Synthesis of a novel prostaglandin analogue

Abstract

The present application relates to a kind of synthetic method of travoprost for treating primary open-angle glaucoma and high eye pressure.The synthetic method is compared with prior art, with cheap and readily available cori ester as raw material, by 7 steps, with shorter route and higher total yield, the chemical synthesis of travoprost is completed.The synthetic method of travoprost described in the present application, its preparation method is simple, intermediate is stable, environmental protection and economy, reaction is easy to control, and the yield of final product travoprost is high, for the artificial synthesis of travoprost provides a new more effective method, while it can also be used to more simply and more high yield preparation of related analogues of travoprost.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic synthesis and pharmaceutical chemistry, in particular to a synthetic method of travoprost. BACKGROUND

[0002] Travoprost is an isopropyl ester derivative of the active compound travoprost free acid, which is a PGF 2α analog that can be used for treating primary open-angle glaucoma and ocular hypertension. Travoprost is stable in nature, and is the first and only preservative-free benzalkonium chloride prostaglandin analog approved by FDA for first-line treatment of glaucoma patients. Travoprost is used in the form of eye drops, and after being administered to the eye, travoprost is hydrolyzed by corneal hydrolytic enzyme into bioactive travoprost free acid, which then selectively stimulates PGFP receptors, thereby increasing the outflow of aqueous humor from the uveal sclera, resulting in a decrease in intraocular pressure. The structure of travoprost is as follows:

[0003]

[0004] The prior art of the reported travoprost bulk drug preparation method has defects such as long route, high production cost, low product purity, and high total impurity content, which cannot meet the quality standard requirements of pharmaceutical bulk drugs.

[0005] In order to overcome the above-mentioned defects, there is an urgent need for a new synthetic process of travoprost which is simple to operate, stable in intermediates, environmentally friendly and economical, and easy to control reaction. SUMMARY

[0006] Based on this, the purpose of the present application is to provide a synthetic method of travoprost.

[0007] To achieve the above-mentioned purpose of the application, the specific technical scheme is as follows:

[0008] A synthetic method of travoprost, the synthetic route is as follows:

[0009]

[0010] The synthetic method comprises the following steps:

[0011] (1) In an organic solvent, coriolin lactone 1 reacts with alkylsilyl chloride under the action of a base for 1-10 hours, and then weak acid is added to obtain compound 2, the reaction temperature is-10℃-50℃, and the molar ratio of coriolin lactone 1 to alkylsilyl chloride is 1.0:1.0-10.0;

[0012] (2) In an organic solvent, compound 2 reacts with an oxidizing agent for 1-20 hours to obtain compound 3, the reaction temperature is 0℃-50℃, and the molar ratio of compound 2 to the oxidizing agent is 1.0:1.0-5.0;

[0013] (3) Compound 3 is reacted with [2-oxo-3-(3-trifluoromethylphenoxy)propyl)] dimethyl phosphate in an organic solvent in the presence of a base for 1-10 hours to obtain compound 4, the reaction temperature is -78-0°C, and the molar ratio of compound 3, [2-oxo-3-(3-trifluoromethylphenoxy)propyl)] dimethyl phosphate and the base is 1.0:1.0-5.0:1.0-5.0;

[0014] (4) Compound 4 is reacted with a chiral reducing agent in an organic solvent for 1-20 hours to obtain compound 5, the reaction temperature is -78- room temperature, and the molar ratio of compound 4 and the chiral reducing agent is 1.0:1.0-5.0;

[0015] (5) Compound 5 is reacted with a reducing agent in an organic solvent for 1-10 hours to obtain the reduction product compound 6, the reaction temperature is -78-0°C, and the molar ratio of compound 5 and the reducing agent is 1.0:1.0-5.0;

[0016] (6) Compound 6 is reacted with isopropyl bromopentanoate triphenylphosphonium salt in an organic solvent for 1-15 hours to obtain compound 7, the reaction temperature is -78-0°C, and the molar ratio of compound 6 and isopropyl bromopentanoate triphenylphosphonium salt is 1.0:1.0-5.0;

[0017] (7) Compound 7 is reacted with an acid in an organic solvent for 1-10 hours to remove the silicon protecting group to obtain compound 8, the reaction temperature is 0-40°C, and the molar ratio of compound 7 and the acid is 1.0:1.0-5.0.

[0018] In some embodiments, the reaction time of the reaction described in step 1 is 1-10 hours, the reaction temperature is -10°C-50°C, the molar ratio of coriolic acid 1 and alkylsilyl chloride is 1.0:1.0-10.0; the reaction time of the reaction described in step 2 is 1-20 hours, the reaction temperature is 0°C-50°C, the molar ratio of compound 2 and oxidant is 1.0:1.0-5.0; the reaction time of the reaction described in step 3 is 1-10 hours, the reaction temperature is 0°C-50°C, the molar ratio of compound 3, [2-oxo-3-(3-trifluoromethylphenoxy)propyl)] dimethyl phosphate and base is 1:1.0-5.0:1.0-5.0; the reaction time of the reaction described in step 4 is 1-20 hours, the reaction temperature is -78°C to room temperature, the molar ratio of compound 4 and chiral reducing agent is 1.0:1.0-5.0; the reaction time of the reaction described in step 5 is 1-10 hours, the reaction temperature is -78°C-0°C, the molar ratio of compound 5 and reducing agent is 1.0:1.0-5.0; the reaction time of the reaction described in step 6 is 1-15 hours, the reaction temperature is -78°C-0°C, the molar ratio of compound 6 and isopropyl bromopentanoate triphenylphosphonium salt is 1.0:1.0-5.0; the reaction time of the reaction described in step 7 is 1-10 hours, the reaction temperature is 0°C-40°C, the molar ratio of compound 7 and acid is 1.0:1.0-5.0.

[0019] In some embodiments, the organic solvent is dichloromethane, tetrahydrofuran, dimethylformamide, dimethylacetamide, ethylene glycol dimethyl ether, 1,2-dichloroethane, dimethyl sulfoxide, toluene, methanol, ethanol, acetonitrile, petroleum ether, 2,2,2-trifluoroethanol, n-hexane or diethyl ether.

[0020] In some embodiments, the organic solvent in steps (1), (2) and (7) is dichloromethane, the organic solvent in steps (3), (4) and (6) is tetrahydrofuran, and the organic solvent in step (5) is toluene.

[0021] In some embodiments, the alkylsilyl chloride in step (1) is tert-butyldimethylsilyl chloride, or triethylsilyl chloride, or trimethylsilyl chloride, or tert-butyldiphenylsilyl chloride.

[0022] In some embodiments, the oxidizing agent in step (2) is Dess-Martin reagent, active manganese dioxide, sodium hypochlorite, PCC or PDC.

[0023] In some embodiments, the reaction in step (3) is carried out under the condition of inert gas protection, and the base is sodium hydride, potassium tert-butoxide, n-butyllithium, lithium chloride, sodium hexamethyldisilylamide (NaHMDS), potassium hexamethyldisilylamide (KHMDS).

[0024] In some embodiments, the reaction in step (6) is carried out under inert gas protection, and the base is sodium hydride, potassium tert-butoxide, n-butyllithium, sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS).

[0025] In some embodiments, the acid in step (7) is trifluoroacetic acid, aluminum trichloride, hydrochloric acid, p-toluenesulfonic acid, hydrofluoric acid, pyridine hydrofluoric acid, sulfuric acid or nitric acid.

[0026] Compared with the prior art, the present application has the following beneficial effects:

[0027] (1) The synthetic method of the present application uses cheap and readily available coriary lactone as the initial raw material to synthesize fluproquensone through 7 steps, which is simple to operate, stable in intermediate, environmentally friendly and economical, and easy to control the reaction.

[0028] (2) In the synthesis of intermediate 5 in step 4, a chiral reducing agent (-)-diisopinocamphylchloroborane is used, which will not produce isomers, and no protecting group needs to be introduced in the subsequent reaction, reducing the post-treatment and thus reducing the introduction of impurities.

[0029] (3) In the synthesis of intermediate 7 in step 6, an isopropyl ester-terminated side chain is directly introduced on the second side chain, and no subsequent esterification reaction is needed, making the synthetic route more simple, more in line with the requirements of green chemistry, and reducing the introduction of impurities, and the product is easy to separate.

[0030] (4) The overall yield of the final product fluproquensone is high, providing a new and more effective method for the artificial synthesis of fluproquensone, and also can be used to more simply and more highly yield related analogs of fluproquensone. DETAILED DESCRIPTION

[0031] The present application will be further described below in conjunction with specific examples.

[0032] In the following examples, the conventional post-treatment method is: after the reaction is completed, an appropriate amount of organic solvent and water is added to the reaction liquid, the organic phase and the aqueous phase are separated, and the organic phases are combined. If necessary, the organic phase is washed with saturated brine in sequence, then dried with anhydrous Na2SO4, filtered and then rotary evaporated under reduced pressure to obtain the crude product, which is then separated and purified by column chromatography to obtain the final product.

[0033] Synthesis of compound

[0034] ​TBSCl (26.3 g, 175 mmol, 3.0 eq) and imidazole (12.5 g, 180 mmol, 3.0 eq) were added to a solution of corinolone (10 g, 58.1 mmol) in dichloromethane (100 mL). The mixture was reacted at room temperature for 8 h, filtered, and 10% hydrochloric acid solution (50 mL) was added to the organic phase. The mixture was then reacted at room temperature for 5 h, quenched with saturated ammonium chloride solution (100 mL), concentrated, and then dichloromethane (100 mL) and water (100 mL) were added. The mixture was allowed to stand for separation, and the aqueous phase was extracted with dichloromethane (100 mL x 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and recrystallized from ethyl acetate (100 mL) to give a white solid compound 2a (13.6 g, 82%). 1 H NMR (400MHz, CDCl3): δ4.35 (brs, OH), 4.25 (dd, J=9.3Hz, J=2.4Hz, 1H), 3.65 (m, 1H), 3.61 (m, 1H), 3.41 ( m, 1H), 2.38-2.20 (m, 3H), 1.80-1.83 (m, 2H), 1.45 (m, 1H), 0.98 (s, 9H), 0.19 (s, 6H)ppm.MS (m / z): 287 (M + +1).

[0035] compound Synthesis

[0036] At 0°C, a solution of compound 2a (8.53 g, 30 mmol) in dichloromethane (150 ml) was added with Dess-Martin oxidant (19.1 g, 45 mmol, 1.5 eq), and the reaction was allowed to proceed overnight at room temperature. The reaction was quenched with saturated ammonium chloride solution (100 ml), concentrated, and then dichloromethane (100 ml) and water (100 ml) were added. The mixture was allowed to stand for separation, and the aqueous phase was extracted with dichloromethane (100 ml * 3), washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid compound 3a (8.19 g, 96%). 1 H NMR (400MHz, CDCl3): δ9.72 (s, 1H), 5.03 (t, J=6.0Hz, 1H), 4.59-4.56 (m, 1H), 3.37-3.33 (m, 1H), 2.97-2.85 ( m, 2H), 2.54-2.47 (m, 1H), 2.16-2.12 (m, 1H), 1.89-1.81 (m, 1H), 0.82 (s, 9H), 0.10 (s, 6H)ppm.MS (m / z): 285 (M + +1).

[0037] compound Synthesis

[0038] Under argon protection, dimethyl 2-oxo-3-(3-trifluoromethylphenoxy)propyl) phosphate (9.79 g, 30 mmol, 1.0 eq) and potassium carbonate (12.5 g, 90 mmol, 3.0 eq) were added sequentially to anhydrous THF (100 ml) and reacted at room temperature for 1 h. Then, a THF (75 ml) solution of compound 3a (8.52 g, 30 mmol, 1 eq) was added dropwise and reacted overnight at -20 °C. The mixture was concentrated, and ethyl acetate (100 ml) and water (50 ml) were added. The mixture was allowed to stand and separate into layers. The aqueous phase was extracted with ethyl acetate (100 ml * 2), washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, and concentrated to give a white solid compound 4a (12.49 g, 86%). 1 H NMR (400MHz, CDCl3): δ7.45 (dd, J=8.2, 7.6Hz, 1H), 7.25 (d, J=7.6, 5.8Hz, 1H), 7.11 (s, 1H), 7.04 (dd, J=8.2, 5.8Hz, 1H), 5.49 (m, 1H), 5.35 (m, 1H), 4 .42(m, 1H), 4.01(m, 1H), 3.80(m, 1H), 3.51(m, 1H), 2.39(m, 1H), 2.21(m, 2 H), 2.10(m, 2H), 1.50(m, 1H), 0.97(s, 9H), 0.21(s, 6H)ppm.MS(m / z): 485(M + +1).

[0039] compound Synthesis

[0040] Under argon protection, at -50°C, (-)-diisopinepine chloroborane (10.6 mL, 18 mmol, 1.7 M solution in Heptane, 1.2 eq) was added dropwise to a THF (100 mL) solution of compound 4a (9.0 g, 15 mmol, 1.0 eq) and then reacted at -50°C for 6 h. The reaction was quenched with saturated ammonium chloride solution (50 mL), concentrated, and then ethyl acetate (100 mL) and water (50 mL) were added. The mixture was allowed to stand for separation, and the aqueous phase was extracted with ethyl acetate (100 mL * 2), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 5a (5.91 g, 81%). 1H NMR (400 MHz, CDC13): δ 7.41 (dd, J = 8.2, 7.6 Hz, 1 H), 7.23 (d, J = 7.6, 5.8 Hz, 1 H), 7.14 (s, 1 H), 7.01 (dd, J = 8.2, 5.8 Hz, 1 H), 5.46 (m, 1 H), 5.31 (m, 1 H), 4.91 (m, 1 H), 4.47 (m, 1 H), 4.09 (m, 1 H), 3.81 (m, 1 H), 3.53 (m, 1 H), 2.36 (m, 1 H), 2.28 (m, 2 H), 2.11 (m, 2 H), 1.53 (m, 1 H), 0.96 (s, 9 H), 0.23 (s, 6 H) ppm. MS (m / z): 487 (M + +1).

[0041] Compound Synthesis of

[0042] To a solution of compound 5a (4.9 g, 10 mmol, 1.0 eq) in toluene (70 ml) was added DIBALH (7.5 ml, 30 mmol, 4 M solution in THF, 3.0 eq) at -20 °C under argon protection, the reaction was stirred for 3 h, quenched with saturated ammonium chloride solution (50 ml), concentrated, ethyl acetate (100 ml) and water (50 ml) were added, the mixture was allowed to stand to separate the layers, the aqueous phase was extracted with ethyl acetate (100 ml*2), washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, concentrated to give compound 6a (4.69 g, 96%). 1 H NMR (400 MHz, CDC13): δ 7.41 (dd, J = 8.2, 7.6 Hz, 1 H), 7.23 (d, J = 7.6, 5.8 Hz, 1 H), 7.14 (s, 1 H), 7.01 (dd, J = 8.2, 5.8 Hz, 1 H), 5.46 (m, 1 H), 5.31 (m, 1 H), 4.91 (m, 1 H), 4.47 (m, 1 H), 4.09 (m, 1 H), 3.81 (m, 1 H), 3.53 (m, 1 H), 2.36 (m, 1 H), 2.28 (m, 2 H), 2.11 (m, 2 H), 1.53 (m, 1 H), 0.96 (s, 9 H), 0.23 (s, 6 H) ppm. MS (m / z): 487 (M + +1).

[0043] Compound Synthesis of

[0044] To a solution of compound 6a (4.9 g, 10 mmol) in THF (100 ml) was added successively isopropyl bromoacetate triphenylphosphonium salt (7.28 g, 15 mmol), potassium tert-butoxide (3.36 g, 30 mmol, 2.0 eq), and the reaction was stirred at -78 °C for 7 h. The reaction was quenched with saturated ammonium chloride solution (20 ml), concentrated, and ethyl acetate (50 ml) and water (20 ml) were added. The mixture was allowed to stand to separate into layers, and the aqueous phase was extracted with ethyl acetate (50 ml*2). The combined organic phase was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated to give compound 7a (5.35 g, 87%). 1 H NMR (400 MHz, CDC13): δ 7.42 (dd, J = 8.2, 7.6 Hz, 1H), 7.25 (d, J = 7.6, 5.8 Hz, 1H), 7.16 (s, 1H), 7.10 (dd, J = 8.2, 5.8 Hz, 1H), 5.86 (dddd, J = 15.4, 15.4, 9.1, 7.7 Hz, 2H), 5.43 (dt, J = 18.1, 7.3 Hz, 1H), 5.33 (dt, J = 18.1, 7.1 Hz, 1H), 4.98 (sept, J = 6.3 Hz, 1H), 4.61 (m, 1H), 4.15 (m, 1H), 4.07 (dd, J = 9.2 3.6 Hz, 1H), 3.98 (dd, J = 9.2, 7.4 Hz, 1H), 2.77 (ddd, J = 11.2, 7.2, 1.3 Hz, 1H), 2.70 (m, 1H), 2.54-2.48 (m, 1H), 2.44-2.32 (m, 2H), 2.28-2.21 (m, 3H), 2.17 (m, 1H), 2.10-1.99 (m, 2H), 1.68-1.59 (m, 2H), 1.52 (m, 1H), 1.21 (d, J = 6.3 Hz, 6H), 0.98 (s, 9H), 0.21 (s, 6H) ppm. MS (m / z): 615 (M + +1).

[0045] Synthesis of compound

[0046] To a solution of compound 7a (1.2 g, 2.0 mmol) in dichloromethane (50 ml) was added hydrofluoric acid (10 ml) under argon protection, and the reaction was stirred at room temperature for 8 h. The reaction was quenched with saturated ammonium chloride solution (20 ml), and the mixture was allowed to stand to separate into layers. The aqueous phase was extracted with dichloromethane (20 ml*2), and the combined organic phase was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated to give compound 8 (1.0 g, 100%). 1 ​H NMR (400 MHz, CDC13): δ 7.43 (dd, J = 8.2, 7.6 Hz, 1 H), 7.26 (d, J = 7.6, 5.8 Hz, 1 H), 7.17 (s, 1 H), 7.11 (dd, J = 8.2, 5.8 Hz, 1 H), 5.87 (dddd, J = 15.4, 15.4, 9.1, 7.7 Hz, 2 H), 5.44 (dt, J = 18.1, 7.3 Hz, 1 H), 5.34 (dt, J = 18.1, 7.1 Hz, 1 H), 4.99 (sept, J = 6.3 Hz, 1 H), 4.62 (m, 1 H), 4.16 (m, 1 H), 4.08 (dd, J = 9.2 3.6 Hz, 1 H), 3.99 (dd, J = 9.2, 7.4 Hz, 1 H), 2.78 (ddd, J = 11.2, 7.2, 1.3 Hz, 1 H), 2.71 (m, 1 H), 2.55-2.49 (m, 1 H), 2.45-2.33 (m, 2 H), 2.29-2.22 (m, 3 H), 2.18 (m, 1 H), 2.11-2.00 (m, 2 H), 1.69-1.60 (m, 2 H); 1.53 (m, 1 H), 1.22 (d, J = 6.3 Hz, 6 H) ppm. MS (m / z): 501 (M + +1).

[0047] Compound Synthesis of

[0048] Method as before. 1 H NMR (400 MHz, CDC13): δ 7.43 (dd, J = 8.2, 7.6 Hz, 1 H), 7.26 (d, J = 7.6, 5.8 Hz, 1 H), 7.17 (s, 1 H), 7.11 (dd, J = 8.2, 5.8 Hz, 1 H), 5.87 (dddd, J = 15.4, 15.4, 9.1, 7.7 Hz, 2 H), 5.44 (dt, J = 18.1, 7.3 Hz, 1 H), 5.34 (dt, J = 18.1, 7.1 Hz, 1 H), 4.99 (sept, J = 6.3 Hz, 1 H), 4.62 (m, 1 H), 4.16 (m, 1 H), 4.08 (dd, J = 9.2 3.6 Hz, 1 H), 3.99 (dd, J = 9.2, 7.4 Hz, 1 H), 2.78 (ddd, J = 11.2, 7.2, 1.3 Hz, 1 H), 2.71 (m, 1 H), 2.55-2.49 (m, 1 H), 2.45-2.33 (m, 2 H), 2.29-2.22 (m, 3 H), 2.18 (m, 1 H), 2.11-2.00 (m, 2 H), 1.69-1.60 (m, 2 H); 1.53 (m, 1 H), 1.22 (d, J = 6.3 Hz, 6 H) ppm. MS (m / z): 501 (M + +1).

[0049] Compound Synthesis of

[0050] Method as before. 1H NMR (400 MHz, CDC13): δ 9.71 (s, 1 H), 4.15 (dd, J = 9.2 Hz, J = 2.5 Hz, 1 H), 3.58 (m, 1 H), 2.37-2.12 (m, 4 H), 2.05-1.83 (m, 2 H), 0.96 (t, J = 6.6 Hz, 9 H), 0.67 (q, J = 6.6 Hz, 6 H) ppm. MS (m / z): 285 (M + +1).

[0051] Compound Synthesis of

[0052] Method as before. 1 H NMR (400 MHz, CDC13): δ 7.41 (dd, J = 8.2, 7.6 Hz, 1 H), 7.21 (d, J = 7.6, 5.8 Hz, 1 H), 7.12 (s, 1 H), 7.04 (dd, J = 8.2, 5.8 Hz, 1 H), 5.50 (m, 1 H), 5.35 (m, 1 H), 4.41 (m, 1 H), 4.02 (m, 1 H), 3.81 (m, 1 H), 3.55 (m, 1 H), 2.35 (m, 1 H), 2.22 (m, 2 H), 2.11 (m, 2 H), 1.51 (m, 1 H), 0.96 (t, J = 6.6 Hz, 9 H), 0.66 (q, J = 6.6 Hz, 6 H) ppm. MS (m / z): 485 (M + +1).

[0053] Compound Synthesis of

[0054] Method as before. 1 H NMR (400 MHz, CDC13): δ 7.44 (dd, J = 8.2, 7.6 Hz, 1 H), 7.23 (d, J = 7.6, 5.8 Hz, 1 H), 7.13 (s, 1 H), 7.06 (dd, J = 8.2, 5.8 Hz, 1 H), 5.44 (m, 1 H), 5.31 (m, 1 H), 4.91 (m, 1 H), 4.47 (m, 1 H), 4.05 (m, 1 H), 3.83 (m, 1 H), 3.51 (m, 1 H), 2.36 (m, 1 H), 2.25 (m, 2 H), 2.10 (m, 2 H), 1.53 (m, 1 H), 0.95 (t, J = 6.6 Hz, 9 H), 0.66 (q, J = 6.6 Hz, 6 H) ppm. MS (m / z): 487 (M + +1).

[0055] Compound Synthesis of

[0056] Method same as above. 1 H NMR (400 MHz, CDC13): δ 7.42 (dd, J = 8.2, 7.6 Hz, 1 H), 7.21 (d, J = 7.6, 5.8 Hz, 1 H), 7.11 (s, 1 H), 7.04 (dd, J = 8.2, 5.8 Hz, 1 H), 5.80 (m, 1 H), 5.43 (m, 1 H), 5.33 (m, 1 H), 4.92 (m, 1 H), 4.44 (m, 1 H), 4.06 (m, 1 H), 3.81 (m, 1 H), 3.55 (m, 1 H), 2.32 (m, 1 H), 2.21 (m, 2 H), 2.17 (m, 2 H), 1.52 (m, 1 H), 0.95 (t, J = 6.6 Hz, 9 H), 0.65 (q, J = 6.6 Hz, 6 H) ppm. MS (m / z): 489 (M + + 1).

[0057] Synthesis of compound

[0058] Method same as above. 1 H NMR (400 MHz, CDC13): δ 7.42 (dd, J = 8.2, 7.6 Hz, 1 H), 7.21 (d, J = 7.6, 5.8 Hz, 1 H), 7.11 (s, 1 H), 7.04 (dd, J = 8.2, 5.8 Hz, 1 H), 5.80 (m, 1 H), 5.43 (m, 1 H), 5.33 (m, 1 H), 4.92 (m, 1 H), 4.44 (m, 1 H), 4.06 (m, 1 H), 3.81 (m, 1 H), 3.55 (m, 1 H), 2.32 (m, 1 H), 2.21 (m, 2 H), 2.17 (m, 2 H), 1.52 (m, 1 H), 0.95 (t, J = 6.6 Hz, 9 H), 0.65 (q, J = 6.6 Hz, 6 H) ppm. MS (m / z): 489 (M + + 1).

[0059] Synthesis of compound

[0060] ​​Method as before. 1 H NMR (400 MHz, CDC13): δ 4.23 (br s, OH), 4.11 (dd, J = 9.2 Hz, J = 2.3 Hz, 1H), 3.54-3.31 (m, 3H), 2.37-2.07 (m, 3H), 1.80-1.78 (m, 2H), 1.41 (m, 1H), 0.20 (s, 9H) ppm. MS (m / z): 245 (M + +1).

[0061] Synthesis of compound

[0062] Method as before. 1 H NMR (400 MHz, CDC13): δ 9.69 (s, 1H), 4.11 (dd, J = 9.0 Hz, J = 2.4 Hz, 1H), 3.55 (m, 1H), 2.35-2.10 (m, 4H), 2.03-1.80 (m, 2H), 0.20 (s, 9H) ppm. MS (m / z): 243 (M + +1).

[0063] Synthesis of compound

[0064] Method as before. 1 H NMR (400 MHz, CDC13): δ 7.41 (dd, J = 8.2, 7.6 Hz, 1H), 7.21 (d, J = 7.6, 5.8 Hz, 1H), 7.12 (s, 1H), 7.04 (dd, J = 8.2, 5.8 Hz, 1H), 5.50 (m, 1H), 5.35 (m, 1H), 4.41 (m, 1H), 4.02 (m, 1H), 3.81 (m, 1H), 3.55 (m, 1H), 2.35 (m, 1H), 2.22 (m, 2H), 2.11 (m, 2H), 1.51 (m, 1H), 0.20 (s, 9H) ppm. MS (m / z): 443 (M + +1).

[0065] Synthesis of compound

[0066] Method as before. 1 ​​​H NMR (400 MHz, CDC13): δ 7.44 (dd, J = 8.2, 7.6 Hz, 1 H), 7.23 (d, J = 7.6, 5.8 Hz, 1 H), 7.13 (s, 1 H), 7.06 (dd, J = 8.2, 5.8 Hz, 1 H), 5.44 (m, 1 H), 5.31 (m, 1 H), 4.91 (m, 1 H), 4.47 (m, 1 H), 4.06 (m, 1 H), 3.83 (m, 1 H), 3.58 (m, 1 H), 2.36 (m, 1 H), 2.25 (m, 2 H), 2.10 (m, 2 H), 1.53 (m, 1 H), 0.21 (s, 9 H) ppm. MS (m / z): 445 (M + +1).

[0067] Compound Synthesis of

[0068] Method as before. 1 H NMR (400 MHz, CDC13): δ 7.42 (dd, J = 8.2, 7.6 Hz, 1 H), 7.21 (d, J = 7.6, 5.8 Hz, 1 H), 7.11 (s, 1 H), 7.01 (dd, J = 8.2, 5.8 Hz, 1 H), 5.80 (m, 1 H), 5.43 (m, 1 H), 5.33 (m, 1 H), 4.92 (m, 1 H), 4.44 (m, 1 H), 4.06 (m, 1 H), 3.81 (m, 1 H), 3.55 (m, 1 H), 2.32 (m, 1 H), 2.21 (m, 2 H), 2.17 (m, 2 H), 1.52 (m, 1 H), 0.20 (s, 9 H) ppm. MS (m / z): 447 (M + +1).

[0069] Compound Synthesis of

[0070] Method as before. 1H NMR (400 MHz, CDC13): δ 7.46 (dd, J = 8.2, 7.6 Hz, 1 H), 7.25 (d, J = 7.6, 5.8 Hz, 1 H), 7.16 (s, 1 H), 7.11 (dd, J = 8.2, 5.8 Hz, 1 H), 5.87 (dddd, J = 15.4, 15.4, 9.1, 7.7 Hz, 2 H), 5.43 (dt, J = 18.1, 7.3 Hz, 1 H), 5.33 (dt, J = 18.1, 7.1 Hz, 1 H), 4.98 (sept, J = 6.3 Hz, 1 H), 4.61 (m, 1 H), 4.16 (m, 1 H), 4.07 (dd, J = 9.2 3.6 Hz, 1 H), 3.98 (dd, J = 9.2, 7.4 Hz, 1 H), 2.78 (ddd, J = 11.2, 7.2, 1.3 Hz, 1 H), 2.71 (m, 1 H), 2.54-2.48 (m, 1 H), 2.44-2.32 (m, 2 H), 2.28-2.21 (m, 3 H), 2.17 (m, 1 H), 2.10-1.99 (m, 2 H), 1.68-1.59 (m, 2 H); 1.52 (m, 1 H), 1.22 (d, J = 6.3 Hz, 6 H), 0.22 (s, 9 H) ppm. MS (m / z): 573 (M + +1).

[0071] Compound Synthesis of

[0072] Method as before. 1 H NMR (400 MHz, CDC13): δ 7.60-7.36 (m, 10 H), 4.36 (br s, OH), 4.27 (dd, J = 9.2 Hz, J = 2.4 Hz, 1 H), 3.67 (m, 1 H), 3.63 (m, 1 H), 3.42 (m, 1 H), 2.39-2.22 (m, 3 H), 1.81-1.85 (m, 2 H), 1.47 (m, 1 H), 0.99 (s, 9 H) ppm. MS (m / z): 411 (M + +1).

[0073] Compound Synthesis of

[0074] Method as before. 1H NMR (400 MHz, CDC13): δ 9.75 (s, IH), 7.60-7.36 (m, 10H), 4.29 (dd, J = 9.6 Hz, J = 2.6 Hz, IH), 3.69 (m, IH), 2.43-2.19 (m, 4H), 2.06-1.85 (m, 2H), 1.47 (m, IH), 0.99 (s, 9H) ppm. MS (m / z): 409 (M + +1).

[0075] Compound Synthesis of

[0076] Method as before. 1 H NMR (400 MHz, CDC13): δ 7.61-7.35 (m, 10H), 7.41 (dd, J = 8.2, 7.6 Hz, IH), 7.21 (d, J = 7.6, 5.8 Hz, IH), 7.12 (s, IH), 7.04 (dd, J = 8.2, 5.8 Hz, IH), 5.50 (m, IH), 5.35 (m, IH), 4.41 (m, IH), 4.02 (m, IH), 3.81 (m, IH), 3.55 (m, IH), 2.35 (m, IH), 2.22 (m, 2H), 2.11 (m, 2H), 1.51 (m, IH), 0.90 (s, 9H) ppm. MS (m / z): 609 (M + +1).

[0077] Compound Synthesis of

[0078] Method as before. 1 H NMR (400 MHz, CDC13): δ 7.62-7.31 (m, 10H), 7.44 (dd, J = 8.2, 7.6 Hz, IH), 7.23 (d, J = 7.6, 5.8 Hz, IH), 7.13 (s, IH), 7.06 (dd, J = 8.2, 5.8 Hz, IH), 5.44 (m, IH), 5.31 (m, IH), 4.91 (m, IH), 4.48 (m, IH), 4.06 (m, IH), 3.85 (m, IH), 3.58 (m, IH), 2.36 (m, IH), 2.26 (m, 2H), 2.10 (m, 2H), 1.53 (m, IH), 0.91 (s, 9H) ppm. MS (m / z): 611 (M + +1).

[0079] Compound Synthesis of

[0080] Method as before. 1H NMR (400 MHz, CDC13): δ 7.61-7.30 (m, 10H), 7.45 (dd, J = 8.2, 7.6 Hz, IH), 7.21 (d, J = 7.6, 5.8 Hz, IH), 7.12 (s, IH), 7.02 (dd, J = 8.2, 5.8 Hz, IH), 5.80 (m, IH), 5.43 (m, IH), 5.33 (m, IH), 4.92 (m, IH), 4.44 (m, IH), 4.06 (m, IH), 3.81 (m, IH), 3.55 (m, IH), 2.36 (m, IH), 2.21 (m, 2H), 2.17 (m, 2H), 1.52 (m, IH), 0.91 (s, 9H) ppm. MS (m / z): 613 (M + +1).

[0081] Compound Synthesis

[0082] Method as before. 1 H NMR (400 MHz, CDC13): δ 7.65-7.33 (m, 10H), 7.46 (dd, J = 8.2, 7.6 Hz, IH), 7.25 (d, J = 7.6, 5.8 Hz, IH), 7.17 (s, IH), 7.13 (dd, J = 8.2, 5.8 Hz, IH), 5.87 (dddd, J = 15.4, 15.4, 9.1, 7.7 Hz, 2H), 5.43 (dt, J = 18.1, 7.3 Hz, IH), 5.33 (dt, J = 18.1, 7.1 Hz, IH), 4.98 (sept, J = 6.3 Hz, IH), 4.64 (m, IH), 4.16 (m, IH), 4.07 (dd, J = 9.2 3.6 Hz, IH), 3.98 (dd, J = 9.2, 7.4 Hz, IH), 2.71 (ddd, J = 11.2, 7.2, 1.3 Hz, IH), 2.71 (m, IH), 2.54-2.48 (m, IH), 2.44-2.32 (m, 2H), 2.28-2.21 (m, 3H), 2.17 (m, IH), 2.10-1.99 (m, 2H), 1.68-1.59 (m, 2H); 1.52 (m, IH), 1.22 (d, J = 6.3 Hz, 6H), 0.93 (s, 9H) ppm. MS (m / z): 739 (M + +1).

[0083] Any combination of the technical features in the above-described embodiments can be made, and for the sake of brevity, not all possible combinations are described, however, as long as the combination of the technical features does not exist in contradiction, it shall be considered within the scope of the present disclosure.

[0084] The above-described embodiments only express several implementation manners of the present application, and the description is relatively specific and detailed, but it shall not be understood as a limitation on the patent scope of the present application. It shall be pointed out that, for ordinary skilled persons in the art, several modifications and improvements can be made without departing from the concept of the present application, and these shall be within the protection scope of the present application. Therefore, the protection scope of the patent of the present application shall be subject to the appended claims.

Claims

1. A method for synthesizing travoprost, characterized in that, Includes the following steps: (1) In an organic solvent, Corinone 1 reacts with alkylsilane chloride under the action of a base for 1 to 10 hours, and then a weak acid is added to obtain compound 2. The reaction temperature is -10℃ to 50℃, and the molar ratio of Corinone 1 to alkylsilane chloride is 1.0:1.0 to 10.

0. (2) In an organic solvent, compound 2 and an oxidant react for 1 to 20 hours to obtain compound 3. The reaction temperature is 0℃ to 50℃, and the molar ratio of compound 2 to oxidant is 1.0:1.0 to 5.

0. The oxidant is Dess-Martin agent, active manganese dioxide, sodium hypochlorite, PCC or PDC. (3) In an organic solvent, compound 3 reacts with dimethyl [2-oxo-3-(3-trifluoromethylphenoxy)propyl] phosphate under the action of a base for 1 to 10 hours to obtain compound 4. The reaction temperature is -78℃ to 0℃, and the molar ratio of compound 3, dimethyl [2-oxo-3-(3-trifluoromethylphenoxy)propyl] phosphate and base is 1.0:1.0 to 5.0:1.0 to 5.0; the base is potassium carbonate. (4) In an organic solvent, compound 4 reacts with a chiral reducing agent for 1 to 20 hours to obtain compound 5, the reaction temperature is -78℃ to room temperature, and the molar ratio of compound 4 to chiral reducing agent is 1.0:1.0 to 5.0; the chiral reducing agent is (-)-diisopinepine chloroborane; (5) In an organic solvent, compound 5 and a reducing agent react for 1 to 10 hours to obtain the reduced product compound 6. The reaction temperature is -78 to 0℃, and the molar ratio of compound 5 to the reducing agent is 1.0:1.0 to 5.

0. (6) In an organic solvent, compound 6 and triphenylphosphine isopropyl bromopentanoate were reacted for 1 to 15 hours to obtain compound 7. The reaction temperature was -78℃ to 0℃, and the molar ratio of compound 6 to triphenylphosphine isopropyl bromopentanoate was 1.0:1.0 to 5.

0. (7) In an organic solvent, compound 7 is reacted with acid for 1 to 10 hours to remove the silicon protecting group and obtain compound 8. The reaction temperature is 0℃ to 40℃ and the molar ratio of compound 7 to acid is 1.0:1.0 to 5.

0. The product 8, the raw material 1, and compounds 2-7 each have the following structures:

2. The method for synthesizing travoprost according to claim 1, characterized in that, The organic solvent is dichloromethane, tetrahydrofuran, dimethylformamide, dimethylacetamide, ethylene glycol dimethyl ether, 1,2-dichloroethane, dimethyl sulfoxide, toluene, methanol, ethanol, acetonitrile, petroleum ether, n-hexane, or diethyl ether.

3. The method for synthesizing travoprost according to claim 2, characterized in that, The organic solvents mentioned in steps (1), (2) and (7) are dichloromethane, the organic solvents mentioned in steps (3), (4) and (6) are tetrahydrofuran, and the organic solvents mentioned in step (5) are toluene.

4. The method for synthesizing travoprost according to any one of claims 1-3, characterized in that, The alkylsilane chloride in step (1) is tert-butyldimethylsilane chloride, or triethylsilane chloride, or trimethylsilane chloride, or tert-butyldiphenylsilane chloride.

5. The method for synthesizing travoprost according to any one of claims 1-3, characterized in that, The reducing agent mentioned in step (5) is lithium borohydride, sodium borohydride, potassium borohydride, diisopropyl aluminum hydride or lithium aluminum hydride.

6. The method for synthesizing travoprost according to any one of claims 1-3, characterized in that, The reaction described in step (6) is carried out under inert gas protection.

7. The method for synthesizing travoprost according to any one of claims 1-3, characterized in that, The acid mentioned in step (7) is: trifluoroacetic acid, aluminum trichloride, hydrochloric acid, p-toluenesulfonic acid, hydrofluoric acid, pyridine hydrofluoric acid, sulfuric acid or nitric acid.

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