Cis-4-(5, 6-diphenylpyrazine-2-amino) cyclohexyloxyacetic acid compound as well as preparation method and application of cis-4-(5, 6-diphenylpyrazine-2-amino) cyclohexyloxyacetic acid compound

Abstract

The invention discloses a cis-4-(5, 6-diphenylpyrazine-2-amino) cyclohexyloxyacetic acid compound as well as a preparation method and application thereof, and belongs to the technical field of medicine synthesis. The cis-4-(5, 6-diphenylpyrazine-2-amino) cyclohexyloxy acetic acid compound is simple in structure, short in synthesis route and low in synthesis cost, and in-vitro anti-platelet aggregation activity detection shows that the prepared cis-4-(5, 6-diphenylpyrazine-2-amino) cyclohexyloxy acetic acid compound has excellent anti-platelet aggregation activity, and can be used for preparing a novel anti-platelet aggregation drug. And the compound can be used as an active ingredient of an antithrombotic drug to exert better prevention and treatment effects on thrombus, blood vessel dilation, pulmonary arterial hypertension resistance and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and specifically relates to a cis-4-(5,6-diphenylpyrazine-2-amino)cyclohexyloxyacetic acid compound and a preparation method and application thereof. Background Art

[0002] Prostaglandin I2 (PGI2) is a member of the eicosanoid family of lipids and an antagonist of thromboxane. Its reduced synthesis promotes thrombosis. Stimulating PGI2 receptors (IP receptors) not only inhibits platelet-mediated aggregation, but also has a strong vasodilation effect. The diseases that can be treated by IP receptor agonists mainly include pulmonary arterial hypertension (PAH), arteriosclerosis obliterans, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, ischemia-reperfusion injury, restenosis, atrial fibrillation, intermittent claudication, Raynaud's phenomenon, varicose veins, thrombosis, diabetes, diabetic nephropathy, hypertension, hyperlipidemia, cerebral infarction, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), etc.

[0003] Currently, most PGI2 drugs on the market have problems such as short half-life, poor chemical stability, and large side effects, and their efficacy is poor. Therefore, it is urgent to develop a non-endogenous PGI2-structured 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 cis-4-(5,6-diphenylpyrazine-2-amino)cyclohexyloxyacetic acid compound and its preparation method and application, so as to obtain an antithrombotic drug with good chemical stability, higher selectivity and less side effects.

[0005] In order to achieve the above object, the technical solution adopted by the present invention is to provide a cis-4-(5,6-diphenylpyrazine-2-amino)cyclohexyloxyacetic acid compound, the structural formula of the compound is shown in Formula I:

[0006]

[0007] Wherein, R is an alkyl group, a deuterated alkyl group or a fluoroalkyl group.

[0008] Based on the above technical solution, the present invention can also be improved as follows.

[0009] Furthermore, R is methyl, deuterated methyl, fluoromethyl, fluoroethyl, fluoropropyl, ethyl, propyl or isobutyl.

[0010] Further, the 4-(5,6-diphenylpyrazine-2-amino)cyclohexyloxyacetic acid compound is one of the compounds having the following structural formula:

[0011]

[0012] The present invention also discloses a method for preparing the cis-4-(5,6-diphenylpyrazine-2-amino)cyclohexyloxyacetic acid compound, comprising the following steps:

[0013] S1: Dissolve 5-chloro-2,3-diphenylpyrazine, a compound as shown in Formula II and a base in an organic solvent, and react at 100-200°C for 8-48h to obtain a compound as shown in Formula III

[0014]

[0015] S2: Dissolve the compound represented by Formula III, tert-butyl bromoacetate and the catalyst in a mixed solution under ice bath, stir and react for 30 to 45 minutes, then naturally raise the temperature to room temperature, and continue to react for 0.5 to 3 hours to obtain a compound represented by Formula IV; the mixed solution is prepared by mixing equal volumes of toluene and a KOH solution having a concentration of 40 wt%;

[0016]

[0017] S3: dissolving the compound of formula IV in a solvent under ice bath, adding NaH, stirring and reacting for 30-45 min, then adding iodide RI, naturally raising the temperature to room temperature, and continuing the reaction for 8-24 h to obtain a compound of formula V; the solvent is tetrahydrofuran, N,N-dimethylformamide or diethyl ether;

[0018]

[0019] Wherein, R is alkyl, deuterated alkyl, or fluoroalkyl;

[0020] S4: Dissolve the compound represented by formula V and LiOH or NaOH in an organic solvent under ice bath, keep warm for 2 to 10 hours, then acidify and extract to obtain the product.

[0021] The above cis-4-(5,6-diphenylpyrazine-2-amino)cyclohexyloxyacetic acid compound can also be prepared by the following steps:

[0022] S1: dissolving 5-chloro-2,3-diphenylpyrazine, a compound as shown in Formula VI and a base in an organic solvent, and reacting at 100 to 180° C. for 12 to 48 hours to obtain a compound as shown in Formula VII;

[0023]

[0024] Wherein, R is alkyl, deuterated alkyl, or fluoroalkyl;

[0025] S2: Dissolve the compound represented by Formula VII, tert-butyl bromoacetate and the catalyst in a mixed solution under ice bath, stir and react for 30 to 45 minutes, then naturally raise the temperature to room temperature, and continue to react for 0.5 to 3 hours to obtain a compound represented by Formula V; the mixed solution is prepared by mixing equal volumes of toluene and a KOH solution having a concentration of 40 wt%;

[0026]

[0027] S3: Dissolve the compound represented by formula V and LiOH or NaOH in an organic solvent under ice bath, keep warm for 2 to 12 hours, then acidify and extract to obtain the product.

[0028] Further, 5-chloro-2,3-diphenylpyrazine is prepared by the following steps:

[0029] (1) Under an inert atmosphere, dissolve dibenzoyl, aminoacetamide and a base in an organic solvent at a molar ratio of 1:1 to 1.5:2 to 2.5, and heat under reflux for 3 to 5 hours to obtain an intermediate as shown in Formula VIII;

[0030]

[0031] (2) Under an inert atmosphere, the intermediate represented by formula VIII and phosphorus oxychloride are mixed at a material-liquid ratio of 1 g:0.5-5 mL, and heated under reflux until the raw materials react completely to obtain the product.

[0032] Furthermore, the base is potassium carbonate; and the catalyst is tetrabutylammonium hydrogen sulfate.

[0033] Further, the compound shown in formula VI, in which R is methyl, is prepared by the following steps:

[0034] Under ice bath conditions, cis-(4-hydroxycyclohexyl)carbamic acid tert-butyl ester and LiAlH4 are added to an organic solvent, and then the reaction system is heated to 55-65°C and refluxed for 5-8h to obtain;

[0035] Alternatively, the compound represented by formula VI, in which R is an alkyl group having 2 or more carbon atoms or a substituted alkyl group having 2 or more carbon atoms, is prepared by the following steps:

[0036] Under ice bath conditions, cis-4-aminocyclohexanol hydrochloride, aldehyde and reducing agent are co-dissolved in an organic solvent, and the reaction is kept warm overnight to obtain the product; the reducing agent is NaBCNH3, NaB(OAc)3H or NaBH4; the aldehyde is an aldehyde having a carbon number greater than or equal to 2 or a substituted aldehyde having a carbon number greater than or equal to 2.

[0037] The invention also discloses the use of the cis-4-(5,6-diphenylpyrazine-2-amino)cyclohexyloxyacetic acid compound in the preparation of IP receptor agonists.

[0038] Furthermore, IP receptor agonists are used as active ingredients of thrombovasodilators or anti-pulmonary hypertension drugs.

[0039] The beneficial effects of the present invention are as follows: the cis-4-(5,6-diphenylpyrazine-2-amino)cyclohexyloxyacetic acid compound of the present invention has a simple structure, a short synthesis route, and a low synthesis cost, and through in vitro antiplatelet aggregation activity detection, it is found that the prepared cis-4-(5,6-diphenylpyrazine-2-amino)cyclohexyloxyacetic acid has excellent antiplatelet aggregation activity and can be used as an active ingredient of antithrombotic, vasodilator, and anti-pulmonary hypertension drugs to exert a more excellent thrombosis prevention and treatment effect. DETAILED DESCRIPTION

[0040] 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 replacements in the art made according to the contents disclosed in the present invention shall fall within the protection scope of the present invention.

[0041] The structures of the compounds were determined by nuclear magnetic resonance ( 1 H NMR) or liquid chromatography-mass spectrometry (LC-MS).

[0042] Liquid chromatography-mass spectrometry (LC-MS); nuclear magnetic resonance (NMR) 1 H NMR) was performed by Bruker AVANCE-600, and nuclear magnetic resonance ( 1 H NMR) shifts (δ) are given in parts per million (ppm) using CDCl3, d6-DMSO as the solvent and tetramethylsilane (TMS) as the internal standard. Chemical shifts are given in 10 -6 (ppm) is given as the unit.

[0043] The specific implementation modes of the present invention are described in detail below with reference to the embodiments.

[0044] Example 1

[0045] A cis-4-(5,6-diphenylpyrazine-2-amino)cyclohexyloxyacetic acid compound, the structural formula of which is as follows:

[0046]

[0047] The compound is cis-2-((4-(5,6-diphenylpyrazin-2-yl)methylaminocyclohexyl)oxy)acetic acid, which is prepared by the following method.

[0048] Method 1:

[0049] Step 1: Preparation of 5,6-diphenyl-2-hydroxypyrazine, the reaction equation is as follows:

[0050]

[0051] Under nitrogen protection, dibenzoyl (21.0 g, 0.10 mol), aminoacetamide (8.9 g, 0.12 mol) and NaOH (9.6 g, 0.24 mol) were added to 1 L methanol solvent in sequence, heated under reflux for 3 h, and the reaction was monitored by TLC. After the raw materials reacted completely, the reaction solution was cooled to 0 ° C, and then 12.5 mL of 12N HCl solution was added dropwise. After the reaction solution was stirred 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 water and methanol in sequence, and then vacuum dried to obtain 22.0 g of a white solid, i.e., 5,6-diphenyl-2-hydroxypyrazine, with a yield of 88.7%.

[0052] Step 2: Preparation of 5-chloro-2,3-diphenylpyrazine, the reaction equation is as follows:

[0053]

[0054] Under nitrogen protection, 5,6-diphenyl-2-hydroxypyrazine (19.8 g, 0.08 mol) was added to 20 mL of phosphorus oxychloride solvent, and a tail gas absorption device was added. The mixture was heated to reflux and the reaction was monitored by TLC until the raw material reacted completely. The reaction mixture was cooled to room temperature and evaporated under reduced pressure, then extracted with ethyl acetate, and then washed with cooled sodium bicarbonate solution, water, and saturated brine in sequence, dried with sodium sulfate, filtered and evaporated to obtain a gray solid (crude 5-chloro-2,3-diphenylpyrazine), which was then slurried with ethyl acetate, filtered, and dried in vacuo to obtain 18.6 g of a white solid, i.e., 5-chloro-2,3-diphenylpyrazine, with a yield of 87.4%.

[0055] Step 3: Preparation of cis-4-((5,6-diphenylpyrazin-2-yl)amino)cyclohexane-1-ol, the reaction equation is as follows:

[0056]

[0057] Under nitrogen protection, 5-chloro-2,3-diphenylpyrazine (533 mg, 2.00 mmol), potassium carbonate (276 mg, 2.00 mmol) and cis-4-aminocyclohexanol hydrochloride (303 mg, 2.00 mmol) were added to 10 mL of N-methylpyrrolidone (NMP), heated to 120°C for 48 h, and the reaction was monitored by LC-MS. The raw materials reacted completely, the reaction solution was cooled and ice water was added to the reaction solution, extracted with ethyl acetate, and the organic mixed phase was washed with water and saturated brine in turn, dried over MgSO4, filtered, and desolventized. The mixture was purified by chromatography on a silica gel column, collected under reduced pressure, and dried in vacuo to obtain 561 mg of a yellow solid, i.e., cis-4-((5,6-diphenylpyrazin-2-yl)amino)cyclohexan-1-ol, with a yield of 81.3%. ESI-MS: m / z=346.2 (M+H) + .

[0058] Step 4: Preparation of cis-2-((4-(5,6-diphenylpyrazin-2-yl)aminocyclohexyl)oxy)acetic acid tert-butyl ester, the reaction equation is as follows:

[0059]

[0060] Under ice bath conditions, cis-4-((5,6-diphenylpyrazin-2-yl)amino)cyclohexan-1-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 to a mixture of 2.5 mL toluene and 2.5 mL 40% KOH in sequence, and the mixture was vigorously stirred for 30 min, and the mixture was naturally heated to room temperature and reacted for 2 h. Then, 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 in sequence, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The mixture was purified by chromatography on a silica gel column, collected under reduced pressure, and dried in vacuo to obtain 471 mg of a yellow oil, i.e., cis-tert-butyl 2-((4-(5,6-diphenylpyrazin-2-yl)aminocyclohexyl)oxy)acetate, with a yield of 68.3%. ESI-MS: m / z=460.3 (M+H) + .

[0061] Step 5: Preparation of cis-2-((4-(5,6-diphenylpyrazine-2-yl)methylaminocyclohexyl)oxy)acetic acid, the reaction equation is as follows:

[0062]

[0063] Under ice bath conditions, cis-2-((4-((5,6-diphenylpyrazin-2-yl)amino)cyclohexyl)oxy)acetic acid tert-butyl ester (230 mg, 0.5 mmol) and NaH (200 mg, 5 mmol) were added to 2 mL of DMF solution in sequence, and the mixture was vigorously stirred for 45 min. Then, iodomethane (213 mg, 1.5 mmol) was added and the mixture was naturally warmed to room temperature, and the reaction was continued to be stirred for 8 h. Under ice bath conditions, saturated NH4Cl was added to quench the reaction, and then 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, and the solvent was removed under reduced pressure. The mixture was purified by chromatography on a silica gel column, collected under reduced pressure, and dried in vacuo to obtain a yellow oil, i.e., cis-2-((4-(5,6-diphenylpyrazin-2-yl)methylaminocyclohexyl)oxy)acetic acid tert-butyl ester.

[0064] Under ice bath conditions, cis-2-((4-(5,6-diphenylpyrazin-2-yl)methylaminocyclohexyl)oxy)acetic acid tert-butyl ester (237 mg, 0.50 mmol) and LiOH (48.0 mg, 2.00 mmol) were added to 2 mL of MeOH solution in sequence, and the reaction was allowed to proceed for 10 h. Then, methanol was removed under reduced pressure, 5 mL of ice water and 5 mL of ethyl acetate were added to the reaction solution, and pH was adjusted to 6 with 1N HCl. 5 mL of ice water and 5 mL of ethyl acetate were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic mixed phase was washed with water and saturated brine in sequence, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The mixture was purified by chromatography on a silica gel column, collected under reduced pressure, and dried in vacuo to obtain 175 mg of a light yellow oily liquid, i.e., cis-2-((4-(5,6-diphenylpyrazin-2-yl)methylaminocyclohexyl)oxy)acetic acid, with a yield of 83.9%. 1 H NMR(600MHz,DMSO-d6)δ8.08(s,1H),7.33-7.17(m,11H),4.30(s,1H),3.62(s,2H),3.56( s, 1H), 2.96 (s, 3H), 1.99 (d, J = 12.5Hz, 2H), 1.87 (d, J = 11.9Hz, 2H), 1.40 (d, J = 8.4Hz, 4H).

[0065] Method 2:

[0066] Step 1: Preparation of cis-4-methylamino-1-cyclohexanol, the reaction equation is as follows:

[0067]

[0068] Under nitrogen protection and ice bath conditions, cis-(4-hydroxycyclohexyl)carbamic acid tert-butyl ester (2 g, 9.24 mmol) and LiAlH4 (7.4 mL, 18.58 mmol) were added to 46 mL THF solution in sequence, heated to 60 ° C, and refluxed for 6 h; then NaOH solution and water were added dropwise in turn to quench the reaction, MgSO4 was added to dry, diatomaceous earth was used as a filter cake for suction filtration, the filter cake was washed with ethyl acetate, and the solvent was removed under reduced pressure to obtain 1.1 g of a white liquid product, i.e., cis-4-methylamino-1-cyclohexanol, with a yield of 92%, ESI-MS: m / z=129.2 (M+H) + .

[0069] Step 2: Preparation of cis-4-((5,6-diphenylpyrazine-2-yl)methylamino)cyclohexyl-1-ol, the reaction equation is as follows:

[0070]

[0071] Under nitrogen protection, 5-chloro-2,3-diphenylpyrazine (532 mg, 2.00 mmol), potassium carbonate (414 mg, 3.00 mmol) and cis-4-methylamino-1-cyclohexanol (388 mg, 3.00 mmol) synthesized in method 1 were added to 10 mL of N-methylpyrrolidone (NMP), heated to 120°C for 48 h, and the reaction was monitored by TLC. After the reaction of the raw materials was complete, the reaction solution was cooled and ice water was added to the reaction solution, and extracted with ethyl acetate. The organic mixed phase was washed with water and saturated brine, dried over MgSO4, filtered, and desolventized. The mixture was purified by chromatography on a silica gel column, collected under reduced pressure, and dried in vacuo to obtain 592 mg of a yellow solid, i.e., cis-4-((5,6-diphenylpyrazin-2-yl)methylamino)cyclohexyl-1-ol, with a yield of 82.3%. ESI-MS: m / z=360.2 (M+H) + .

[0072] Step 3: Preparation of cis-2-((4-(5,6-diphenylpyrazin-2-yl)methylaminocyclohexyl)oxy)acetic acid tert-butyl ester, the reaction equation is as follows:

[0073]

[0074] In an ice bath, 2.5 mL of toluene and 2.5 mL of 40% To the mixed solution of KOH were added cis-4-((5,6-diphenylpyrazin-2-yl)methylamino)cyclohexyl-1-ol (539 mg, 1.50 mmol), tetrabutylammonium hydrogen sulfate (510 mg, 1.50 mmol) and tert-butyl bromoacetate (438 mg, 2.25 mmol) in sequence, and the mixture was stirred vigorously for 30 min. After the mixture was naturally warmed to room temperature, the mixture was stirred and reacted for 0.5 h. Then, 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, and the solvent was removed under reduced pressure. The mixture was purified by chromatography on a silica gel column, collected under reduced pressure, and dried under vacuum to obtain 478 mg of a yellow oil, i.e., tert-butyl cis-2-((4-(5,6-diphenylpyrazin-2-yl)methylaminocyclohexyl)oxy)acetate, with a yield of 67.4%. ESI-MS: m / z=474.3 (M+H) + .

[0075] Step 4: Preparation of cis-2-((4-(5,6-diphenylpyrazine-2-yl)methylaminocyclohexyl)oxy)acetic acid, the reaction equation is as follows:

[0076]

[0077] Under ice bath conditions, cis-2-((4-(5,6-diphenylpyrazin-2-yl)methylaminocyclohexyl)oxy)acetic acid tert-butyl ester (237 mg, 0.50 mmol) and LiOH (48.0 mg, 2.00 mmol) were added to 2 mL of MeOH solution in sequence, and the reaction was carried out for 12 h; then, methanol was removed under reduced pressure, 5 mL of ice water and 5 mL of ethyl acetate were added to the reaction solution, pH was adjusted to 5 with 2N HCl, and extraction was performed 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 purified by chromatography on a silica gel column, collected under reduced pressure, and dried under vacuum to obtain 181 mg of a light yellow oily liquid, i.e., cis-2-((4-(5,6-diphenylpyrazin-2-yl)methylaminocyclohexyl)oxy)acetic acid, with a yield of 86.5%, and ESI-MS: m / z=418.2 (M+H). + ; 1 H NMR(600MHz,DMSO-d6)δ8.08(s,1H),7.33-7.17(m,11H),4.30(s,1H),3.62(s,2H),3.56( s, 1H), 2.96 (s, 3H), 1.99 (d, J = 12.5Hz, 2H), 1.87 (d, J = 11.9Hz, 2H), 1.40 (d, J = 8.4Hz, 4H).

[0078] Example 2

[0079] A cis-4-(5,6-diphenylpyrazine-2-amino)cyclohexyloxyacetic acid compound, the structural formula of which is as follows:

[0080]

[0081] The compound is cis-2-((4-(5,6-diphenylpyrazin-2-yl)ethylaminocyclohexyl)oxy)acetic acid, which is prepared by the following method.

[0082] Method 1:

[0083] Step 1: Preparation of 5,6-diphenyl-2-hydroxypyrazine, the reaction equation is as follows:

[0084]

[0085] Under nitrogen protection, dibenzoyl (21.0 g, 0.10 mol), aminoacetamide (8.9 g, 0.12 mol) and NaOH (9.6 g, 0.24 mol) were added to 1 L methanol solvent in sequence, heated under reflux for 5 h, and the reaction was monitored by TLC. After the reaction of the raw materials was complete, the reaction solution was cooled to 0 ° C, and then 12.5 mL of 12N HCl solution was added dropwise. After the reaction solution was stirred 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 water and methanol in sequence. 23.0 g of a white solid, i.e., 5,6-diphenyl-2-hydroxypyrazine, was obtained by vacuum drying with a yield of 92.7%.

[0086] Step 2: Preparation of 5-chloro-2,3-diphenylpyrazine, the reaction equation is as follows:

[0087]

[0088] Under nitrogen protection, 5,6-diphenyl-2-hydroxypyrazine (19.8 g, 0.08 mol) was added to 100 mL of phosphorus oxychloride solvent, and a tail gas absorption device was added. The mixture was heated to reflux and the reaction was monitored by TLC until the raw material reacted completely. The reaction mixture was cooled to room temperature and evaporated under reduced pressure, and then extracted with ethyl acetate. The mixture was then washed with cooled sodium bicarbonate solution, water, and saturated brine in sequence, dried with sodium sulfate, filtered and evaporated to obtain a crude gray solid 5-chloro-2,3-diphenylpyrazine. The crude product was then slurried with ethyl acetate, filtered, and dried under vacuum to obtain 16.4 g of a white solid, i.e., 5-chloro-2,3-diphenylpyrazine, with a yield of 77.1%.

[0089] Step 3: Preparation of cis-4-((5,6-diphenylpyrazin-2-yl)amino)cyclohexane-1-ol, the reaction equation is as follows:

[0090]

[0091] Under nitrogen protection, 5-chloro-2,3-diphenylpyrazine (533 mg, 2.00 mmol), potassium carbonate (828 mg, 6.00 mmol) and cis-4-aminocyclohexanol hydrochloride (910 mg, 6.00 mmol) were added to 10 mL of N-methylpyrrolidone (NMP), heated to 120°C for 48 h, and the reaction was monitored by LC-MS. The raw materials reacted completely, and the reaction solution was cooled and ice water was added to the reaction solution. The organic mixed phase was washed with water and saturated brine, dried over MgSO4, filtered, and desolventized. The mixture was purified by chromatography on a silica gel column, collected under reduced pressure, and dried in vacuo to obtain 525 mg of a yellow solid, i.e., cis-4-((5,6-diphenylpyrazin-2-yl)amino)cyclohexan-1-ol, with a yield of 76.1%. ESI-MS: m / z=346.2 (M+H) + .

[0092] Step 4: Preparation of cis-2-((4-(5,6-diphenylpyrazin-2-yl)aminocyclohexyl)oxy)acetic acid tert-butyl ester, the reaction equation is as follows:

[0093]

[0094] Under ice bath conditions, cis-4-((5,6-diphenylpyrazin-2-yl)amino)cyclohexan-1-ol (519 mg, 1.50 mmol), tetrabutylammonium hydrogen sulfate (255 mg, 0.75 mmol) and tert-butyl bromoacetate (292 mg, 1.50 mmol) were added to a mixture of 2.5 mL toluene and 2.5 mL 40% KOH in sequence, and the mixture was stirred vigorously for 45 min, and the mixture was naturally heated to room temperature and reacted for 3 h. Then, 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, and the solvent was removed under reduced pressure. The mixture was purified by chromatography on a silica gel column, collected under reduced pressure, and dried in vacuo to obtain 586 mg of a yellow oil, i.e., cis-tert-butyl 2-((4-(5,6-diphenylpyrazin-2-yl)aminocyclohexyl)oxy)acetate, with a yield of 63.8%, and ESI-MS: m / z=460.3 (M+H). + .

[0095] Step 5: Preparation of cis-2-((4-(5,6-diphenylpyrazine-2-yl)ethylaminocyclohexyl)oxy)acetic acid, the reaction equation is as follows:

[0096]

[0097] Under ice bath conditions, cis-2-((4-((5,6-diphenylpyrazin-2-yl)amino)cyclohexyl)oxy)acetic acid tert-butyl ester (230 mg, 0.5 mmol) and NaH (200 mg, 5 mmol) were added to 2 mL of DMF solution in sequence, and the mixture was vigorously stirred for 30 min. After adding iodoethane (234 mg, 1.5 mmol), the mixture was naturally warmed to room temperature and the reaction was continued to be stirred for 8 h. Under ice bath conditions, saturated NH4Cl was added to quench the reaction, and then ice water was added to the reaction solution, 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 purified by chromatography on a silica gel column, collected under reduced pressure, and dried in vacuo to obtain a yellow oil, i.e., cis-2-((4-(5,6-diphenylpyrazin-2-yl)ethylaminocyclohexyl)oxy)acetic acid tert-butyl ester.

[0098] Under ice bath conditions, cis-2-((4-(5,6-diphenylpyrazin-2-yl)ethylaminocyclohexyl)oxy)acetic acid tert-butyl ester (243 mg, 0.50 mmol) and NaOH (80.0 mg, 2.00 mmol) were added to 2 mL of MeOH solution in sequence, and the reaction was allowed to proceed for 2 h. Then, methanol was removed under reduced pressure, 5 mL of ice water and 5 mL of ethyl acetate were added to the reaction solution, and pH was adjusted to 6 with 1N HCl. 5 mL of ice water and 5 mL of ethyl acetate were 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, and the solvent was removed under reduced pressure. The mixture was purified by chromatography on a silica gel column, collected under reduced pressure, and dried under vacuum to obtain 165 mg of a light yellow powder, i.e., cis-2-((4-(5,6-diphenylpyrazin-2-yl)ethylaminocyclohexyl)oxy)acetic acid, with a yield of 76.6%. 1 H NMR (600MHz, CDCl3) δ7.90 (s, 1H), 7.41-7.38 (m, 2H), 7.32-7.30 (m, 2H), 7.25-7.17 (m, 6H), 4.22 (q, J = 7.1Hz, 2H), 4.10 (s, 2H), 3.89 (q, J = 8. 4,6.5Hz,1H),3.61(tt,J=5.6,3.0Hz,1H),1.95-1.92(m,2H),1.90-1. 84(m,2H),1.80-1.74(m,2H),1.71-1.68(m,2H),1.29(t,J=7.1Hz,3H).

[0099] Method 2:

[0100] Step 1: Preparation of cis-4-ethylamino-1-cyclohexanol, the reaction equation is as follows:

[0101]

[0102] Under ice bath conditions, cis-4-aminocyclohexanol hydrochloride (249 mg, 1.65 mmol), acetaldehyde (0.13 mL, 2.31 mmol) and NaBH3CN (176 mg, 2.8 mmol) were added to 8 mL of MeOH solution in sequence, and the reaction was allowed to proceed overnight. Methanol was removed under reduced pressure, and 5 mL of tetrahydrofuran was added. The mixture was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The mixture was dried in vacuo to obtain 180 mg of crude cis-2-((4-(5,6-diphenylpyrazin-2-yl)methylaminocyclohexyl)oxy)acetic acid, which was used directly in the next step without purification.

[0103] Step 2: Preparation of cis-4-((5,6-diphenylpyrazin-2-yl)ethylamino)cyclohexyl-1-ol, the reaction equation is as follows:

[0104]

[0105] Under nitrogen protection, 5-chloro-2,3-diphenylpyrazine (532 mg, 2.00 mmol), potassium carbonate (414 mg, 3.00 mmol) and cis-4-ethylamino-1-cyclohexanol (429 mg, 3.00 mmol) synthesized in method 1 were added to 10 mL of N-methylpyrrolidone (NMP), heated to 180°C for 12 h, and the reaction was monitored by TLC. After the reaction of the raw materials was complete, the reaction solution was cooled and ice water was added to the reaction solution, and extracted with ethyl acetate. The organic mixed phase was washed with water and saturated brine, dried over MgSO4, filtered, and desolventized. The mixture was purified by chromatography on a silica gel column, collected under reduced pressure, and dried in vacuo to obtain 550 mg of a yellow solid, i.e., cis-4-((5,6-diphenylpyrazin-2-yl)ethylamino)cyclohexyl-1-ol, with a yield of 73.7%. ESI-MS: m / z=374.2 (M+H) + .

[0106] Step 3: Preparation of cis-2-((4-(5,6-diphenylpyrazin-2-yl)ethylaminocyclohexyl)oxy)acetic acid tert-butyl ester, the reaction equation is as follows:

[0107]

[0108] In an ice bath, 2.5 mL of toluene and 2.5 mL of 40% To the mixed solution of KOH were added cis-4-((5,6-diphenylpyrazin-2-yl)ethylamino)cyclohexyl-1-ol (559.5 mg, 1.50 mmol), tetrabutylammonium hydrogen sulfate (1.02 g, 3.00 mmol) and tert-butyl bromoacetate (876 mg, 4.50 mmol) in sequence, and the mixture was stirred vigorously for 30 min. After the mixture was naturally warmed to room temperature, the mixture was stirred and reacted for 3 h. Then, 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, and the solvent was removed under reduced pressure. The mixture was purified by chromatography on a silica gel column, collected under reduced pressure, and dried under vacuum to obtain 488 mg of a yellow oil, i.e., tert-butyl cis-2-((4-(5,6-diphenylpyrazin-2-yl)ethylaminocyclohexyl)oxy)acetate. The yield was 66.8%, and ESI-MS: m / z=488.2 (M+H). + .

[0109] Step 4: Preparation of cis-2-((4-(5,6-diphenylpyrazin-2-yl)ethylaminocyclohexyl)oxy)acetic acid, the reaction equation is as follows:

[0110]

[0111] Under ice bath conditions, cis-2-((4-(5,6-diphenylpyrazin-2-yl)ethylaminocyclohexyl)oxy)acetic acid tert-butyl ester (243 mg, 0.50 mmol) and NaOH (80.0 mg, 2.00 mmol) were added to 2 mL of MeOH solution in sequence, and the reaction was continued for 2 h. Then, methanol was removed under reduced pressure, 5 mL of ice water and 5 mL of ethyl acetate were added to the reaction solution, pH was adjusted to 5 with 2N HCl, and extraction was performed 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 purified by chromatography on a silica gel column, collected under reduced pressure, and dried in vacuo to obtain 191 mg of a light yellow powder product, namely, cis-2-((4-(5,6-diphenylpyrazin-2-yl)ethylaminocyclohexyl)oxy)acetic acid, with a yield of 88.6%. 1 H NMR (600MHz, CDCl3) δ7.90 (s, 1H), 7.41-7.38 (m, 2H), 7.32-7.30 (m, 2H), 7.25-7.17 (m, 6H), 4.22 (q, J = 7.1Hz, 2H), 4.10 (s, 2H), 3.89 (q, J = 8. 4,6.5Hz,1H),3.61(tt,J=5.6,3.0Hz,1H),1.95-1.92(m,2H),1.90-1. 84(m,2H),1.80-1.74(m,2H),1.71-1.68(m,2H),1.29(t,J=7.1Hz,3H).

[0112] Example 3

[0113] A cis-4-(5,6-diphenylpyrazine-2-amino)cyclohexyloxyacetic acid compound, the structural formula of which is as follows:

[0114]

[0115] The compound is cis-2-((4-(5,6-diphenylpyrazin-2-yl)propylaminocyclohexyl)oxy)acetic acid, which is prepared by the following method.

[0116] Method 1:

[0117] The synthesis steps are the same as steps 1 to 5 in method 1 of Example 1, except that iodomethane in step 5 is replaced by iodopropane, and a light yellow oil is finally obtained, namely cis-2-((4-(5,6-diphenylpyrazin-2-yl)propylaminocyclohexyl)oxy)acetic acid. 1 H NMR(600MHz, CDCl3)δ8.01(s,1H),7.45-7.43(m,2H),7.37-7.34(m,2H),7. 30-7.27(m,2H),7.24(t,J=7.6Hz,4H),4.50-4.44(m,1H),4.16(s,2H),3.45 -3.4(m,1H),3.35-3.30(m,2H),2.23-2.18(m,2H),1.92(d,J=11.8Hz,2H),1. 70-1.66(m,2H),1.65-1.60(m,2H),1.57-1.52(m,2H),0.98(t,J=7.4Hz,3H).

[0118] Method 2:

[0119] The synthesis steps are the same as steps 1 to 4 in method 2 of Example 2, except that acetaldehyde in step 1 is replaced by propionaldehyde, and a light yellow oil is finally obtained, namely cis-2-((4-(5,6-diphenylpyrazin-2-yl)propylaminocyclohexyl)oxy)acetic acid. 1H NMR(600MHz, CDCl3)δ8.01(s,1H),7.45-7.43(m,2H),7.37-7.34(m,2H),7.3 0-7.27(m,2H),7.24(t,J=7.6Hz,4H),4.50-4.44(m,1H),4.16(s,2H),3.45- 3.4(m,1H),3.35-3.30(m,2H),2.23-2.18(m,2H),1.92(d,J=11.8Hz,2H),1. 70-1.66(m,2H),1.65-1.60(m,2H),1.57-1.52(m,2H),0.98(t,J=7.4Hz,3H).

[0120] Example 4

[0121] A cis-4-(5,6-diphenylpyrazine-2-amino)cyclohexyloxyacetic acid compound, the structural formula of which is as follows:

[0122]

[0123] The compound is cis-2-((-4-(5,6-diphenylpyrazin-2-yl)isobutylamino)cyclohexyl)oxy)acetic acid, which is prepared by the following method.

[0124] Method 1:

[0125] The synthesis steps are the same as steps 1 to 5 in method 1 of Example 1, except that iodomethane in step 5 is replaced by isobutyl iodide, and a brown oily substance is finally obtained, namely cis-2-((-4-(5,6-diphenylpyrazin-2-yl)isobutylaminocyclohexyl)oxy)acetic acid. 1 H NMR (600MHz, CDCl3) δ7.92(s,1H),7.43-7.40(m,2H),7.35-7.31(m,2H),7.29-7.26(m,3H),7.25-7.21(m,3H),4.13(s,2H),3.95(d,J=6.7Hz,2 H),3.89(s,1H),3.62(tt,J=5.5,2.9Hz,1H),1.99-1.92(m,4H),1.91-1 .85(m,2H),1.81-1.75(m,3H),1.73-1.66(m,2H),0.95(d,J=6.8Hz,6H).

[0126] Method 2:

[0127] The synthesis steps are the same as steps 1 to 4 in method 2 of Example 2, except that acetaldehyde in step 1 is replaced by isobutylaldehyde, and finally a brown oily substance cis-2-((-4-(5,6-diphenylpyrazin-2-yl)isobutylaminocyclohexyl)oxy)acetic acid is obtained. 1 H NMR (600MHz, CDCl3) δ7.92(s,1H),7.43-7.40(m,2H),7.35-7.31(m,2H),7.29-7.26(m,3H),7.25-7.21(m,3H),4.13(s,2H),3.95(d,J=6.7Hz,2 H),3.89(s,1H),3.62(tt,J=5.5,2.9Hz,1H),1.99-1.92(m,4H),1.91-1 .85(m,2H),1.81-1.75(m,3H),1.73-1.66(m,2H),0.95(d,J=6.8Hz,6H).

[0128] Example 5

[0129] A cis-4-(5,6-diphenylpyrazine-2-amino)cyclohexyloxyacetic acid compound, the structural formula of which is as follows:

[0130]

[0131] The compound is cis-2-((-4-(5,6-diphenylpyrazin-2-yl)2-fluoroethylamino)cyclohexyl)oxy)acetic acid, which is prepared by the following method.

[0132] The synthesis steps are the same as steps 1 to 5 in method 1 of Example 1, except that iodomethane in step 5 is replaced by iodo-2-fluoroethane, and a light yellow powder is finally obtained, namely cis-2-((-4-(5,6-diphenylpyrazin-2-yl)2-fluoroethylamino)cyclohexyl)oxy)acetic acid. 1 H NMR(600MHz, CDCl3)δ7.91(s,1H),7.42-7.39(m,2H),7.35-7.31(m,2H),7.30-7.19(m,6H),4.68-4.65(m,1H),4.60-4.57(m,1H),4.44-4.42(m, 1H),4.40-4.37(m,1H),4.18(s,2H),3.90(s,1H),3.64-3.59(m,1H),1.9 7-1.90(m,2H),1.89-1.84(m,2H),1.80-1.74(m,2H),1.71-1.66(m,2H).

[0133] Example 6

[0134] A cis-4-(5,6-diphenylpyrazine-2-amino)cyclohexyloxyacetic acid compound, the structural formula of which is as follows:

[0135]

[0136] The compound is cis-2-((4-(5,6-diphenylpyrazin-2-yl)(2,2-difluoroethyl)aminocyclohexyl)oxy)acetic acid, which is prepared by the following method.

[0137] The synthesis steps are the same as steps 1 to 5 in method 1 of Example 1, except that iodomethane in step 5 is replaced by iodo-2,2-difluoroethane, and finally a brown oily substance cis-2-((4-(5,6-diphenylpyrazin-2-yl)(2,2-difluoroethyl)aminocyclohexyl)oxy)acetic acid is obtained. 1 H NMR(600MHz, CDCl3)δ7.91(s,1H),7.43-7.40(m,2H),7.34-7.32(m,2H),7.29-7.27(m,2H),7.26-7.19(m,4H),5.97(tt,J=54.9,4.0Hz,1H),4 .36(m,2H),4.20(s,2H),3.90(s,1H),3.62(tt,J=55,2.9Hz,1H),1.96 -1.90(m,2H),1.88-1.85(m,2H),1.81-1.73(m,2H),1.69-1.66(m,2H).

[0138] Example 7

[0139] A cis-4-(5,6-diphenylpyrazine-2-amino)cyclohexyloxyacetic acid compound, the structural formula of which is as follows:

[0140]

[0141] The compound is cis-2-((4-(5,6-diphenylpyrazin-2-yl)(3,3,3-trifluoropropyl)aminocyclohexyl)oxy)acetic acid, which is prepared by the following method.

[0142] Method 1:

[0143] The synthesis steps are the same as steps 1 to 5 in method 1 of Example 1, except that iodomethane in step 5 is replaced by iodo-3,3,3-trifluoropropane, and a white oil is finally obtained, namely cis-2-((4-(5,6-diphenylpyrazin-2-yl)(3,3,3-trifluoropropyl)aminocyclohexyl)oxy)acetic acid, 1H NMR(600MHz, CDCl3)δ7.93(s,1H),7.44-7.39(m,2H),7.34-7.33(dd,J=7.7,1.9Hz,2H),7.30-7.26(m,3H),7.25-7.22(m,3H),4.39(t,J=6.3Hz, 2H),4.14(s,2H),3.89(s,1H),3.62-3.60(m,1H),2.55-2.47(m,2H),1.9 6-1.90(m,2H),1.90-1.85(m,2H),1.82-1.74(m,2H),1.71-1.67(m,2H).

[0144] Method 2:

[0145] The synthesis steps are the same as steps 1 to 4 in method 2 of Example 2, except that acetaldehyde in step 1 is replaced by 3,3,3-trifluoropropanal, and a white oil is finally obtained, namely cis-2-((4-(5,6-diphenylpyrazin-2-yl)(3,3,3-trifluoropropyl)aminocyclohexyl)oxy)acetic acid, 1 H NMR (600MHz, CDCl3) δ7.93(s,1H),7.44-7.39(m,2H),7.33(dd,J=7.7,1.9Hz,2H),7.30-7.26(m,3H),7.25-7.22(m,3H),4.39(t,J=6.3Hz,2H) ,4.14(s,2H),3.89(s,1H),3.62-3.60(m,1H),2.55-2.47(m,2H),1.96 -1.90(m,2H),1.90-1.85(m,2H),1.82-1.74(m,2H),1.71-1.67(m,2H).

[0146] Example 8

[0147] A cis-4-(5,6-diphenylpyrazine-2-amino)cyclohexyloxyacetic acid compound, the structural formula of which is as follows:

[0148]

[0149] The compound is cis-2-((4((5,6-diphenylpyrazin-2-yl)deuterated methylaminocyclohexyl)oxy)acetic acid, which is prepared by the following method.

[0150] The synthesis steps are the same as steps 1 to 5 in method 1 of Example 1, except that the iodomethane in step 5 is replaced with deuterated iodomethane, and finally cis-2-((4((5,6-diphenylpyrazin-2-yl)deuterated methylaminocyclohexyl)oxy)acetic acid is obtained as a light yellow powder.1 H NMR (600MHz, DMSO-d6) δ8.21 (s, 1H), 7.36 (dd, J = 7.5, 2.2Hz 2H),7.31-7.26(m,5H),7.26-7.21(m,3H),4.37(t,J=12.2Hz,1H),4.01(s,2H),3.63(t,J=2.9 Hz,1H),2.03-1.98(m,2H),1.88(tt,J=12.5,7.2Hz,2H),1.56-1.51(m,2H),1.50-1.46(m,2H).

[0151] Comparative Example 1

[0152] 2-(4-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)butoxy)acetic acid (MRE-269), the structural formula of which is as follows:

[0153]

[0154] According to the method disclosed in Example 42 of the patent CN1516690A specification, 2-(4-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)butoxy)acetic acid (MRE-269) was obtained as a yellow oil, 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).

[0155] Comparative Example 2

[0156] Trans-2-((4-(5,6-diphenylpyrazine-2-yl)methylaminocyclohexyl)oxy)acetic acid, the structural formula of which is as follows:

[0157]

[0158] The synthesis steps are the same as steps 1 to 4 in method 2 of Example 1, except that cis-(4-hydroxycyclohexyl)carbamic acid tert-butyl ester in step 1 is replaced by trans-(4-hydroxycyclohexyl)carbamic acid tert-butyl ester, and trans-2-((4-(5,6-diphenylpyrazin-2-yl)methylaminocyclohexyl)oxy)acetic acid is finally obtained as a light yellow powder, ESI-MS: m / z=418.2 (M+H) + .

[0159] Experimental example: In vitro platelet aggregation assay

[0160] 1. Purpose of the test

[0161] The antiplatelet aggregation activity of the compounds in the examples and comparative examples of the present invention was evaluated by studying their inhibitory effects on ADP-induced platelet aggregation in vitro.

[0162] 2. Test materials

[0163] 2.1 Test materials

[0164] Fully automatic platelet aggregation instrument (Tai Li Tai Kang AG800); ADP (sigma); DMSO, 0.9% sodium chloride injection, sodium hydroxide, blood collection tubes, etc.

[0165] 2.2 Experimental animals

[0166] Rabbit, male, 2.1±0.2kg.

[0167] 2.3 Test drugs

[0168] The compounds in Examples 1 to 8 and Comparative Examples 1 to 2.

[0169] 3. Test methods

[0170] 3.1 Preparation of test solution

[0171] Weigh each of the above test drugs, prepare a 200 mM stock solution with DMSO and an equimolar 1N NaOH aqueous solution, fully dissolve and mix, then aspirate the stock solution and add 0.9% sodium chloride injection to prepare a series of test solutions (0.15 μM-50 μM) of different concentrations;

[0172] 3.2 Preparation of PRP and PPP

[0173] Rabbit blood was collected in plastic centrifuge tubes, anticoagulated with 3.2% sodium citrate (the ratio of anticoagulant to whole blood was 1:9), and centrifuged at 140 g for 10 min. The upper liquid was carefully aspirated as PRP, and the remaining plasma was centrifuged at 2000 g for 10 min. The supernatant was PPP.

[0174] 3.3 Preparation of ADP solution

[0175] Weigh ADP and dissolve it in 0.9% sodium chloride injection to prepare ADP stock solution, dispense into centrifuge tubes, and freeze at -20°C. Redissolve before use and dilute to 300 μM with 0.9% sodium chloride injection for later use.

[0176] 3.4 Maximum aggregation rate detection

[0177] After the platelet aggregation instrument is turned on, preheat for 30 minutes and start the test after the temperature rises to 37°C. Place 270μL PRP and 30μL test solution in the PRP cup of the double cup, and place 300μL PPP in the PPP cup of the double cup, and the instrument starts the test. The maximum aggregation rate of ADP-induced platelets at different test drug concentrations is calculated. The results are shown in Table 1.

[0178] Table 1 Maximum aggregation rate of platelets acted on by compounds of Examples and Preparation Examples

[0179]

[0180] It can be seen from Table 1 that the maximum platelet aggregation rate of the compound in Comparative Example 1 is 12.3% when the concentration of the compound is 12.5 um, and the compounds in Examples 1 to 8 of the present invention have a greater inhibitory effect on platelet aggregation than the compound in Preparation Example 1, among which the compounds in Examples 1, 2, 5, and 8 have a very large inhibitory effect on platelet aggregation.

[0181] Although the specific implementation of the present invention is described in detail in conjunction with the embodiments, it should not be understood as limiting the scope of protection of this patent. Within the scope described in the claims, various modifications and variations that can be made by those skilled in the art without creative work still fall within the scope of protection of this patent.

Claims

1. A cis-4-(5,6-diphenylpyrazine-2-amino)cyclohexyloxyacetic acid compound, characterized in that: The structural formula of the compound is shown in Formula I: ； Wherein, R is an alkyl group, a deuterated alkyl group or a fluoroalkyl group.

2. The cis-4-(5,6-diphenylpyrazine-2-amino)cyclohexyloxyacetic acid compound according to claim 1, characterized in that: The R is methyl, deuterated methyl, fluoromethyl, fluoroethyl, fluoropropyl, ethyl, propyl or isobutyl.

3. The cis-4-(5,6-diphenylpyrazine-2-amino)cyclohexyloxyacetic acid compound according to claim 2, characterized in that: The 4-(5,6-diphenylpyrazine-2-amino)cyclohexyloxyacetic acid compound is one of the compounds having the following structural formula: 、 、 、 、 、 、 、 。 4. The method for preparing the cis-4-(5,6-diphenylpyrazine-2-amino)cyclohexyloxyacetic acid compound according to any one of claims 1 to 3, characterized in that: The following steps are involved: S1: Dissolve 5-chloro-2,3-diphenylpyrazine, a compound as shown in Formula II and a base in an organic solvent, and react at 100-200°C for 8-48h to obtain a compound as shown in Formula III 、 ； S2: Dissolve the compound represented by Formula III, tert-butyl bromoacetate and the catalyst in a mixed solution under ice bath, stir and react for 30-45 min, then naturally raise the temperature to room temperature, and continue to react for 0.5-3 h to obtain a compound represented by Formula IV; the mixed solution is prepared by mixing equal volumes of toluene and a KOH solution having a concentration of 40 wt %; ； S3: dissolving the compound represented by Formula IV in a solvent under ice bath, adding NaH, stirring and reacting for 30-45 min, then adding iodide RI, naturally raising the temperature to room temperature, and continuing the reaction for 8-24 h to obtain a compound represented by Formula V; the solvent is tetrahydrofuran, N,N-dimethylformamide or diethyl ether; ； Wherein, R is alkyl, deuterated alkyl, or fluoroalkyl; S4: Dissolve the compound represented by formula V and LiOH or NaOH in an organic solvent under ice bath, keep warm for 2-10 hours, then acidify and extract to obtain the product.

5. The method for preparing the cis-4-(5,6-diphenylpyrazine-2-amino)cyclohexyloxyacetic acid compound according to any one of claims 1 to 3, characterized in that: The following steps are involved: S1: dissolving 5-chloro-2,3-diphenylpyrazine, a compound as shown in Formula VI and a base in an organic solvent, and reacting at 100-180° C. for 12-48 hours to obtain a compound as shown in Formula VII; 、 ； Wherein, R is alkyl, deuterated alkyl, or fluoroalkyl; S2: Dissolve the compound represented by Formula VII, tert-butyl bromoacetate and the catalyst in a mixed solution under ice bath, stir and react for 30-45 min, then naturally raise the temperature to room temperature, and continue to react for 0.5-3 h to obtain a compound represented by Formula V; the mixed solution is prepared by mixing equal volumes of toluene and a KOH solution having a concentration of 40 wt %; ； S3: Dissolve the compound represented by formula V and LiOH or NaOH in an organic solvent under ice bath, keep warm for 2-12 hours, then acidify and extract to obtain the product.

6. The preparation method according to claim 4 or 5, characterized in that: The 5-chloro-2,3-diphenylpyrazine is prepared by the following steps: (1) Under an inert atmosphere, dissolving benzyl, aminoacetamide and a base in an organic solvent at a molar ratio of 1:1-1.5:2-2.5, heating and refluxing for 3-5 hours to obtain an intermediate as shown in Formula VIII; ； (2) Under an inert atmosphere, the intermediate represented by formula VIII and phosphorus oxychloride are mixed at a material-liquid ratio of 1 g:0.5-5 mL, and heated under reflux until the raw materials react completely to obtain the product.

7. The preparation method according to claim 4 or 5, characterized in that: The base is potassium carbonate; the catalyst is tetrabutylammonium hydrogen sulfate.

8. The preparation method according to claim 5, characterized in that: The compound shown in formula VI, in which R is methyl, is prepared by the following steps: Under ice bath conditions, cis-(4-hydroxycyclohexyl)carbamic acid tert-butyl ester and LiAlH4 are added to an organic solvent, and then the reaction system is heated to 55-65°C and refluxed for 5-8h to obtain; Alternatively, the compound represented by formula VI, in which R is an alkyl group having 2 or more carbon atoms or a substituted alkyl group having 2 or more carbon atoms, is prepared by the following steps: Under ice bath conditions, cis-4-aminocyclohexanol hydrochloride, aldehyde and reducing agent are co-dissolved in an organic solvent, and the reaction is kept warm overnight to obtain the product; the reducing agent is NaBCNH3, NaB(OAc)3H or NaBH4; the aldehyde is an aldehyde having a carbon number greater than or equal to 2 or a substituted aldehyde having a carbon number greater than or equal to 2.

9. Use of the cis-4-(5,6-diphenylpyrazine-2-amino)cyclohexyloxyacetic acid compound according to any one of claims 1 to 3 in the preparation of IP receptor agonists.

10. The use according to claim 9, characterized in that: The IP receptor agonist is used as an active ingredient of a thrombovasodilation drug or an anti-pulmonary hypertension drug.

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