Intermediates of beraprost sodium and processes for their preparation

Abstract

The present application relates to a preparation method of beraprost sodium and its intermediates, and belongs to the field of pharmaceutical chemistry. The method comprises the following steps: taking compound 1 as a starting material, and preparing beraprost sodium and its key intermediates through substitution, deprotection, reduction, double bond shift, double bond oxidation cracking, hydrolysis and other steps. The preparation method shortens the synthesis route, has mild reaction conditions and simple operation; the raw materials are cheap and easy to obtain, the generation of waste is reduced, and the cost is reduced; the product yield is significantly improved, and the method is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry and relates to a method for preparing beraprost sodium, specifically to beraprost sodium intermediates and their preparation methods. Background Technology

[0002] Beprost sodium (trade name Dorner) is a prostacyclin derivative with the chemical name (±)-2,3,3a,8b-tetrahydro-2-hydroxy-1-(3-hydroxy-4-methyl-1-octen-6-ynyl)-1H-cyclopentano[b]benzofuran-5-butyrate sodium, an antiplatelet drug developed by Toray Industries, Inc. of Japan.

[0003] Beraprost is the first biologically stable, orally active prostacyclin analogue. In 1992, beraprost was approved for marketing in Japan as a treatment for chronic arterial occlusion. The racemic form of beraprost for the treatment of pulmonary arterial hypertension (PAH) has been approved by the US FDA for Phase II clinical trials. In 2007, Beraprost sodium extended-release tablets (Careload LA) from Toray and Astellas (formerly Yamanouchi) were approved in Japan for the treatment of PAH, becoming the first extended-release formulation of prostacyclin drugs. Beraprost sodium is a derivative of prostacyclin (PGI2), the final product of arachidonic acid metabolism in the body, and has a strong inhibitory effect on platelet aggregation and vasodilation.

[0004] Endogenous PGI2 is primarily synthesized by vascular endothelial cells and is a metabolite of arachidonic acid (AA). AA is metabolized by cyclooxygenases (COX-1 or COX-2) into the unstable prostaglandin H2 (PGH2). PGH2 is a common precursor to five major prostaglandins, including thromboxane A2 (TXA2), prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), PGI2, and prostaglandin F. 2A (PGF 2APGI2 is unstable and has a short plasma half-life of approximately 2 minutes after intravenous injection. PGI2 specifically binds to the prostacyclin membrane (IP) receptor. The IP receptor is abundantly expressed in blood vessels, leukocytes, and platelets and can be rapidly activated by prostaglandins. The IP receptor couples with the GS protein and activates adenylate cyclase (AC), leading to increased levels of cyclic adenosine monophosphate (cAMP), relaxation of pulmonary vascular smooth muscle, inhibition of smooth muscle proliferation, and promotion of nitric oxide (NO) release from endothelial cells. NO promotes increased PGI2 production, exerting its main biological effects. Under certain specific conditions, the IP receptor may also couple with the Gq protein, activating vasoconstriction pathways. However, prostacyclin does not only select for the IP receptor but may also activate prostaglandin E receptors (EP) located on the cell surface and in the nucleus, as well as peroxisome proliferator-activated receptor (PPAR) located in the nucleus. PGI2 also has potent anti-inflammatory, anti-platelet aggregation, and collagen-inhibiting effects on pulmonary fibroblasts.

[0005] Beraprost sodium is an exogenous prostacyclin analogue, structurally similar to endogenous prostacyclin. It is rapidly absorbed on an empty stomach, chemically stable, reaches peak concentration after 30 minutes, and has a clearance half-life of approximately 35–40 minutes. Beraprost sodium specifically binds to the IP receptor, increasing intracytoplasmic cAMP concentration and inhibiting Ca2+ absorption. 2+ Released from intracellular space, it relaxes vascular smooth muscle, inhibits platelet aggregation, suppresses cell proliferation and inflammatory response, and protects vascular endothelial cells, thereby counteracting the vasoconstrictive effect induced by TAX2. Ultimately, it dilates pulmonary arterioles, reduces pulmonary artery pressure, and inhibits pulmonary vascular remodeling and in situ thrombus formation.

[0006] Regarding the preparation method of beraprost sodium, patents US5202447, JP59134787 and JP2003002885 describe the synthesis method of beraprost sodium (see route 1). This method uses cyclopentadiene as a starting material, has many synthesis steps, and has an extremely low yield.

[0007] Route 1:

[0008]

[0009] Patents WO2004 / 005274 and JP07238046 describe another synthetic route (see Route 2). This route uses phenol as a starting material, which undergoes bromination, protection with bromopropene, and then reacts with furan followed by a series of rearrangement reactions to obtain the product. This process has a higher yield than Route 1, but the yield of the 1,4-addition reaction is not high, and it requires the use of highly toxic chemicals such as osmium tetroxide to break and oxidize the double bonds. The reaction has disadvantages such as high safety requirements for the synthesizers and inconvenient operation.

[0010] Route 2:

[0011]

[0012] Therefore, there is a need in the field to develop a key intermediate compound that is low in production cost, efficient in process, easy to operate, and suitable for industrial production, and that can be applied to the synthetic route of beraprost sodium. Summary of the Invention

[0013] This invention addresses the problems existing in the prior art by providing a method for preparing beraprost sodium that is mild in reaction conditions, simple in operation, safe, and has a high yield. It also provides a new intermediate for preparing beraprost sodium and its preparation method.

[0014] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0015] In a first aspect, the present invention provides a method for preparing beraprost sodium, the preparation route of which is as follows:

[0016]

[0017] * and ** are both in the R configuration, or * and ** are both in the S configuration; when * and ** are both in the R configuration, *** is in the S configuration; when * and ** are both in the S configuration, *** is in the R configuration.

[0018] Where R 1 For R 1-1 R 1-2 R 1-3 Si-, acetyl or benzoyl, R 1-1 R 1-2 and R 1-3 It is independently selected from C1-4 alkyl or phenyl.

[0019] According to one embodiment of the present invention, the specific steps of the method include:

[0020] (1) In a solvent, under alkaline conditions, compound 1 and compound 14 react to produce compound 2;

[0021] (2) In the solvent, under the action of a catalyst, compound 2 undergoes a deprotection reaction to generate compound 3;

[0022] (3) In the solvent, under the action of azobisisobutyronitrile, compound 3 reacts with tri-n-butylallyltin to generate compound 4;

[0023] (4) In the solvent, under the action of the reducing agent, compound 4 reacts with the reducing agent to generate compound 5;

[0024] (5) In the solvent, under the action of a catalyst, compound 5 undergoes double bond displacement to generate compound 6;

[0025] (6) In a solvent, under the action of an alkali, compound 6 reacts with a hydroxyl protecting agent to generate compound 7;

[0026] (7) In the solvent, under the action of the oxidation system, compound 7 undergoes a double bond oxidative cleavage reaction to generate compound 8;

[0027] (8) In a solvent, under the action of a base, compound 8 reacts with compound 15 to form compound 9;

[0028] (9) In the solvent, under the action of the reducing agent, compound 9 undergoes a reduction reaction to generate compound 10;

[0029] (10) In a solvent, under alkaline conditions, compound 10 reacts to form compound 11;

[0030] (11) In a solvent, under the action of a base, compound 11 reacts to form compound 12;

[0031] (12) In the solvent, under the action of sodium hydroxide, compound 12 reacts to form biological compound 13, namely beraprost sodium.

[0032] According to one embodiment of the present invention, in step (1), the solvent is an ether solvent or an amide solvent; preferably, the ether solvent is tetrahydrofuran, diethyl ether, or 1,4-dioxane; the amide solvent is N,N-dimethylformamide or N,N-dimethylacetamide;

[0033] According to one embodiment of the present invention, in step (1), the alkali is sodium hydroxide, lithium diisopropylamino, or sodium hydride; preferably lithium diisopropylamino; the molar ratio of the alkali to compound 1 is 1 to 1.2:1.0;

[0034] According to one embodiment of the present invention, the reaction temperature of step (1) is 25°C to 40°C.

[0035] According to one embodiment of the present invention, in step (2), the solvent is one or more of ketone solvents, alcohol solvents and water; preferably, the ketone solvent is acetone; the alcohol solvent is methanol, ethanol or isopropanol; more preferably, the solvent is a mixture of acetone and water.

[0036] According to one embodiment of the present invention, in step (2), the catalyst is hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid and its pyridine salt, camphorsulfonic acid, preferably p-toluenesulfonic acid or pyridine p-toluenesulfonate; the molar ratio of the catalyst to compound 2 is 0.1 to 2.0:1.0;

[0037] According to one embodiment of the present invention, the reaction temperature of step (2) is 30°C to 100°C, preferably 60°C to 80°C.

[0038] According to one embodiment of the present invention, in step (3), the solvent is a benzene-based solvent or an ether-based solvent; preferably, the benzene-based solvent is toluene; and the ether-based solvent is tetrahydrofuran.

[0039] According to one embodiment of the present invention, in step (3), the molar ratio of the azobisisobutyronitrile to compound 3 is 0.2 to 0.5:1.0.

[0040] According to one embodiment of the present invention, in step (4), the solvent is an alcohol solvent or an ether solvent; preferably, the alcohol solvent is methanol, ethanol or isopropanol; the ether solvent is tetrahydrofuran, diethyl ether or 1,4-dioxane.

[0041] According to one embodiment of the present invention, in step (4), the reducing agent is: sodium borohydride, potassium borohydride, lithium borohydride, lithium diisobutylaluminum hydride, lithium tritert-butylaluminum hydride, lithium triethylborohydride or Red-Al; preferably sodium borohydride; the molar ratio of the reducing agent to compound 4 is 0.8 to 1.0:1.0.

[0042] According to one embodiment of the present invention, in step (5), the solvent is toluene;

[0043] According to one embodiment of the present invention, in step (5), the catalyst is a Grubbs catalyst (including first and second generation), a Hoveyda-Grubbs catalyst (including first and second generation), or ruthenium carbonyl chloride tris(triphenylphosphine)carbonyl, preferably ruthenium carbonyl chloride tris(triphenylphosphine)carbonyl; the molar ratio of the catalyst to compound 5 is 0.01 to 0.5:1; preferably 0.01 to 0.05:1.

[0044] According to one embodiment of the present invention, the reaction temperature of step (5) is 90 to 110°C.

[0045] According to one embodiment of the present invention, in step (6), the solvent is an amide solvent, a nitrile solvent, an ether solvent, or a halocarbon solvent; preferably, the amide solvent is N,N-dimethylformamide or N,N-dimethylacetamide; the nitrile solvent is acetonitrile; the ether solvent is tetrahydrofuran or 1,4-dioxane; and the halocarbon solvent is dichloromethane, chloroform, carbon tetrachloride, or dichloroethane.

[0046] According to one embodiment of the present invention, in step (6), the base is an organic base; preferably, the base is triethylamine; the molar ratio of the base to compound 6 is 1.1 to 6.0:1.0;

[0047] According to one embodiment of the present invention, in step (6), the hydroxyl protecting agent is R. 1-1 R 1-2 R 1-3 SiCl, R 1- 1 R 1-2 R 1-3 SiOTf, acetic anhydride or benzoic anhydride, wherein R 1 For R 1-1 R 1-2 R 1-3 Si-, acetyl or benzoyl, R 1-1 R 1-2 and R 1-3 Independently selected from C1-4 alkyl or phenyl; preferably, the R 1-1 R 1-2 and R 1-3 It is independently selected from methyl, ethyl, isopropyl, tert-butyl, or phenyl;

[0048] More preferably, the hydroxyl protecting agent is selected from... Acetic anhydride or benzoic anhydride;

[0049] The molar ratio of the hydroxyl protectant to compound 6 is 1.0 to 3.0:1.0.

[0050] According to one embodiment of the present invention, in step (7), the solvent is a mixture of tetrahydrofuran and water;

[0051] According to one embodiment of the present invention, in step (7), the oxidation system is potassium osmium tetroxide / sodium periodate, osmium tetroxide / sodium periodate, ozone / triphenylphosphine, preferably potassium osmium tetroxide / sodium periodate; the molar ratio of the oxidant and compound 7 in the oxidation system is 0.01-0.1:3-6:1; preferably 0.01-0.02:3-4:1;

[0052] According to one embodiment of the present invention, the reaction temperature of step (7) is 0°C to 25°C.

[0053] According to one embodiment of the present invention, in step (8), the solvent is an ether solvent or an amide solvent; preferably, the ether solvent is tetrahydrofuran; the amide solvent is N,N-dimethylformamide or N,N-dimethylacetamide;

[0054] According to one embodiment of the present invention, in step (8), the base is an organic base or an inorganic base; preferably, the organic base is selected from triethylamine, DBU, potassium tert-butoxide, n-butyllithium, sodium hexamethyldisilamide, potassium hexamethyldisilamide, or lithium hexamethyldisilamide; the inorganic base is selected from sodium hydrogen or lithium chloride;

[0055] According to one embodiment of the present invention, in step (8), the molar ratio of the base to compound 8 is 1.0 to 3.0:1.0; the molar ratio of compound 15 to compound 8 is 1.0 to 3.0:1.0.

[0056] According to one embodiment of the present invention, in step (9), the solvent is an ether solvent or an alcohol solvent; preferably, the ether solvent is tetrahydrofuran; the alcohol solvent is methanol, ethanol or isopropanol;

[0057] According to one embodiment of the present invention, in step (9), the reducing agent is: sodium borohydride / cerium trichloride, potassium borohydride, lithium borohydride, borane diethyl ether complex, borane dimethyl sulfide complex, aminoborane, tert-butylaminoborane, lithium diisobutylaluminum hydride, (-)-diisopinepinelchloroborane, (R)-CAS-Me, sodium borohydride / cobalt chloride, or (R)-B-isopinepinel-9-borane bicyclo[3.3.1]nonane; the molar ratio of the reducing agent to compound 9 is 2.0 to 6.0:1.0.

[0058] According to one embodiment of the present invention, in step (10), the solvent is an alcohol solvent; preferably, the solvent is methanol, ethanol or isopropanol;

[0059] According to one embodiment of the present invention, in step (10), the base is sodium methoxide; the molar ratio of the base to compound 10 is 1:1 to 4.

[0060] According to one embodiment of the present invention, in step (11), the solvent is methanol and water;

[0061] According to one embodiment of the present invention, in step (11), the alkali is sodium hydroxide; the molar ratio of the alkali to compound 11 is 2 to 5:1.

[0062] According to one embodiment of the present invention, in step (12), the solvent is methanol and water.

[0063] Secondly, the present invention provides an intermediate compound 2 for preparing beraprost sodium and a method for preparing compound 2.

[0064] The structure of compound 2 is as follows:

[0065]

[0066] The preparation method of compound 2 includes the following steps:

[0067]

[0068] Under alkaline conditions, compound 1 undergoes nucleophilic substitution to generate compound 2;

[0069] Specifically, compound 1 and (Compound 14) undergoes nucleophilic substitution to generate compound 2;

[0070] Preferably, the alkali is sodium hydroxide, lithium diisopropylamino, or sodium hydride; preferably lithium diisopropylamino; the molar ratio of the alkali to compound 1 is 1–1.2:1.0; preferably, the reaction temperature is 25°C–40°C.

[0071] Thirdly, the present invention provides an intermediate compound 3 for preparing beraprost sodium and a method for preparing compound 3.

[0072] The structure of compound 3 is as follows:

[0073]

[0074] The preparation method of compound 3 includes the following steps:

[0075]

[0076] Under the action of a catalyst, compound 2 undergoes a deprotection reaction to generate compound 3;

[0077] Preferably, the catalyst is hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid and its pyridine salt or camphorsulfonic acid, preferably p-toluenesulfonic acid or pyridine p-toluenesulfonate; the molar ratio of the catalyst to compound 2 is 0.1-2.0:1.0;

[0078] Preferably, the deprotection reaction temperature is 30℃~100℃, more preferably 60~80℃.

[0079] Fourthly, the present invention provides an intermediate compound 4 for the preparation of beraprost sodium and a method for preparing compound 4.

[0080] The structure of compound 4 is as follows:

[0081]

[0082] * and ** are both in the R configuration or * and ** are both in the S configuration;

[0083] The preparation method of compound 4 includes the following steps:

[0084]

[0085] Under the action of a free radical initiator, compound 3 undergoes a free radical tandem reaction to generate compound 4;

[0086] Preferably, the free radical initiator is azobisisobutyronitrile; more preferably, this step specifically involves the reaction of compound 3 and tri-n-butylallyltin under the action of azobisisobutyronitrile to generate compound 4;

[0087] Preferably, the molar ratio of azobisisobutyronitrile to compound 3 is 0.2 to 0.5:1.0.

[0088] Compared with the prior art, the present invention has the following beneficial effects:

[0089] This invention provides a novel reaction route for synthesizing beraprost sodium and offers a new intermediate compound. The preparation method described in this invention has simple synthesis steps and significantly improves the reaction yield compared to existing technologies. The method avoids the use of highly toxic reagents, making it environmentally friendly, green, and pollution-free.

[0090] This invention provides novel intermediate compounds 2 and 3 for the synthesis of beraprost sodium. The reaction methods for intermediates 2 and 3 are simple and have high yields, providing a new approach for the synthesis of beraprost sodium.

[0091] The present invention also provides a method for preparing intermediate compound 4 for the synthesis of beraprost sodium. Compared with the prior art, the method is simpler, has a higher yield, and uses milder reaction conditions, making it more suitable for industrial production. Attached Figure Description

[0092] Figure 1 For beraprost sodium 1 HNMR spectrum. Detailed Implementation

[0093] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. In addition, it is worth noting that the raw materials involved in the present invention are all commercially available products unless otherwise specified.

[0094] For experimental methods in the following examples where specific conditions are not specified, conventional methods and conditions should be followed, or the product instructions should be followed. Unless otherwise specified, temperature generally refers to reactions conducted at room temperature; in this invention, room temperature refers to 10–30°C.

[0095] Example 1: Synthesis of Compound 2

[0096]

[0097] At 0 °C under argon protection, compound 1 (25.0 g, 91.5 mmol) dissolved in tetrahydrofuran (152.5 mL) was slowly added to a solution of diisopropylaminolithium (45.75 mL, 2 M in THF) and compound 14 (24.4 g, 118.9 mmol) dissolved in tetrahydrofuran (152.5 mL). The reaction was carried out at room temperature (25 °C) for 5 hours. The reaction was quenched with saturated ammonium chloride (50 mL), the layers were separated, extracted with ethyl acetate (50 mL × 2), washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 2 (35.5 g, 97%). 1 H NMR (300MHz, Chloroform-d) δ7.41 (dd, J=8.0, 1.6Hz, 1H), 7.13 (dd, J=7.6, 1.6Hz, 1H), 6. 92(t,J=7.8Hz,1H),6.18(dd,J=5.7,2.0Hz,1H),5.93(dd,J=5.7,1.2Hz,1H),5.27(dddd,J =7.1,4.1,2.0,1.2Hz,1H),4.05–3.91(m,4H),3.66(s,3H),2.79–2.64(m,2H),2.60(dd,J= 14.3,7.0Hz,1H),2.36(dd,J=14.2,4.2Hz,1H),2.31(t,J=7.5Hz,2H).m / z(ESI-MS):397.0

[0098] [M+H]+.

[0099] Example 2 Synthesis of Compound 3

[0100]

[0101] Add pyridine p-toluenesulfonate (15.18 g, 60.4 mmol) to a solution of compound 2 (12.0 g, 30.2 mmol) in acetone / water at a ratio of 8:1 (604 mL), heat to 80 °C and react for 6 hours. The reaction was confirmed to be complete by TLC. The solution was concentrated and column chromatography was used to obtain compound 3 (10.30 g, 96%). 1H NMR(300MHz,Chloroform-d)δ7.67(dd,J=5.7,2.3Hz,1H),7.45(dd,J=7.9,1.6Hz,1 H),7.17(dd,J=7.6,1.6Hz,1H),6.98(t,J=7.8Hz,1H),6.32(dd,J=5.7,1.2Hz,1H),5 .45(dtd,J=6.0,2.4,1.2Hz,1H),3.65(s,3H),2.86(dd,J=18.5,6.1Hz,1H),2.77–2. 58(m,3H),2.31(t,J=7.3Hz,2H),1.91(p,J=7.5Hz,2H).m / z(ESI-MS):353.0[M+H]+.

[0102] Example 3 Synthesis of Compound 4

[0103]

[0104] Under argon protection, azobisisobutyronitrile (642.0 mg, 3.91 mmol) and allyl tributyltin (4.7 g, 14.2 mmol) were added to a toluene (47 mL) solution of compound 3 (5.0 g, 14.2 mmol) and reacted for 1 hour. The reaction was confirmed to be complete by TLC. The solution was then evaporated to dryness and passed through a column to give compound 4 (3.70 g, 83%). 1 H NMR(400MHz,Chloroform-d)δ7.05(dt,J=7.4,1.1Hz,1H),6.98–6.95(m,1H),6.81(t,J=7.5Hz,1H), 5.80(dddd,J=16.8,10.1,7.8,6.5Hz,1H),5.35–5.30(m,1H),5.21(dq,J=7.5,1.2Hz,1H),5.17(d,J =1.2Hz,1H),3.71(dd,J=8.0,6.8Hz,1H),3.65(s,3H),2.81–2.76(m,2H),2.62–2.55(m,3H),2.43(d ddd,J=8.2,6.3,4.7,1.2Hz,1H),2.35–2.29(m,2H),1.97–1.89(m,2H).m / z(ESI-MS):315.2[M+H]+.

[0105] Example 4 Synthesis of Compound 5

[0106]

[0107] Sodium borohydride (734.0 mg, 19.4 mmol) was added in portions to a methanol solution (30 mL) of compound 4 (6.1 g, 19.4 mmol) and reacted for 1 hour. The reaction was confirmed to be complete by TLC. The mixture was quenched with 2 M hydrochloric acid solution (3 mL), separated into layers, extracted with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 5 (6.0 g, 97%). 1 H NMR(400MHz,Chloroform-d)δ7.19(dt,J=7.4,1.1Hz,1H),7.00(dt,J=7.6,1.0Hz,1H),6.8 5(t,J=7.5Hz,1H),5.38(ddd,J=9.4,7.1,2.4Hz,1H),4.47(tt,J=5.2,3.6Hz,1H),4.25–4. 18(m,2H),3.67(s,3H),2.76(m,J=15.0,6.9,5.3Hz,1H),2.62(m,J=23.6,13.9,7.2Hz,2H) ,2.38–2.19(m,4H),2.10(s,3H),2.08–1.96(m,1H),1.95–1.84(m,1H).m / z(ESI-MS):317.2

[0108] [M+H]+.

[0109] Example 5: Synthesis of Compound 6

[0110]

[0111] Under argon protection, ruthenium carbonyl chloride tris(triphenylphosphine) (1.18 g, 1.24 mmol) was added to a toluene solution (100 mL) of compound 5 (7.8 g, 24.7 mmol) and heated to 100 °C for 2 hours. The reaction was confirmed to be complete by TLC. The mixture was filtered through diatomaceous earth, concentrated, and column chromatography was used to obtain compound 6 (7.5 g, 96%). 1H NMR(400MHz,Chloroform-d)δ7.10–7.02(m,1H),7.00–6.91(m,1H),6.80(t,J=7.4Hz,1 H),5.93(m,1H),5.25–5.12(m,3H),4.03(d,J=5.3Hz,1H),3.67(s,2H),3.48(dd,J=8.6 ,4.8Hz,1H),2.60(m,2H),2.50–2.41(m,1H),2.37–2.20(m,4H),2.10(s,3H),2.05–1.8 6(m,2H),1.79(brs,1H),1.62(brs,1H),1.32–1.26(m,1H).m / z(ESI-MS):317.2[M+H]+.

[0112] Example 6 Synthesis of Compound 7

[0113]

[0114] Triethylamine (0.77 mL, 5.52 mmol) and acetic anhydride (0.52 mL, 5.52 mmol) were added to an anhydrous dichloromethane solution (25 mL) of compound 6 (1.45 g, 4.6 mmol) under argon protection at 0 °C. The reaction was carried out at room temperature for 5 hours. The reaction was confirmed to be complete by TLC. The solution was concentrated and column chromatography was used to obtain compound 7 (1.47 g, 90%). 1 H NMR(400MHz,Chloroform-d)δ7.10–7.02(m,1H),7.00–6.91(m,1H),6.80(t,J=7.4H z,1H),5.66(m,2H),4.03(d,J=5.3Hz,1H),3.67(s,2H),3.48(dd,J=8.6,4.8Hz,1H), 2.90(m,1H),2.60(m,2H),2.37–2.20(m,4H),2.10(s,3H),2.05–1.86(m,2H),1.79(b rs,1H),1.67(m,3H),1.62(brs,1H),1.32–1.26(m,1H).m / z(ESI-MS):359.2[M+H]+.

[0115] Example 7 Synthesis of Compound 8

[0116]

[0117] At 0 °C, under argon protection, potassium osmium dihydrate (23.4 mg, 0.06 mmol), 2,6-dimethylpyridine (0.11 mL, 0.88 mmol), and sodium periodate (2.72 g, 12.72 mmol) were added to a tetrahydrofuran / water solution (4 mL, 3:1) of compound 7 (1.14 g, 3.18 mmol). The mixture was moved to room temperature and reacted for 5 hours. The reaction was confirmed to be complete by TLC. The mixture was quenched with water (10 mL), filtered through diatomaceous earth, extracted with dichloromethane (80 mL × 3), dried and filtered with anhydrous sodium sulfate, and concentrated to obtain compound 8 (0.99 g, 89%). 1 HNMR(400MHz,Chloroform-d)δ9.12(s,1H),7.10–7.02(m,1H),7.00–6.91(m,1H),6 .80(t,J=7.4Hz,1H),4.03(d,J=5.3Hz,1H),3.67(s,2H),3.48(dd,J=8.6,4.8Hz,1H) ,2.60(m,2H),2.50–2.41(m,1H),2.37–2.20(m,4H),2.10(s,3H),2.05–1.86(m,2H) ,1.79(brs,1H),1.67(m,3H),1.62(brs,1H),1.32–1.26(m,1H).m / z(ESI-MS):347.1

[0118] [M+H]+.

[0119] Example 8 Synthesis of Compound 9

[0120]

[0121] Under argon protection, at 0°C, a solution of compound 15 (1.49 g, 6.4 mmol) in THF (5 mL) was slowly added to a solution of sodium hydride (256.0 mg, 6.4 mmol) in THF (5 mL), followed by the dropwise addition of a solution of compound 8 (1.0 g, 2.9 mmol) in tetrahydrofuran (5 mL). The reaction was allowed to proceed at room temperature for approximately 2 hours. The reaction was confirmed to be complete by TLC. The reaction was quenched with saturated ammonium chloride (5 mL), and the THF was removed by concentration under reduced pressure. Ethyl acetate (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The mixture was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 9 (1.05 g, 79%). 1H NMR(300MHz,Chloroform-d)δ7.01–6.91(m,2H),6.89–6.72(m,2H),6.29(dd,J=15.4,4.7Hz,1H),5.31–5.16(m,1H),5.08–4.95(m,1H),3.71 -3.69(m,1H),3.66(s,3H),2.98-2.87(m,2H),2.68–2.55(m,3H),2.52–2.40(m,1H),2.38–2.37(m,3H),2 .21–2.09(m,1H),1.99–1.88m,2H),1.80–1.75(m,5H),1.26–1.26(m,1H),1.22and1.20(d,J=0.8Hz,1.5H and 1.5H,diastereomericCH3.m / z(ESI-MS):453.2[M+H]+.

[0122] Example 9 Synthesis of Compound 10

[0123]

[0124] Compound 9 (2.9 g, 6.4 mmol) was dissolved in methanol (128 mL) at -78 °C. Cerium chloride heptahydrate (2.38 g, 6.4 mmol) was added, followed by the addition of sodium borohydride (242.1 mg, 6.4 mmol) in portions. The reaction was monitored by TLC until complete. The solution was quenched with saturated sodium bicarbonate solution (25.6 mL), filtered through diatomaceous earth, evaporated to dryness with methanol, extracted with ethyl acetate (100 mL × 2), and the organic phases were combined. The solution was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The concentrate was then subjected to column chromatography to obtain compound 10 (2.85 g, 97%). 1H NMR(300MHz,Chloroform-d)δ6.99–6.93(m,2H),6.76(t,J=7.4Hz,1H),5.75–5.59(m,1H),5.30–5.14(m,1H),4.92(q,J=6.0Hz,1H),4.24-4.19and 4.08-4.03(m,0.5H and 0.5H,diastereomeric CH),3.66(s,3H),3.65 -3.60(m,1H),2.87–2.77(m,1H),2.66–2.53(m,3H),2.34(m,2H),2.24(m,1H),2.16–2.02(m,2H),1.93( quint,J=7.4Hz,3H),1.80(q,J=2.4Hz,3H),1.77(s,3H),1.02–0.94(m,3H).m / z(ESI-MS):454.2[M+H]+.

[0125] Example 10 Synthesis of Compound 11

[0126]

[0127] A methanol solution of sodium methoxide (207.4 mg, 3.84 mmol) in methanol was added to a methanol solution of 226 mL containing compound 10 (5.83 g, 12.8 mmol). The reaction was allowed to proceed at room temperature for 3 hours. The reaction was confirmed to be complete by TLC. The reaction was quenched with saturated ammonium chloride solution (10 mL), methanol was removed under reduced pressure, and ethyl acetate (50 mL) was added. The mixture was allowed to separate into two phases. The aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The concentrate was then subjected to column chromatography to give compound 11 (2.4 g, 45%). m / z (ESI-MS): 413.2 [M+H]+. 1H NMR(300MHz,Chloroform-d)δ6.99–6.93(m,2H),6.76(t,J=7.4Hz,1H),5.75–5.59(m,1H),5.30–5.14(m,1H),4.92(q,J=6.0Hz,1H),4.24-4.19and 4.08 -4.03(m,0.5H and 0.5H,diastereomeric CH),3.66(s,3H),3.65 -3.60(m,1H),2.87–2.77(m,1H),2.34(m,2H),2.24(m,1H),2.16–2.02(m,2H),1.93(quint,J= 7.4Hz, 3H), 1.80 (q, J = 2.4Hz, 3H), 1.77 (s, 3H), 1.02–0.94 (m, 3H). m / z (ESI-MS): 413.2[M+H]+.

[0128] Example 11 Synthesis of Compound 12

[0129]

[0130] At 0 °C, 5 mL of an aqueous solution of sodium hydroxide (604.8 mg, 15.12 mmol) was added to a methanol / water (50 mL / 50 mL) solution of compound 11 (2.08 g, 5.04 mmol). The reaction was allowed to proceed at room temperature for 1 hour. The reaction was confirmed to be complete by TLC. The pH was adjusted to 4 with dilute hydrochloric acid, THF was removed under reduced pressure, and ethyl acetate (50 mL) and water (50 mL) were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The concentrate was then subjected to column chromatography to give compound 12 (1.88 g, 94%). m / z (ESI-MS): 413.2 [M+H]+. 1H NMR(300MHz,Chloroform-d)δ6.99–6.93(m,2H),6.76(t,J=7.4Hz,1H),5.75–5.59(m,1H),5.30–5.14(m,1H),4.92(q,J=6.0Hz,1H),4.24-4.19and 4.08 -4.03(m,0.5H and0.5H,diastereomeric CH),3.65 -3.60(m,1H),2.87–2.77(m,1H),2.34(m,2H),2.24(m,1H),2.16–2.02(m,2H),1.93(quint,J= 7.4Hz,3H),1.80(q,J=2.4Hz,3H),1.77(s,3H),1.02–0.94(m,3H).m / z(ESI-MS):399.2[M+H]+.

[0131] Example 12 Synthesis of beraprost sodium

[0132]

[0133] At 0 °C, 50 mL of NaOH aqueous solution (184 mg, 4.6 mmol) was added to a methanol (50 mL) solution of compound 12 (1.85 g, 4.6 mmol). The reaction was allowed to proceed at room temperature for 2 hours, and methanol and water were removed under reduced pressure. The product was then recrystallized from ethyl acetate to give beraprost sodium (1.69 g, 87%). 1 HNMR (MeOD, 400MHz): 6.98–6.95 (m, 2H), 6.73 (t, J = 7.6Hz, 1H), 5.75-5.73 (m, 1H), 5.62-5.57 (m, 1H), 5.0 7(q,J=7.6Hz,1H),4.08(t,J=7.6Hz,0.5H),4.01(t,J=7.6Hz,0.5H),3.91-3.89(m,1H),3.34(t,J=1.6Hz ,1H),2.68-2.65(m,1H),2.61-2.58(m,2H),2.34-2.27(m,2H),2.22-2.18(m,2H),2.17-2.10(m,1H),1.9 1-1.87(m,3H),1.78(d,J=2.4Hz,3H),1.76-1.72(m,1H),1.07(d,J=6.8Hz,1.5H),1.02d,J=6.8Hz,1.5H). m / z(ESI-MS):399.2[M+H]+.

[0134] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing beraprost sodium, comprising the following steps: ； in, * and ** are both in the R configuration, or * and ** are both in the S configuration; when * and ** are both in the R configuration, *** is in the S configuration; when * and ** are both in the S configuration, *** is in the R configuration. Among them, R 1 For R 1-1 R 1-2 R 1-3 Si-, acetyl or benzoyl, R 1-1 R 1-2 and R 1-3 It is independently selected from C1-4 alkyl or phenyl.

2. The method according to claim 1, characterized in that, The method includes the following steps: (1) In a solvent, under alkaline conditions, compound 1 and compound 14 react to form compound 2; (2) In the solvent, under the action of a catalyst, compound 2 undergoes a deprotection reaction to generate compound 3; (3) In the solvent, under the action of azobisisobutyronitrile, compound 3 reacts with tri-n-butylallyltin to generate compound 4; (4) In the solvent, under the action of the reducing agent, compound 4 reacts with the reducing agent to generate compound 5; (5) In the solvent, under the action of a catalyst, compound 5 undergoes double bond displacement to generate compound 6; (6) In a solvent, under the action of an alkali, compound 6 reacts with a hydroxyl protecting agent to generate compound 7; (7) In the solvent, under the action of the oxidation system, compound 7 undergoes a double bond oxidative cleavage reaction to generate compound 8; (8) In a solvent, under the action of a base, compound 8 reacts with compound 15 to form compound 9; (9) In the solvent, under the action of the reducing agent, compound 9 undergoes a reduction reaction to generate compound 10; (10) In a solvent, under alkaline conditions, compound 10 reacts to form compound 11; (11) In a solvent, under the action of a base, compound 11 reacts to form compound 12; (12) In the solvent, under the action of sodium hydroxide, compound 12 reacts to generate compound 13, namely beraprost sodium.

3. The method according to claim 2, characterized in that: In step (1), the solvent is an ether solvent or an amide solvent; In step (1), the base is sodium hydroxide, lithium diisopropylaminohydride, or sodium hydride; the molar ratio of the base to compound 1 is 1 to 1.2:1.

0. The reaction temperature in step (1) is 25℃~40℃.

4. The method according to claim 3, characterized in that: The ether solvent is tetrahydrofuran, diethyl ether, or 1,4-dioxane; the amide solvent is N,N-dimethylformamide or N,N-dimethylacetamide; and the base is lithium diisopropylamino.

5. The method according to claim 2, characterized in that: In step (2), the solvent is one or more of ketone solvents, alcohol solvents, and water; in step (2), the catalyst is hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, pyridine p-toluenesulfonate, camphorsulfonic acid; the molar ratio of the catalyst to compound 2 is 0.1~2.0:1.0; The reaction temperature in step (2) is 30℃~100℃.

6. The method according to claim 5, characterized in that: The ketone solvent is acetone; the alcohol solvent is methanol, ethanol or isopropanol; the catalyst is p-toluenesulfonic acid or pyridine p-toluenesulfonate; the reaction temperature in step (2) is 60~80℃.

7. The method according to claim 2, characterized in that: In step (3), the solvent is a benzene-based solvent or an ether-based solvent; In step (3), the molar ratio of azobisisobutyronitrile to compound 3 is 0.2~0.5:1.

0.

8. The method according to claim 7, characterized in that: The benzene solvent is toluene; the ether solvent is tetrahydrofuran.

9. The method according to claim 2, characterized in that: In step (4), the solvent is an alcohol solvent or an ether solvent; In step (4), the reducing agent is: sodium borohydride, potassium borohydride, lithium borohydride, lithium diisobutylaluminum hydride, lithium tritert-butylaluminum hydride, lithium triethylborohydride or Red-Al; the molar ratio of the reducing agent to compound 4 is 0.8 to 1.0:1.

0.

10. The method according to claim 9, characterized in that: The alcohol solvent is methanol, ethanol or isopropanol; the ether solvent is tetrahydrofuran, diethyl ether or 1,4-dioxane; in step (4), the reducing agent is sodium borohydride.

11. The method according to claim 2, characterized in that: In step (5), the solvent is toluene; the catalyst is Hoveyda-Grubbs second-generation catalyst or carbonyl chloride tris(triphenylphosphine)ruthenium; The molar ratio of the catalyst to compound 5 is 0.01~0.5:1; The reaction temperature in step (5) is 90~110℃.

12. The method according to claim 11, characterized in that: The catalyst is ruthenium carbonyl chloride tris(triphenylphosphine) .

13. The method according to claim 2, characterized in that: In step (6), the solvent is an amide solvent, a nitrile solvent, an ether solvent, or a halocarbon solvent; In step (6), the base is an organic base; the molar ratio of the base to compound 6 is 1.1 to 6.0:1.0; In step (6), the hydroxyl protecting agent is R. 1-1 R 1-2 R 1-3 SiCl, R 1-1 R 1-2 R 1-3 SiOTf, acetic anhydride or benzoic anhydride, wherein R 1 For R 1-1 R 1-2 R 1-3 Si-, acetyl or benzoyl, R 1-1 R 1-2 and R 1-3 Independently selected from C1-4 alkyl or phenyl; The molar ratio of the hydroxyl protectant to compound 6 is 1.0 to 3.0:1.

0.

14. The method according to claim 13, characterized in that: The amide solvent is N,N-dimethylformamide or N,N-dimethylacetamide; the nitrile solvent is acetonitrile; the ether solvent is tetrahydrofuran or 1,4-dioxane; the halocarbon solvent is dichloromethane, chloroform, carbon tetrachloride or dichloroethane; The base is triethylamine; The hydroxyl protecting agent is selected from... , , , , ,or, , ,or, Acetic anhydride or benzoic anhydride.

15. The method according to claim 2, characterized in that: In step (7), the solvent is a mixture of tetrahydrofuran and water; the oxidation system is potassium osmium tetroxide / sodium periodate, osmium tetroxide / sodium periodate, ozone / triphenylphosphine; the molar ratio of the oxidant and compound 7 in the oxidation system is 0.01~0.1:3~6:1; The reaction temperature in step (7) is 0~25℃.

16. The method according to claim 15, characterized in that: The oxidation system is potassium osmium tetroxide / sodium periodate; the molar ratio of the oxidant to compound 7 in the oxidation system is 0.01~0.02:3~4:

1.

17. The method according to claim 2, characterized in that: In step (8), the solvent is an ether solvent or an amide solvent; In step (8), the base is an organic base or an inorganic base; In step (8), the molar ratio of the base to compound 8 is 1.0 to 3.0:1.0; the molar ratio of compound 15 to compound 8 is 1.0 to 3.0:1.

0.

18. The method according to claim 17, characterized in that: The ether solvent is tetrahydrofuran; the amide solvent is N,N-dimethylformamide or N,N-dimethylacetamide; the organic base is selected from triethylamine, DBU, potassium tert-butoxide, n-butyllithium, sodium hexamethyldisilamide, potassium hexamethyldisilamide or lithium hexamethyldisilamide; and the inorganic base is sodium hydrogen.

19. The method according to claim 2, characterized in that: In step (9), the solvent is an ether solvent or an alcohol solvent; In step (9), the reducing agent is: sodium borohydride / cerium trichloride, potassium borohydride, lithium borohydride, boroethane diethyl ether complex, boroethane dimethyl sulfide complex, aminoborane, tert-butylaminoborane, lithium diisobutylaluminum hydride, (-)-diisopinepine chloride borane, sodium borohydride / cobalt chloride, or (R)-B-isopinepine-9-borane bicyclo[3.3.1]nonane; the molar ratio of the reducing agent to compound 9 is 2.0~6.0:1.

0.

20. The method according to claim 19, characterized in that: The ether solvent is tetrahydrofuran; the alcohol solvent is methanol, ethanol or isopropanol.

21. The method according to claim 2, characterized in that: In step (10), the solvent is an alcohol solvent; In step (10), the base is sodium methoxide; the molar ratio of the base to compound 10 is 1:1~4.

22. The method according to claim 21, characterized in that: In step (10), the solvent is methanol, ethanol or isopropanol.

23. A method for preparing intermediate 4 for preparing beraprost sodium, comprising the following steps: ； Under the action of a free radical initiator, compound 3 undergoes a free radical tandem reaction to generate compound 4; wherein... * and ** are both R configurations or * and ** are both S configurations.

24. The method according to claim 23, characterized in that: The method specifically involves reacting compound 3 and tri-n-butylallyltin under the action of azobisisobutyronitrile to generate compound 4; the molar ratio of azobisisobutyronitrile to compound 3 is 0.2~0.5:1.0.

Images