Synthesis method of beraprost

Abstract

The invention provides a synthesis method of beraprost. The synthesis method comprises the following steps: step a), preparing a compound 39 from a compound 30 and a compound 31; step b), preparing a compound 10 from a compound 02 and the compound 39 through a free radical cyclization reaction; and step c): taking the compound 10 as a raw material, and carrying out reduction reaction, deprotection, column chromatography and hydrolysis to obtain a beprostaglandin compound 14. The preparation method disclosed by the invention utilizes the free radical cyclization reaction participated by an organic tin reagent, and realizes efficient and simple synthesis of beprostaglandin with short route and simple operation through a convergent route.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, specifically to a method for synthesizing betaine prostaglandins, and more particularly to a method for the aggregation synthesis of betaine prostaglandins. Background Technology

[0002] Beraprost Sodium, chemically named (±)-2,3,3a,8b-tetrahydro-2-hydroxy-1-(2-hydroxy-4-methyl-1-octen-6-ynyl)-1H-cyclopentano[b]-benzofuran-5-butyrate sodium, was developed by Toray Industries, Inc. of Japan. It is primarily used to improve symptoms such as ulcers, intermittent claudication, pain, and coldness caused by chronic arterial occlusive disease. Commercially available beraprost contains four isomers, with the following structural formulas:

[0003]

[0004] Patent US2017 / 0166545 describes a method for preparing betaine prostaglandins, which involves multiple steps. The reaction from intermediate 03 to intermediate 04 is a noble metal-catalyzed carbon-carbon double bond migration reaction, requiring expensive ruthenium or palladium catalysts. Furthermore, because the reaction is in dynamic equilibrium, the reactants cannot react completely, resulting in homologue impurities that are difficult to separate. The step from intermediate 04 to intermediate 05 is an ozonochemical bond-breaking reaction, which carries certain risks.

[0005]

[0006] Patent US7345181 uses in-situ prepared copper-lithium reagents to introduce side chains. The preparation of copper-lithium reagents requires the use of highly toxic CuCN, which poses a significant challenge to the safety of the reaction. Furthermore, even after introducing the side chains, multiple steps are still required to construct the furan ring.

[0007]

[0008] Patent US5202447 describes a method for preparing betaprosin from cyclopentadiene through bromination, nucleophilic substitution, in-situ Grignard reagent-involved cyclization, Prins reaction, introduction of butyric acid side chain, oxidation, and HWE reaction. This invention route has many reaction steps, especially the conversion of the hydroxyl protecting group, which is inefficient and cumbersome. The lengthy linear steps also lead to a low overall yield.

[0009]

[0010] In summary, although there are many methods available for synthesizing beta-prostaglandins, these processes generally suffer from drawbacks such as long routes and complex operations. Summary of the Invention

[0011] In view of the deficiencies in the prior art, the purpose of this invention is to provide a method for synthesizing beta-prostaglandins.

[0012] The objective of this invention is achieved through the following solution:

[0013] This invention provides a method for synthesizing betaine prostaglandins, comprising the following steps:

[0014] Step b), from compound O2 and compound 39 Compound 10 was prepared by free radical cyclization reaction. The reaction equation is as follows:

[0015]

[0016] Among them, R 1 Selected from methyl, ethyl, propyl, butyl; R 3 Selected from formyl, acetyl, propionyl, benzoyl, isobutyryl, 4-phenylbenzoyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl; R 4 Selected from methyl, ethyl, propyl, butyl, isopropyl, and benzyl;

[0017] Step c) from compound 10 Compound 14 of beta-prostaglandin was prepared from the raw materials.

[0018]

[0019] Preferably, in step b), compounds 02 and 39 are dissolved in an organic solvent, benzoyl peroxide is added, and the mixture is refluxed for 6-8 hours to prepare compound 10. The organic solvent can be a 1:1 volume ratio of n-heptane / toluene, and the benzoyl peroxide is added in two batches. More preferably, the molar ratio of compound 02, compound 39, and benzoyl peroxide is 1.0:(2.0-6.0):(0.01-0.05), and most preferably 1:2:0.05.

[0020] More preferably, the reflux reaction solution is concentrated to dryness and then purified by silica gel column chromatography to obtain compound 10, wherein the silica gel is selected as 200-300 mesh and the elution conditions are PE / EA = 10 / 1 to 5 / 1.

[0021] Preferably, in step c), compound 10 is used to prepare prostaglandin compound 14 via the following reaction route:

[0022]

[0023] The specific steps are as follows:

[0024] (I) Compound 10 is dissolved in an organic solvent, and CeCl3 is added. A reduction reaction occurs under the action of a reducing agent. The resulting reaction solution is quenched and purified to obtain compound 11. The molar ratio of compound 10, CeCl3, and NaBH4 is 1.0:(1.0–1.5):(1.0–1.3), with an optimal ratio of 1:1.2:1. The organic solvent can be MeOH, which is reduced with NaBH4 (added in batches) and the reaction is quenched with an aqueous HCl solution. Subsequent separation and purification steps are as follows: after removing MeOH by vacuum concentration, EA is added for dilution. The organic phase is washed sequentially with H2O, saturated NaHCO3 solution, H2O, and saturated brine. After vacuum concentration, compound 11 is obtained and directly used in the next reaction.

[0025] (II) Compound 11 is dissolved in an organic solvent, NaOMe is added, and the resulting reaction solution is quenched and purified to obtain compound 13. The molar ratio of compound 11 to NaOMe is 1:(0.05–0.3), preferably 1:0.1. The organic solvent can be MeOH, and the reaction time is 16–20 h. Subsequent separation and purification steps are as follows: the reaction is quenched with hydrochloric acid, MeOH is removed by vacuum concentration, the concentrate is dissolved in EA, and the solution is washed successively with H2O and saturated brine. The organic phase is dried with MgSO4, concentrated, and subjected to silica gel (200–300 mesh) column chromatography (PE / EA = 4 / 1–2 / 1–1 / 1) to obtain a syrupy viscous liquid, compound 13.

[0026] (III) Compound 13 was dissolved in an organic solvent, reacted with NaOH solution, and then neutralized with dilute hydrochloric acid. The resulting reaction solution was extracted and concentrated to obtain a solid. The solid was recrystallized from ethyl acetate / n-hexane to obtain compound 14. The organic solvent could be MeOH, the reaction time was 2-4 hours, and the subsequent separation and purification steps were as follows: MeOH was removed by vacuum concentration, the concentrate was extracted with EA, the combined organic phases were washed successively with H2O and saturated brine, dried with MgSO4, and concentrated under vacuum to obtain a foamy solid. The solid was recrystallized from ethyl acetate / n-hexane to obtain a white solid, compound 14.

[0027] Preferably, step a) is included before step b):

[0028] Compound 30 and compound 31 Compound 39 was prepared and obtained Among them, R 1 Selected from methyl, ethyl, propyl, butyl; R 2 Selected from N,O-dimethylhydroxylamine and morpholine; the reaction equation is as follows:

[0029]

[0030] Specifically, in step a), under low temperature conditions, compounds 30 and 31 react in the presence of n-BuLi. The resulting reaction solution is quenched and purified to obtain compound 39. The molar ratio of compounds 30, 31, and n-BuLi is 1.0:(1.0~2.0):(1.0~1.3); the optimal ratio is 1:1:1; the reaction temperature is <-60℃, preferably -70~-80℃, and the reaction time is 2-4 h. Subsequent separation and purification steps involve quenching the reaction with saturated NH4Cl aqueous solution, extracting the reaction solution with methyl ether, washing the combined organic phases with saturated NaCl solution, drying with MgSO4, filtering, concentrating the filtrate under vacuum to dryness, and purifying the residue by silica gel (200~300 mesh) column chromatography (PE / EA=60 / 1~30 / 1) to obtain compound 39.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] 1. The preparation method of the present invention uses compound 39 instead of the traditional allyltin reagent, which increases the yield of free radical cyclization from 30-60% to 80-90%, and at the same time eliminates the need for subsequent dangerous double bond cleavage reaction and preparation of HWE reaction precursor.

[0033] 2. The preparation method of this invention utilizes a free radical cyclization reaction involving organotin reagents, and through a convergent route, achieves the synthesis of beta-prostaglandins in a short, simple, efficient and concise manner. Detailed Implementation

[0034] The present invention will now be described in detail with reference to specific embodiments. These embodiments will help those skilled in the art to further understand the present invention, but do not limit the invention in any way. It should be noted that those skilled in the art can make several changes and improvements without departing from the concept of the present invention. These all fall within the protection scope of the present invention.

[0035] Existing techniques involve radical cyclization with allyl tin reagents to construct benzofuran rings, followed by functional group modification of the double bonds to introduce side chains. Therefore, these methods are generally lengthy and complex. To address this, the present invention modifies the "allyl precursor" to introduce the side chain in advance, achieving furan cyclization and side chain introduction in a single step, thus improving the yield of radical cyclization. Furthermore, it attempts to integrate subsequent linear steps into the radical cyclization reaction, achieving a short, simple, efficient, and concise synthesis of beta-prostaglandins.

[0036]

[0037] Among them, R 1 Selected from methyl, ethyl, propyl, butyl; R2 Selected from N,O-dimethylhydroxylamine, morpholine; R 3 Selected from formyl, acetyl, propionyl, benzoyl, isobutyryl, 4-phenylbenzoyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl; R 4 Selected from methyl, ethyl, propyl, butyl, isopropyl, and benzyl.

[0038] The following uses R 1 Select butyl; R 2 Choose N,O-dimethylhydroxylamine, R 3 Choose acetyl, R 4 Taking methyl ester as an example, the technical solution of the present invention will be further explained.

[0039] The synthesis route is as follows:

[0040]

[0041] Example 1, Synthesis of Compound 39:

[0042] Compound 30 is a commercially available reagent. The synthesis of compound 31 is based on US7345181, and the synthetic route is as follows:

[0043]

[0044] Trans-1,2-bis(tributyltin)ethylene was dissolved in (compound 30, 60.63 g, 100 mmol) in THF (300 mL), and the solution was cooled to -78 °C. n-BuLi (2.5 M in Hexane, 40 mL, 100 mmol) was added dropwise through a constant-pressure dropping funnel, with the internal temperature controlled between -70 and -80 °C during the addition. After the addition was complete, the mixture was stirred at -78 °C for 1 h. Then, N-methoxy-N-methyl-2-methyl-4-ethynylhexamide (compound 39, 16.92 g, 100 mmol) dissolved in THF (50 mL) was added dropwise, with the internal temperature controlled below -60 °C during the addition. After the addition was complete, the reaction mixture was stirred at this temperature for 2 h, and then the reaction was quenched with a saturated NH4Cl aqueous solution (100 mL). The reaction mixture was extracted with tertiary methyl ether (300 mL * 2). The combined organic phases were washed with saturated NaCl solution (200 mL * 2), dried over MgSO4, and filtered. The filtrate was concentrated to dryness under vacuum, and the residue was purified by silica gel (200–300 mesh) column chromatography (PE / EA = 60 / 1–30 / 1) to give 33.47 g of compound 39 as a colorless oil, with a yield of 78.7%.

[0045] The proton NMR data for compound 39 are as follows: 1H NMR (400MHz, CDCl3): δ0.91(t,J=7.4Hz,9H),0.97–1.04(m,6H),1.19(d,J=7.1Hz,3H),1.27–1.35(m,6H),1.47–1.56(m,6H),1.77(t,J=2.7Hz,3 H), 2.24 (ddq, J = 16.5, J = 8.0, J = 2.7Hz, 1H), 2.44 (ddq, J = 16.5, J = 6.0, J = 2.7Hz, 1H), 3.11 (m, 1H), 6.61 (d, J = 19.5Hz, 1H), 7.66 (d, J = 19.5Hz, 1H).

[0046] Example 2, Synthesis of Compound 10:

[0047] The synthesis of compound 02 is based on US2017 / 0166545, and the synthetic route is as follows:

[0048]

[0049] Compound 02 (14.01 g, 35.27 mmol) and compound 39 (30.00 g, 70.55 mmol) were dissolved in a mixed solvent of n-heptane / toluene (140 mL / 140 mL), and benzoyl peroxide (256 mg, 1.06 mmol) was added. The reaction mixture was stirred under vigorous reflux for 3 h, followed by the addition of benzoyl peroxide (171 mg, 0.71 mmol), and reflux was continued for another 3 h. The reaction mixture was cooled to 30–40 °C and concentrated to dryness under vacuum. The residue was purified by silica gel column chromatography (200–300 mesh silica gel, PE / EA = 10 / 1–5 / 1) to give 14.22 g of compound 10 as a colorless oil, with a yield of 89.1%.

[0050] The proton NMR data for compound 10 are as follows: 1H NMR (400MHz, CDCl3): δ1.209and 1.211(d,J=7.0Hz,3H),1.80-1.74(m,6H),1.94(pent.,J=7.6Hz,2H),2.14(ddd,J1=14.4,J2=6.1,J3=3.7Hz,1H),2. 31-2.21(m,1H),2.35(t,J=7.2Hz,2H),2.50-2.40(m,1H),2.68-2.54(m,3H),3.00-2.85(m,2H),3.72-3.62(m,1H),3 .66(s,3H),5.00(ddd,J1=12.2,J2=6.1,J3=4.0Hz,1H),5.24(ddd,J1=J2=7.9,J3=3.6Hz,1H),6.29(ddd,J1=15.7,J2 =5.5, J3=1.0Hz, 1H), 6.77 (dd, J1=J2=7.5Hz, 1H), 6.83 (ddd, J1=15.7Hz, J2=8.4Hz, J3=1.2Hz, 1H), 6.99-6.92 (m, 2H).

[0051] Example 3, Synthesis of Compound 11:

[0052] Compound 10 (12.73 g, 28.13 mmol) was dissolved in MeOH (250 mL), and CeCl3 (8.32 g, 33.76 mmol) was added. After stirring at 25 °C for 0.5 h, NaBH4 (1.07 g, 28.13 mmol) was added in 5 batches, with each batch 10 min apart. After the reaction was complete, 40 mL of 3M HCl aqueous solution was added to quench the reaction. After removing MeOH by vacuum concentration, 120 mL of EA was added for dilution. The organic phase was washed successively with H2O (30 mL), saturated NaHCO3 solution (30 mL * 2), H2O (30 mL), and saturated brine (30 mL). After vacuum concentration, compound 11 was obtained and used directly in the next reaction (theoretical yield 12.79 g).

[0053] Example 4, Synthesis of Compound 13:

[0054] Compound 11 (12.79 g, 28.13 mmol) was dissolved in MeOH (260 mL), and NaOMe (152 mg, 2.81 mmol) was added. The reaction mixture was stirred at 25 °C for 18 h, and then quenched with hydrochloric acid (1 M, 10 mL). The MeOH was removed by concentration under reduced pressure. The concentrate was dissolved in EA (130 mL), washed successively with H₂O (35 mL * 2), saturated brine (35 mL), dried over MgSO₄, concentrated, and subjected to silica gel (200-300 mesh) column chromatography (PE / EA = 4 / 1 ~ 2 / 1 ~ 1 / 1) to give 5.51 g of compound 13 as a syrupy viscous liquid, with a yield of 47.5%.

[0055] The proton NMR data for compound 13 are as follows: 1 H NMR (400MHz, CDCl3): δ1.01and 1.00(d,J=6.9Hz,3H),1.85-1.72(m,4H),2.03-1.87(m,3H),2.18-2.06(m,1H),2. 27-2.20(m,1H),2.38-2.27(m,4H),2.50-2.40(m,1H),2.69-2.55(m,3H),3.45and 3.44(dd,J1=J2=8.4Hz,1H),3.65(s,3H),3.97-3.88(m,1H),4.05(dd,J1=J2=7.1Hz, 0.5H),4.18(dd,J1≈J2=5.5Hz,0.5H),5.15-5.05(m,1H),5.73-5.55(m,2H),6.764and 6.758 (dd, J1=J2=7.4Hz, 1H), 6.99-6.91 (m, 2H).

[0056] Example 5, Synthesis of Compound 14:

[0057] Compound 13 (4.93 g, 11.95 mmol) was dissolved in MeOH (50 mL), and NaOH solution (1.0 M, 23.9 mL) was added. The reaction mixture was stirred at 25 °C for 3 h, and then neutralized with dilute hydrochloric acid (1.0 M, 35.9 mL). The MeOH was removed by concentration under reduced pressure, and the concentrate was extracted with EA (50 mL x 3). The combined organic phases were washed successively with H₂O (30 mL x 3) and saturated brine (30 mL), dried over MgSO₄, and concentrated under reduced pressure to obtain a foamy solid. The solid was recrystallized from ethyl acetate / n-hexane to give 4.08 g of compound 14 as a white solid, with a yield of 85.6%.

[0058] The proton NMR data for compound 14 are as follows: 1¹H NMR (400MHz, CDCl₃): δ 1.02 and 0.99(d,J=6.8Hz,3H),1.84-1.70(m,4H),2.04-1.84(m,3H),2.18-2.04(m,1H) ,2.27-2.18(m,1H),2.33(t,J=7.4Hz,2H),2.42(pent.,J=7.5Hz,1H),2.72-2. 53(m,3H),3.48-3.36(m,1H),3.97-3.86(m,1H),4.03(dd,J1=J2=7.3Hz,0.5H) ,4.16(dd,J1=J2=5.7Hz,0.5H),5.15-5.03(m,1H),5.73-5.51(m,1H),6.76and 6.75(dd,J1=J2=7.4Hz,1H),7.01-6.89(m,2H).

[0059] Specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the specific embodiments described above, and those skilled in the art can make various changes or modifications within the scope of the claims, which do not affect the essence of the present invention. Unless otherwise specified, the embodiments and features described in this application can be arbitrarily combined with each other.

Claims

1. A method for synthesizing prostaglandins, characterized in that, Includes the following steps: Step b), from compound O2 and compound 39 Compound 10 was prepared by free radical cyclization reaction. The reaction equation is as follows: Among them, R 1 Selected from methyl, ethyl, propyl, butyl; R 3 Selected from formyl, acetyl, propionyl, benzoyl, isobutyryl, 4-phenylbenzoyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl; R 4 Selected from methyl, ethyl, propyl, butyl, isopropyl, and benzyl; Step c) from compound 10 Compound 14 of beta-prostaglandin was prepared from the raw materials.

2. The method for synthesizing prostaglandins according to claim 1, characterized in that, In step b), compounds 02 and 39 are dissolved in an organic solvent, benzoyl peroxide is added, and the reaction is carried out to prepare compound 10.

3. The method for synthesizing prostaglandins according to claim 2, characterized in that, The molar ratio of compound 02, compound 39, and benzoyl peroxide is 1.0:(2.0-6.0):(0.01-0.05).

4. The method for synthesizing prostaglandins according to claim 2, characterized in that, In step b), the reaction solution is concentrated to dryness and then purified by silica gel column chromatography to obtain compound 10.

5. The method for synthesizing prostaglandins according to claim 1, characterized in that, Step a) is included before step b): Compound 30 and compound 31 Compound 39 was prepared and obtained Among them, R 1 Selected from methyl, ethyl, propyl, butyl; R 2 Selected from N,O-dimethylhydroxylamine and morpholine; the reaction equation is as follows:

6. The method for synthesizing prostaglandins according to claim 5, characterized in that, In step a), under low temperature conditions, compounds 30 and 31 react under the action of n-BuLi, and the resulting reaction solution is quenched and purified to obtain compound 39.

7. The method for synthesizing betaine prostaglandins according to claim 1, characterized in that, In step c), compound 10 Compound 14 of betaprostaglandin was prepared via the following reaction route.

8. The method for synthesizing prostaglandins according to claim 7, characterized in that, Compound 10 was dissolved in an organic solvent, and CeCl3 was added. A reduction reaction was carried out under the action of a reducing agent. The resulting reaction solution was quenched and purified to obtain compound 11.

9. A method for synthesizing prostaglandins according to claim 7, characterized in that, Compound 11 was dissolved in an organic solvent, NaOMe was added, and the resulting reaction solution was quenched and purified to obtain compound 13.

10. A method for synthesizing betaine prostaglandins according to claim 7, characterized in that, Compound 13 was dissolved in an organic solvent, and NaOH solution was added to react with it. Then, it was neutralized with dilute hydrochloric acid. The resulting reaction solution was extracted and concentrated to obtain a solid. The solid was recrystallized from ethyl acetate / n-hexane to obtain compound 14.

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