] 2-((1-(5,6-diphenylpyrazin-2-yl)-4-methylpiperidin-4-yl)oxy)acetic acid, its structural formula is as follows:

[0126]

[0127] The synthesis steps are the same as in Example 1, except that 3-hydroxypiperidine in step 3 of Example 1 is replaced with 4-hydroxy-4-methylpiperidine, ultimately yielding a yellow oily 2-((1-(5,6-diphenylpyrazin-2-yl)-4-methylpiperidin-4-yl)oxy)acetic acid; ESI-MS: m / z = 404.2 (M+H) + ; 1H NMR(600MHz, CDCl3)δ8.22(s,1H),7.45-7.41(m,2H),7.36-7.32(m,2H),7.31-7.22(m,6H),4.08(s,2H),4.05(dt ,J=13.2,3.9Hz,2H),3.50-3.44(m,2H),1.93(d,J=13.6Hz,2H),1.69(ddd,J=14.6,11.2,5.6Hz,2H),1.27(s,3H).

[0128] Example 16

[0129] 2-((1-(5,6-diphenylpyrazin-2-yl)-3-methylpiperidin-4-yl)oxy)acetic acid, its structural formula is as follows:

[0130]

[0131] The synthesis steps were the same as in Example 3, except that (R)-2-methyl-4-oxopiridine-1-carboxylic acid tert-butyl ester in step 3 of Example 3 was replaced with 3-methyl-4-oxopiridine-1-carboxylic acid tert-butyl ester, yielding a yellow oily 2-((1-(5,6-diphenylpyrazin-2-yl)-3-methylpiperidin-4-yl)oxy)acetic acid; ESI-MS: m / z = 404.2 (M+H) + ; 1 H NMR(600MHz,DMSO)δ8.44(d,J=10.4Hz,1H),7.41(dd,J=7.6,1.7Hz,2H),7.38-7.27(m,8H),4 .39-4.29(m,1H),4.16(d,J=2.4Hz,2H),3.79-3.69(m,2H),3.34-3.29(m,1H),3.14(dd,J=17. 8,6.9Hz,1H),2.88(dd,J=13.3,10.2Hz,1H),2.21-2.16(m,1H),2.08-2.04(m,1H),1.96-1.9 1(m,1H),1.72(ddd,J=14.4,7.3,4.9Hz,1H),1.45-1.39(m,1H),1.06(dd,J=44.5,6.7Hz,3H).

[0132] Example 17

[0133] 2-((3-Acrylonitrile-1-(5,6-diphenylpyrazin-2-yl)piperidin-4-yl)oxy)acetic acid, its structural formula is as follows:

[0134]

[0135] The synthesis steps were the same as in Example 3, except that (R)-2-methyl-4-oxopiridine-1-carboxylic acid tert-butyl ester in step 3 of Example 3 was replaced with 3-acrylonitrile-4-oxopiridine-1-carboxylic acid tert-butyl ester, yielding a yellow oily 2-((3-acrylonitrile-1-(5,6-diphenylpyrazin-2-yl)piperidin-4-yl)oxy)acetic acid; ESI-MS: m / z = 415.2 (M+H) + .

[0136] Example 18

[0137] 2-((1-(5,6-diphenylpyrazin-2-yl)-3-methoxypiperidin-4-yl)oxy)acetic acid, its structural formula is as follows:

[0138]

[0139] Its synthesis steps 1 and 2 are the same as steps 1 and 2 in Example 1.

[0140] Step 3: Preparation of tert-butyl 4-hydroxy-3-methoxypiperidine-1-carboxylate

[0141]

[0142] 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (796 mg, 4.00 mmol) was added to 20 mL of methanol. Sodium methoxide (1080 mg, 20.00 mmol) was slowly added under ice bath conditions. The mixture was stirred and refluxed at 60 °C for 12 h. The reaction was monitored by LC-MS until the reactants were completely reacted. The solvent was removed under reduced pressure, ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic mixed phase was washed with water and saturated brine, dried over MgSO4, filtered, collected under reduced pressure, and dried under vacuum to give 480 mg of a pale yellow liquid, 4-hydroxy-3-methoxypiperidine-1-carboxylic acid tert-butyl ester, yield: 51.9%, ESI-MS: m / z = 232.2 (M+H). + .

[0143] The remaining synthetic steps 4, 5, 6, and 7 are the same as those in Example 3, except that (2R)-4-hydroxy-2-methylpiperidin-1-carboxylic acid tert-butyl ester in step 4 of Example 3 is replaced with 4-hydroxy-3-methoxypiperidin-1-carboxylic acid tert-butyl ester, yielding a yellow oily 2-((1-(5,6-diphenylpyrazin-2-yl)-3-methoxypiperidin-4-yl)oxy)acetic acid; ESI-MS: m / z = 420.2 (M+H) + ; 1H NMR (600MHz, DMSO) δ8.37 (s, 1H), 7.37-7.34 (m, 2H), 7.31-7.21 (m, 8H), 4.20 (d, J = 5.4Hz, 2H), 4.06-4 .01(m,1H),3.87-3.81(m,1H),3.56-3.46(m,4H),3.35(s,3H),2.05-1.99(m,1H),1.53-1.45(m,1H).

[0144] Example 19

[0145] 2-((1-(5,6-diphenylpyrazin-2-yl)piperidin-4-yl)methoxy)acetic acid, with the following structural formula:

[0146]

[0147] The synthesis steps were the same as in Example 1, except that 3-hydroxypiperidine in step 3 of Example 1 was replaced with piperidine-4-methanol, yielding a yellow solid 2-((1-(5,6-diphenylpyrazin-2-yl)piperidine-4-yl)methoxy)acetic acid; ESI-MS: m / z = 404.2 (M+H) + ; 1 H NMR (600MHz, CDCl3) δ8.22(s,1H),7.45-7.42(m,2H),7.35-7.32(m,2H),7.31-7.21(m,6H),4.51(d,J=13.2Hz,2 H), 4.12 (s, 2H), 3.46 (d, J = 6.5Hz, 2H), 2.97 (td, J = 13.0, 2.5Hz, 2H), 2.02-1.94 (m, 1H), 1.91 (d, J = 12.9Hz, 2H).

[0148] Example 20

[0149] (R)-2-((1-(5,6-diphenylpyrazin-2-yl)piperidin-3-yl)oxy)acetic acid, with the following structural formula:

[0150]

[0151] The synthesis steps were the same as in Example 1, except that 3-hydroxypiperidine in step 3 of Example 1 was replaced with (R)-3-hydroxypiperidine, yielding a yellow oily 2-((1-(5,6-diphenylpyrazin-2-yl)piperidin-3-yl)oxy)acetic acid; ESI-MS: m / z = 390.2 (M+H) + ; 1H NMR (600MHz, CDCl3) δ8.32 (s, 1H), 7.40 (dd, J = 8.1, 1.4Hz, 2H), 7.34-7.23 (m, 8H),4.24-4.15(m,3H),4.02(dt,J=9.1,4.3Hz,1H),3.64-3.58(m,1H),3.48( dd,J=13.0,8.0Hz,1H),3.36(ddd,J=12.7,9.3,3.1Hz,1H),2.11-2.06(m,1H) ,1.95-1.88(m,1H),1.70(dd,J=8.8,3.7Hz,1H),1.59(dd,J=9.6,3.9Hz,1H).

[0152] Example 21

[0153] (S)-2-((1-(5,6-diphenylpyrazin-2-yl)piperidin-3-yl)oxy)acetic acid, with the following structural formula:

[0154]

[0155] The synthesis steps were the same as in Example 1, except that 3-hydroxypiperidine in step 3 of Example 1 was replaced with (S)-3-hydroxypiperidine, yielding a yellow oily 2-((1-(5,6-diphenylpyrazin-2-yl)piperidin-3-yl)oxy)acetic acid; ESI-MS: m / z = 390.2 (M+H) + ; 1 H NMR(600MHz, CDCl3)δ8.32(s,1H),7.43-7.39(m,2H),7.33-7.23(m,8H),4.2 4-4.18(m,3H),4.02(dt,J=12.9,4.6Hz,1H),3.66-3.57(m,1H),3.53-3.45( m,1H),3.37(ddd,J=12.8,9.3,3.3Hz,1H),2.12-2.06(m,1H),1.92(ddd,J=1 2.5, 6.2, 3.1Hz, 1H), 1.70 (ddd, J=12.6, 9.3, 4.8Hz, 1H), 1.65-1.55 (m, 1H).

[0156] Example 22

[0157] 2-((1-(5,6-diphenylpyrazin-2-yl)piperidin-3-yl)methoxy)acetic acid, with the following structural formula:

[0158]

[0159] The synthesis steps are the same as in Example 1, except that 3-hydroxypiperidine in step 3 of Example 1 is replaced with piperidine-3-methanol, yielding a yellow oily 2-((1-(5,6-diphenylpyrazin-2-yl)piperidin-3-yl)methoxy)acetic acid; ESI-MS: m / z = 404.2 (M+H) + .

[0160] Example 23

[0161] 2-((1-(5,6-diphenylpyrazin-2-yl)piperidin-2-yl)methoxy)acetic acid, with the following structural formula:

[0162]

[0163] The synthesis steps were the same as in Example 1, except that 3-hydroxypiperidine in step 3 of Example 1 was replaced with piperidine-2-methanol, potassium carbonate was replaced with DIEA, and the reaction temperature was 180°C, followed by a sealed tube reaction. The final product was a yellow oily 2-((1-(5,6-diphenylpyrazin-2-yl)piperidin-2-yl)methoxy)acetic acid; ESI-MS: m / z = 404.2 (M+H) + .

[0164] Example 24

[0165] 2-(2-(1-(5,6-diphenylpyrazin-2-yl)piperidin-2-yl)ethoxy)acetic acid, with the following structural formula:

[0166]

[0167] The synthesis steps were the same as in Example 1, except that 3-hydroxypiperidine in step 3 of Example 1 was replaced with 2-(piperidin-2-yl)-1-ethanol, potassium carbonate was replaced with DIEA, the reaction temperature was 190℃, and the reaction was carried out in sealed tubes. The final product was a yellow oily 2-(2-(1-(5,6-diphenylpyrazin-2-yl)piperidin-2-yl)ethoxy)acetic acid; ESI-MS: m / z = 418.2 (M+H) + ESI-MS: m / z = 417.2(M+H) + ; 1H NMR(600MHz, CDCl3)δ8.30(s,1H),7.43-7.40(m,2H),7.33-7.29(m,2H),7.27(d ,J=2.7Hz,1H),7.24(dd,J=12.8,6.3Hz,5H),4.79(s,1H),4.55(d,J=12.5Hz,1H ),4.11-3.91(m,2H),3.56(d,J=31.5Hz,2H),2.98(dd,J=12.6,11.0Hz,1H),2.1 7(t,J=21.0Hz,1H),1.92(d,J=6.1Hz,1H),1.80-1.67(m,5H),1.63-1.52(m,1H).

[0168] Example 25

[0169] 2-(2-(1-(5,6-diphenylpyrazin-2-yl)piperidin-4-yl)ethoxy)acetic acid, with the following structural formula:

[0170]

[0171] The synthesis steps were the same as in Example 1, except that 3-hydroxypiperidine in step 3 of Example 1 was replaced with 2-(piperidin-4-yl)-1-ethanol, yielding a yellow oily 2-(2-(1-(5,6-diphenylpyrazin-2-yl)piperidin-4-yl)ethoxy)acetic acid; ESI-MS: m / z = 418.2 (M+H) + ; 1 H NMR (600MHz, CDCl3) δ8.26 (s, 1H), 7.45-7.41 (m, 2H), 7.35-7.31 (m, 2H), 7.29-7.24 (m, 6H), 4.49 (d, J = 13.2Hz, 2H), 4.11 (s, 2H) ), 3.65 (t, J = 6.3Hz, 2H), 2.96 (td, J = 12.9, 2.4Hz, 2H), 1.89 (d, J = 12.3Hz, 2H), 1.84-1.75 (m, 1H), 1.30 (dt, J = 13.7, 5.7Hz, 4H).

[0172] Preparation Example 1

[0173] 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butoxy}acetic acid (MRE-269) has the following structural formula:

[0174]

[0175] The preparation was carried out according to the method disclosed in Example 42 of patent CN1516690A, yielding a yellow oily 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butoxy}acetic acid (MRE-269), ESI-MS: m / z = 420.2 (M+H). + ; 1 H NMR(400MHz,d6-DMSO)δ12.59(s,1H),8.14(s,1H),7.38-7.21(m,10H),4.82-4.74 (m,1H),4.00(s,2H),3.53-3.33(m,4H),1.69-1.61(m,4H),1.22(d,J=6.8Hz,6H).

[0176] Experimental example: In vitro platelet aggregation test

[0177] 1. Experimental Objective

[0178] The antiplatelet aggregation activity of the compounds in this invention was evaluated by studying their inhibitory effect on ADP-induced platelet aggregation in vitro.

[0179] 2. Test materials

[0180] 2.1 Test Materials

[0181] Fully automated platelet aggregation analyzer (Talitaikang AG800); ADP (Sigma); DMSO, 0.9% sodium chloride injection, sodium hydroxide, blood collection tubes, etc.

[0182] 2.2 Laboratory Animals

[0183] Domestic rabbit, male, 2.1±0.2kg.

[0184] 2.3 Test Drug

[0185] Compounds of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 15, 16, 17, 18, 19, 21, 22, and 23; compound of Preparation Example 1.

[0186] 3. Test methods

[0187] 3.1 Preparation of the test solution

[0188] Weigh each of the above test drugs and prepare a stock solution with a concentration of 200mM using DMSO. After fully dissolving and mixing, take the stock solution and add 0.9% sodium chloride injection to prepare a series of test solutions of different concentrations (0.15μM-50μM).

[0189] 3.2 Preparation of PRP and PPP

[0190] Rabbit blood was collected in plastic centrifuge tubes and anticoagulated with 3.2% sodium citrate (the ratio of anticoagulant to whole blood was 1:9). The blood was centrifuged at 140g for 10 minutes, and the supernatant was carefully aspirated to obtain PRP. The remaining plasma was centrifuged at 2000g for 10 minutes, and the supernatant was obtained to obtain PPP.

[0191] 3.3 Preparation of ADP solution

[0192] Weigh out ADP and dissolve it in 0.9% sodium chloride injection to prepare ADP stock solution. Aliquot the stock solution into centrifuge tubes and store at -20°C. Reconstitute before use and dilute to 300 μM with 0.9% sodium chloride injection.

[0193] 3.4 Maximum Aggregation Rate Detection

[0194] After powering on the platelet aggregation analyzer, preheat for 30 minutes until the temperature reaches 37°C before starting the test. Place 270 μL of PRP and 30 μL of the test solution into the PRP cup of the double-cup, and place 300 μL of PPP into the PPP cup of the double-cup. The instrument will then begin the test. Calculate the maximum platelet aggregation rate induced by ADP at a concentration of 100 μM.

[0195] 4. Experimental Data Results

[0196] Table 1. Maximum platelet aggregation rate of the compounds in the examples and preparation examples.

[0197]

[0198] Compared with preparation example 1: *P<0.01

[0199] The above experimental results show that the maximum platelet aggregation rate of the compound in Preparation Example 1 was 22.6% at a concentration of 12.5 μm. The compounds in Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 15, 16, 17, 18, and 19 of this invention all had a greater inhibitory effect on platelet aggregation than the compound in Preparation Example 1. Among them, the compounds in Examples 7, 8, 9, and 11 had a very large inhibitory effect on platelet aggregation.

[0200] Although specific embodiments of the present invention have been described in detail with reference to examples, they should not be construed as limiting the scope of protection of this patent. Various modifications and variations that can be made by those skilled in the art without inventive effort within the scope described in the claims are still within the scope of protection of this patent.

Claims

1. A 5,6-diphenylpyrazin-2-piperidine compound characterized in that, The 5,6-diphenylpyrazine-2-piperidine compound is one of the compounds having the following structural formula: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 2. The method for preparing the 5,6-diphenylpyrazine-2-piperidine compound according to claim 1, characterized in that, Includes the following steps: S1: 5-Chloro-2,3-diphenylpyrazine, the compound shown in Formula II, and a base are co-dissolved in an organic solvent and reacted at 100-200°C for 8-48 h to obtain the compound shown in Formula III; ， ； wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and n correspond to the specific compound of claim 1 ; S2: The compound shown in Formula III, tert-butyl bromoacetate, and the catalyst are co-dissolved in a mixed solution under ice bath conditions. The mixture is stirred for 30-45 min, then naturally heated to room temperature and the reaction continues for 0.5-3 h to obtain the compound shown in Formula IV. The mixed solution is prepared by mixing equal volumes of toluene and a 40 wt% KOH solution. ； S3: Dissolve the compound shown in Formula IV with LiOH or NaOH in an organic solvent under ice bath conditions, react for 2-10 hours, then acidify and extract to obtain the product.

3. The production method according to claim 2, wherein The 5-chloro-2,3-diphenylpyrazine was prepared by the following steps: SS1: Under an inert atmosphere, biphenyl amide, aminoacetamide and base are dissolved in an organic solvent in a molar ratio of 1:1~1.5:2~2.5 and heated under reflux for 3~5 hours to obtain the intermediate shown in Formula V; SS2: Under an inert atmosphere, the intermediate shown in Formula V is mixed with phosphorus oxychloride in a molar ratio of 1:5 to 10, a tail gas absorption device is added, and the mixture is heated and refluxed until the raw materials react completely to obtain the final product.

4. The method of claim 2, wherein: The molar ratio of 5-chloro-2,3-diphenylpyrazine, the compound shown in Formula II, and the base in S1 is 1:1~3:0~3, wherein the base is selected from potassium carbonate, triethylamine, or N,N-diisopropylethylamine.

5. The method of claim 2, wherein: The catalyst described in S2 is tetrabutylammonium bisulfate, and the molar ratio of the compound shown in Formula III, tert-butyl bromoacetate, and tetrabutylammonium bisulfate is 1:1~3:0.5~2.

6. The use of the 5,6-diphenylpyrazine-2-piperidine compound of claim 1 in the preparation of IP receptor agonists.

7. Use according to claim 6, characterized in that: IP receptor agonists are the active ingredients in antithrombotic drugs.

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