Synthesis method of latanoprost

Abstract

The present invention relates to a method for synthesizing latanoprost for treating glaucoma. The method uses inexpensive and readily available corinolactone as a raw material and completes the chemical synthesis of latanoprost in a nine-step reaction process with a high overall yield. The novel method for synthesizing latanoprost of the present invention features a simple preparation method, stable intermediates, environmental friendliness, economy, and easy reaction control.

Description

Technical Field

[0001] The present invention relates to the fields of organic synthesis and medicinal chemistry, in particular to a synthesis method of latanoprost. Background Art

[0002] Latanoprost is a prostaglandin PGF2a analogue and a selective F2a receptor agonist. It is inactive but rapidly penetrates the cornea. It hydrolyzes into its active free acid in the cornea and plasma, increasing the outflow of aqueous humor through the corneal layer. While a small dosage promotes a large outflow of aqueous humor, the drug penetrates the upper ciliary choroidal layer of the eyeball, exhibiting a significant intraocular pressure-lowering effect. Therefore, it is a preferred treatment for glaucoma and ocular hypertension. However, the reported preparation methods for latanoprost APIs are lengthy, resulting in high production costs, low product purity, and a high total impurity content, which fail to meet the quality standards required for pharmaceutical APIs.

[0003] There are two reported methods for synthesizing latanoprost: (1) Using benzoyl Corey lactone as a raw material, benzoyl Corey aldehyde and (2-oxo-4-phenylbutyl) dimethyl phosphate are reacted through HWE to produce the corresponding product. The operation is simple, but the yield is not high. (2) Using benzoyl Corey lactone as a raw material, benzoyl Corey aldehyde is reacted with 4-phenylbutyne, and then the final product is obtained through Meyer-Schuster rearrangement. The yield is higher than the former, but the reaction conditions are harsh, and the catalyst is expensive and difficult to recover. It is not suitable for large-scale production and difficult to achieve industrialization.

[0004] Prior art IN 2009CH01233A discloses the following synthetic route:

[0005]

[0006] The above patent adopts a three-step operation of silicon-based protection-benzoyl protection-silicon-based protective group deprotection, which has the disadvantages of complicated process.

[0007] In order to overcome the above-mentioned defects of the prior art, there is an urgent need for a synthetic route for latanoprost that is simple to operate, has stable intermediates, is environmentally friendly and economical, and has easily controllable reactions. Summary of the Invention

[0008] Based on this, the object of the present invention is to provide a method for synthesizing latanoprost.

[0009] In order to achieve the above-mentioned invention object, the specific technical solution is as follows:

[0010] A method for synthesizing latanoprost, the synthetic route is as follows:

[0011]

[0012] The synthesis method comprises the following steps:

[0013] (1) In an organic solvent, core lactone 1 reacts with alkylsilyl chloride in the presence of a base for 1 to 10 hours, followed by the addition of a weak acid to obtain compound 2. The reaction temperature is -10°C to 50°C, and the molar ratio of core lactone 1 to alkylsilyl chloride is 1.0:1.0 to 10.0.

[0014] (2) Compound 2 and an oxidant are reacted in an organic solvent for 1 to 20 hours to obtain Compound 3, the reaction temperature is 0°C to 50°C, and the molar ratio of Compound 2 to the oxidant is 1.0:1.0 to 5.0;

[0015] (3) Compound 3 is reacted with dimethyl 2-oxo-4-phenylbutylphosphonate in an organic solvent in the presence of a base for 1 to 10 hours to obtain compound 4. The reaction temperature is -78°C to 0°C, and the molar ratio of compound 3, dimethyl 2-oxo-4-phenylbutylphosphonate, and the base is 1.0:1.0-5.0:1.0-5.0;

[0016] (4) Compound 4 is reacted with a chiral reducing agent in an organic solvent for 1 to 20 hours to obtain compound 5, the reaction temperature is -78°C to room temperature, and the molar ratio of compound 4 to the chiral reducing agent is 1.0:1.0 to 5.0;

[0017] (5) Compound 5 and a reducing agent are reacted in an organic solvent for 1 to 24 hours to obtain a reduced product, Compound 6, the reaction temperature is 0°C to room temperature, and the molar ratio of Compound 5 to the reducing agent is 1.0:1.0 to 5.0;

[0018] (6) Compound 6 and a reducing agent are reacted in an organic solvent for 1 to 10 hours to obtain a reduced product, Compound 7, the reaction temperature is -78 to 0°C, and the molar ratio of Compound 6 to the reducing agent is 1.0:1.0 to 5.0;

[0019] (7) Compound 7 and isopropyl bromopentanoate triphenylphosphine are reacted in an organic solvent for 1 to 15 hours to obtain Compound 8. The reaction temperature is -78°C to 0°C, and the molar ratio of Compound 7 to isopropyl bromopentanoate triphenylphosphine is 1.0:1.0 to 5.0;

[0020] (8) In an organic solvent, compound 8 is reacted with an acid for 1 to 10 hours to remove the silicon protecting group to obtain compound 9. The reaction temperature is 0°C to 40°C, and the molar ratio of compound 8 to the acid is 1.0:1.0 to 5.0.

[0021] In some embodiments, the reaction time of the reaction in step 1 is 1 to 10 hours, the reaction temperature is -10°C to 50°C, and the molar ratio of Corian lactone 1 to alkylsilyl chloride is 1.0:1.0-10.0; the reaction time of the reaction in step 2 is 1 to 20 hours, the reaction temperature is 0°C to 50°C, and the molar ratio of compound 2 to the oxidant is 1.0:1.0-5.0; the reaction time of the reaction in step 3 is 1 to 10 hours, the reaction temperature is 0°C to 50°C, and the molar ratio of compound 3, 2-oxo-4-phenylbutylphosphonic acid dimethyl ester and the base is 1:1.0-5.0:1.0-5.0; the reaction time of the reaction in step 4 is 1 to 20 hours, the reaction temperature is -78°C to room temperature, and compound 4 and chiral reduction The molar ratio of the reducing agent is 1.0:1.0~5.0; the reaction time of the reaction in step 5 is 1 to 24 hours, the reaction temperature is 0°C to room temperature, and the molar ratio of compound 5 to the reducing agent is 1:1.0~5.0; the reaction time of the reaction in step 6 is 1 to 10 hours, the reaction temperature is -78°C to 0°C, and the molar ratio of compound 6 to the reducing agent is 1:1.0~5.0; the reaction time of the reaction in step 7 is 1 to 15 hours, the reaction temperature is -78°C to 0°C, and the molar ratio of compound 7 to isopropyl bromovalerate triphenylphosphine salt is 1.0:1.0~5.0; the reaction time of the reaction in step 8 is 1 to 10 hours, the reaction temperature is 0°C to 40°C, and the molar ratio of compound 8 to the acid is 1.0:1.0~5.0.

[0022] 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.

[0023] In some embodiments, the organic solvent in steps (1), (2) and (8) is dichloromethane, the organic solvent in (3), (4) and (7) is tetrahydrofuran, the organic solvent in step (6) is toluene, and the organic solvent in step (5) is ethanol.

[0024] In some embodiments, the alkylsilyl chloride in step (1) is tert-butyldimethylsilyl chloride, or triethylsilyl chloride, or trimethylsilyl chloride or tert-butyldiphenylsilyl chloride.

[0025] In some embodiments, the oxidizing agent in step (2) is Dess-Martin reagent, activated manganese dioxide, sodium hypochlorite, PCC or PDC. The reducing agent in step (5) is 10% palladium on carbon. The reducing agent in step (6) is lithium borohydride, sodium borohydride, potassium borohydride, diisopropylaluminum hydride or lithium aluminum tetrahydride.

[0026] In some embodiments, the reaction in step (3) is carried out under inert gas protection, and the base is sodium hydrogen sulfide, potassium tert-butoxide, n-butyl lithium, lithium chloride, sodium hexamethyldisilazide (NaHMDS), or potassium hexamethyldisilazide (KHMDS).

[0027] In some embodiments, the reaction in step (7) is carried out under inert gas protection, and the base is sodium hydrogen sulfide, potassium tert-butoxide, n-butyl lithium, sodium hexamethyldisilazide (NaHMDS), or potassium hexamethyldisilazide (KHMDS).

[0028] In some embodiments, the acid in step (8) is trifluoroacetic acid, aluminum chloride, hydrochloric acid, p-toluenesulfonic acid, hydrofluoric acid, pyridine hydrofluoride, sulfuric acid or nitric acid.

[0029] The method for synthesizing latanoprost of the present invention is simple to operate, produces stable intermediates, is environmentally friendly and economical, and has easily controllable reactions. The method can be used to synthesize related analogs of latanoprost. Furthermore, the silicon-protected colline lactone diol intermediate exhibits higher stability and significantly reduced impurities when subjected to alkenyl side chain coupling. Furthermore, compared to the prior art, the method of the present invention does not produce isomers when synthesizing intermediate 7, making the products easily separable and the final product yield high. DETAILED DESCRIPTION

[0030] The present invention will be further described below with reference to specific embodiments.

[0031] In the following examples, conventional post-processing methods include: after the reaction is completed, an appropriate amount of water is added to the reaction solution, 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, dried over anhydrous Na2SO4, filtered, and then dried under reduced pressure to obtain a crude product, which is then separated and purified by column chromatography to obtain the final product.

[0032] Compound Synthesis

[0033] To a solution of corianolide (10 g, 58.1 mmol) in dichloromethane (100 ml) were added TBSC1 (26.3 g, 175 mmol, 3.0 eq) and imidazole (12.5 g, 180 mmol, 3.0 eq), and the mixture was reacted at room temperature for 8 h. The mixture was filtered and 10% hydrochloric acid solution (50 mL) was added to the organic phase, followed by reaction at room temperature for 5 h. The reaction was quenched with saturated ammonium chloride solution (100 ml), concentrated, and 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, concentrated, and recrystallized from ethyl acetate (100 ml) to obtain compound 2a (13.6 g, 82%) as a white solid. 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).

[0034] Compound Synthesis

[0035] To a solution of compound 2a (8.53 g, 30 mmol) in dichloromethane (150 ml) was added Dess-Martin oxidant (19.1 g, 45 mmol, 1.5 eq) at 0°C. The reaction was allowed to react at room temperature overnight. The reaction was quenched with saturated ammonium chloride solution (100 ml) and concentrated. Dichloromethane (100 ml) and water (100 ml) were added. The mixture was allowed to stand for separation. 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 compound 3a (8.19 g, 96%) as a yellow solid. 1 H NMR (400MHz, CDCl3): δ9.72 (s, 1H), 5.01 (t, J=6.0Hz, 1H), 4.59-4.53 (m, 1H), 3.37-3.32 (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).

[0036] Compound Synthesis

[0037] Under argon protection, dimethyl 2-oxo-4-phenylbutylphosphonate (7.69 g, 30.0 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 solution of compound 3a (8.58 g, 30 mmol, 1 eq) in THF (75 ml) was added dropwise. The reaction was allowed to proceed at -20°C overnight, and the mixture was concentrated. Ethyl acetate (100 ml) and water (50 ml) were added, and the mixture was allowed to stand for separation. 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 obtain compound 4a (10.71 g, 86%). 1 H NMR (400MHz, CDCl3) δ7.32-7.26 (m, 2H), 7.21-7.15 (m, 3H), 5.80 (m, 1H), 5.43 (m, 1H), 2.31-2.25 (m, 3H), 2.15-2. 11(m, 1H), 1.87-1.83(m, 2H), 1.80-1.54(m, 4H), 1.38-1.24(m, 2H), 0.98(s, 9H), 0.21(s, 6H)ppm.MS(m / z): 415(M + +1).

[0038] Compound Synthesis

[0039] Under argon protection, to a solution of compound 4a (6.23 g, 15 mmol, 1.0 eq) in THF (100 ml) at -50 ° C was added (-)-diisopinocampheyl chloroborane (10.6 mL, 18 mmol, 1.7 M solution in Heptane, 1.2 eq). After completion, the reaction was allowed to react at -50 ° C for 6 h, quenched with saturated ammonium chloride solution (50 ml), concentrated, and 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 give compound 5a (5.06 g, 81%). 1H NMR (400MHz, CDCl3) δ7.32-7.26 (m, 2H), 7.21-7.13 (m, 3H), 5.80 (m, 1H), 5.43 (m, 1H), 2.83-2.78 (m, 1H), 2.31-2.26 (m, 3H) , 2.15-2.11(m, 1H), 1.87-1.82(m, 2H), 1.80-1.51(m, 4H), 1.38-1.24(m, 2H), 0.98(s, 9H), 0.22(s, 6H)ppm.MS(m / z): 417(M + +1).

[0040] Compound Synthesis

[0041] Compound 5a (6.37 g, 12 mmol, 1.0 eq) was dissolved in anhydrous ethanol (79 ml), and 10% palladium carbon (0.64 g) was added. The hydrogen was replaced three times, and the reaction was carried out at room temperature under normal pressure for 24 h. The reaction was detected by TLC. The palladium carbon was filtered out and concentrated to obtain compound 6a (4.82 g, 96%). 1 H NMR (400MHz, CDCl3) δ7.32-7.26 (m, 2H), 7.21-7.15 (m, 3H), 2.83-2.78 (m, 1H), 2.71-2.67 (m, 1H), 2.28-2.21 (m, 5H), 2. 15-2.12(m, 2H), 1.87-1.82(m, 2H), 1.81-1.51(m, 4H), 1.38-1.24(m, 2H), 0.98(s, 9H), 0.21(s, 6H)ppm.MS(m / z): 419(M + +1).

[0042] Compound Synthesis

[0043] At -20 ° C, under argon protection, to a toluene (70 ml) solution of compound 6a (5.3 g, 10 mmol, 1.0 eq) was added DIBALH (7.5 ml, 30 mmol, 4 M solution in THF, 3.0 eq), and the reaction was carried out for 3 h. The reaction was quenched with saturated ammonium chloride solution (50 ml) and concentrated. Ethyl acetate (100 ml) and water (50 ml) were added, and the layers were allowed to stand. 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 obtain compound 7a (4.04 g, 96%). 1H NMR (400MHz, CDCl3) δ7.32-7.26 (m, 2H), 7.21-7.15 (m, 3H), 3.63 (quint, J=5.6Hz, 1H), 2.83-2.76 (m, 1H), 2.71-2.66 (m, 1H), 2.31-2 .25 (m, 5H), 2.15-2.11 (m, 2H), 1.87-1.82 (m, 2H), 1.80-1.51 (m, 4H), 1.38-1.24 (m, 2H), 0.98 (s, 9H), 0.21 (s, 6H)ppm.MS (m / z): 421 (M + +1).

[0044] Compound Synthesis

[0045] To a solution of compound 7a (5.35 g, 10.0 mmol) in THF (100 ml) were added isopropyl bromopentanoate triphenylphosphine salt (7.28 g, 15 mmol) and potassium tert-butoxide (3.36 g, 30 mmol, 2.0 eq) in sequence, and the mixture was reacted at -78°C for 7 h. The reaction was quenched with saturated ammonium chloride solution (20 ml) and concentrated. Ethyl acetate (50 ml) and water (20 ml) were added, and the layers were allowed to stand. The aqueous phase was extracted with ethyl acetate (50 ml*2), washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated to give compound 8a (4.75 g, 87%). 1 H NMR (400MHz, CDCl3) δ7.31-7.28(m, 2H), 7.22-7.17(m, 3H), 5.48-5.33(m, 2H), 5.00 (quint, J=6.4Hz, 1H), 3.66 (quint, J=5.6Hz, 1H), 2.81-2.77 (m, 1H), 2.71-2.66 (m, 1H), 2.31-2.25(m, 5H), 2.15-2.12(m, 2H), 1.87-1.82(m, 2H), 1.80-1.58(m, 9H), 1. 36-1.24(m, 2H), 1.22(d, J=6.0Hz, 6H), 0.98(s, 9H), 0.21(s, 6H)ppm.MS(m / z): 547(M + +1).

[0046] Compound Synthesis

[0047] Under argon protection, hydrofluoric acid (10 ml) was added to a solution of compound 8a (1.32 g, 2.0 mmol) in dichloromethane (50 ml), and the reaction was carried out at room temperature for 8 h. The reaction was quenched with saturated ammonium chloride solution (20 ml), and the layers were separated by standing. The aqueous phase was extracted with dichloromethane (20 ml*2), and the combined organic phases were washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated to obtain compound 9 (0.87 g, 100%). 1 H NMR (400MHz, CDCl3) δ7.30-7.26 (m, 2H), 7.21-7.16 (m, 3H), 5.49-5.35 (m, 2H), 5.00 (quint, J=6.4Hz, 1H), 3.66 (quint, J=5.6Hz, 1H), 2.80-2.76 (m, 1H), 2 .71-2.65(m, 1H), 2.33-2.26(m, 5H), 2.14-2.11(m, 2H), 1.87-1.81(m, 2H), 1. 80-1.48(m, 9H), 1.38-1.25(m, 2H), 1.22(d, J=6.0Hz, 6H)ppm.MS(m / z): 433(M + +1).

[0048] Compound Synthesis

[0049] The method is the same as before. 1 H NMR (400MHz, CDCl3): δ4.25 (brs, OH), 4.13 (dd, J=9.2Hz, J=2.3Hz, 1H), 3.56-3.33 (m, 3H), 2.37-2.08 ( m, 3H), 1.80-1.83 (m, 2H), 1.42 (m, 1H), 0.95 (t, J=6.6Hz, 9H), 0.66 (q, J=6.6Hz, 6H) ppm.MS (m / z): 287 (M + +1).

[0050] Compound Synthesis

[0051] The method is the same as before. 1 H NMR (400MHz, CDCl3): δ9.71 (s, 1H), 4.15 (dd, J=9.2Hz, J=2.5Hz, 1H), 3.58 (m, 1H), 2.37-2.1 2 (m, 4H), 2.05-1.83 (m, 2H), 0.96 (t, J = 6.6Hz, 9H), 0.67 (q, J = 6.6Hz, 6H) ppm.MS (m / z): 285 (M + +1).

[0052] Compound Synthesis

[0053] The method is the same as before. 1 H NMR (400MHz, CDCl3) δ7.32-7.26 (m, 2H), 7.21-7.15 (m, 3H), 5.80 (m, 1H), 5.43 (m, 1H), 2.31-2.25 (m, 3H), 2.15-2.11 (m, 1H) , 1.87-1.83 (m, 2H), 1.80-1.54 (m, 4H), 1.38-1.24 (m, 2H), 0.96 (t, J=6.6Hz, 9H), 0.67 (q, J=6.6Hz, 6H) ppm.MS (m / z): 415 (M + +1).

[0054] Compound Synthesis

[0055] The method is the same as before. 1 H NMR (400MHz, CDCl3) δ7.32-7.26 (m, 2H), 7.21-7.13 (m, 3H), 5.80 (m, 1H), 5.43 (m, 1H), 2.83-2.78 (m, 1H), 2.31-2.26 (m, 3H), 2.15-2. 11 (m, 1H), 1.87-1.82 (m, 2H), 1.80-1.51 (m, 4H), 1.38-1.24 (m, 2H), 0.96 (t, J=6.6Hz, 9H), 0.67 (q, J=6.6Hz, 6H) ppm.MS (m / z): 417 (M + +1).

[0056] Compound Synthesis

[0057] The method is the same as before. 1 H NMR (400MHz, CDCl3) δ7.32-7.26(m, 2H), 7.21-7.15(m, 3H), 2.83-2.78(m, 1H), 2.71-2.67(m, 1H), 2.28-2.21(m, 5H), 2.15-2.12( m, 2H), 1.87-1.82 (m, 2H), 1.81-1.51 (m, 4H), 1.38-1.24 (m, 2H), 0.96 (t, J=6.6Hz, 9H), 0.67 (q, J=6.6Hz, 6H) ppm.MS (m / z): 419 (M + +1).

[0058] Compound Synthesis

[0059] The method is the same as before. 1 H NMR (400MHz, CDCl3) δ7.32-7.26 (m, 2H), 7.21-7.15 (m, 3H), 3.63 (quint, J=5.6Hz, 1H), 2.83-2.76 (m, 1H), 2.71-2.66 (m, 1H), 2.31-2.25 (m, 5H) ), 2.15-2.11 (m, 2H), 1.87-1.82 (m, 2H), 1.80-1.51 (m, 4H), 1.38-1.24 (m, 2H), 0.96 (t, J = 6.6Hz, 9H), 0.67 (q, J = 6.6Hz, 6H) ppm. MS (m / z): 421 (M + +1).

[0060] Compound Synthesis

[0061] The method is the same as before. 1 H NMR (400MHz, CDCl3) δ7.32-7.26(m, 2H), 7.21-7.15(m, 3H), 5.48-5.32(m, 2 H), 3.63 (quint, J=5.6Hz, 1H), 2.83-2.78 (m, 1H), 2.71-2.66 (m, 1H), 2.31-2 .24(m, 5H), 2.16-2.12(m, 2H), 1.87-1.82(m, 2H), 1.80-1.51(m, 9H), 1.38-1 .24 (m, 2H), 0.96 (t, J=6.6Hz, 9H), 0.67 (q, J=6.6Hz, 6H) ppm.MS (m / z): 547 (M + +1).

[0062] Compound Synthesis

[0063] The method is the same as before. 1 H NMR (400MHz, CDCl3): δ4.23 (brs, OH), 4.11 (dd, J=9.2Hz, J=2.3Hz, 1H), 3.54-3.31 (m, 3 H), 2.37-2.07(m, 3H), 1.80-1.78(m, 2H), 1.41(m, 1H), 0.20(s, 9H)ppm.MS(m / z): 246(M + +1).

[0064] Compound Synthesis

[0065] The method is the same as before.1 H NMR (400MHz, CDCl3): δ9.69 (s, 1H), 4.11 (dd, J=9.0Hz, J=2.4Hz, 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).

[0066] Compound Synthesis

[0067] The method is the same as before. 1 H NMR (400MHz, CDCl3) δ7.32-7.26 (m, 2H), 7.21-7.15 (m, 3H), 5.80 (m, 1H), 5.43 (m, 1H), 2.31-2.25 (m, 3H), 2 .15-2.11(m, 1H), 1.87-1.83(m, 2H), 1.80-1.54(m, 4H), 1.38-1.24(m, 2H), 0.21(s, 9H)ppm.MS(m / z): 373(M + +1).

[0068] Compound Synthesis

[0069] The method is the same as before. 1 H NMR (400MHz, CDCl3) δ7.32-7.26 (m, 2H), 7.21-7.13 (m, 3H), 5.80 (m, 1H), 5.43 (m, 1H), 2.83-2.78 (m, 1H), 2.31-2.26 (m, 3H), 2.15-2.11 (m, 1H), 1.87-1.82 (m, 2H), 1.80-1.51 (m, 4H), 1.38-1.24 (m, 2H), 0.22 (s, 9H)ppm.MS (m / z): 375 (M + +1).

[0070] Compound Synthesis

[0071] The method is the same as before. 1H NMR (400MHz, CDCl3) δ7.32-7.26(m, 2H), 7.21-7.15(m, 3H), 2.83-2.78(m, 1H), 2.71-2.67(m, 1H), 2.28-2.21(m, 5H), 2.15-2.12(m, 2H), 1.87-1.82(m, 2H), 1.81-1.51(m, 4H), 1.38-1.24(m, 2H), 0.21(s, 9H)ppm.MS(m / z): 377(M + +1).

[0072] Compound Synthesis

[0073] The method is the same as before. 1 H NMR (400MHz, CDCl3) δ7.32-7.26 (m, 2H), 7.21-7.15 (m, 3H), 3.63 (quint, J=5.6Hz, 1H), 2.83-2.76 (m, 1H), 2.71-2.66 (m, 1H), 2 .31-2.25(m, 5H), 2.15-2.11(m, 2H), 1.87-1.82(m, 2H), 1.80-1.51(m, 4H), 1.38-1.24(m, 2H), 0.21(s, 9H)ppm.MS(m / z): 379(M + +1).

[0074] Compound Synthesis

[0075] The method is the same as before. 1 H NMR (400MHz, CDCl3) δ7.31-7.28(m, 2H), 7.22-7.17(m, 3H), 5.48-5.33(m, 2H), 5 .00 (quint, J=6.4Hz, 1H), 3.66 (quint, J=5.6Hz, 1H), 2.81-2.77 (m, 1H), 2.71-2. 66(m, 1H), 2.31-2.25(m, 5H), 2.15-2.12(m, 2H), 1.87-1.82(m, 2H), 1.80-1.58( m, 9H), 1.36-1.24 (m, 2H), 1.22 (d, J=6.0Hz, 6H), 0.21 (s, 9H)ppm.MS (m / z): 505 (M + +1).

[0076] Compound Synthesis

[0077] The method is the same as before. 1H NMR (400MHz, CDCl3): δ7.60-7.36 (m, 10H), 4.36 (brs, OH), 4.27 (dd, J=9.2Hz, J=2.4Hz, 1H), 3.67 (m, 1H), 3. 63(m, 1H), 3.42(m, 1H), 2.39-2.22(m, 3H), 1.81-1.85(m, 2H), 1.47(m, 1H), 0.99(s, 9H)ppm.MS(m / z): 411(M + +1).

[0078] Compound Synthesis

[0079] The method is the same as before. 1 H NMR (400MHz, CDCl3): δ9.75 (s, 1H), 7.60-7.36 (m, 10H), 4.29 (dd, J=9.6Hz, J=2.6Hz, 1H), 3.6 9(m, 1H), 2.43-2.19(m, 4H), 2.06-1.85(m, 2H), 1.47(m, 1H), 0.99(s, 9H)ppm.MS(m / z): 409(M + +1).

[0080] Compound Synthesis

[0081] The method is the same as before. 1 H NMR (400MHz, CDCl3) δ7.60-7.36 (m, 10H), 7.32-7.26 (m, 2H), 7.21-7.15 (m, 3H), 5.80 (m, 1H), 5.43 (m, 1H), 2.31-2.25 (m, 3H), 2.15-2.11 (m, 1H), 1.87-1.83 (m, 2H), 1.80-1.54 (m, 4H), 1.38-1.24 (m, 2H), 0.98 (s, 9H)ppm.MS (m / z): 539 (M + +1).

[0082] Compound Synthesis

[0083] The method is the same as before. 1H NMR (400MHz, CDCl3) δ7.60-7.36 (m, 10H), 7.32-7.26 (m, 2H), 7.21-7.13 (m, 3H), 5.80 (m, 1H), 5.43 (m, 1H), 2.83-2.78 (m, 1H), 2 .31-2.26(m, 3H), 2.15-2.11(m, 1H), 1.87-1.82(m, 2H), 1.80-1.51(m, 4H), 1.38-1.24(m, 2H), 0.98(s, 9H)ppm.MS(m / z): 541(M + +1).

[0084] Compound Synthesis

[0085] The method is the same as before. 1 H NMR (400MHz, CDCl3) δ7.60-7.36 (m, 10H), 7.32-7.26 (m, 2H), 7.21-7.15 (m, 3H), 2.83-2.78 (m, 1H), 2.71-2.67 (m, 1H), 2.28 -2.21(m, 5H), 2.15-2.12(m, 2H), 1.87-1.82(m, 2H), 1.81-1.51(m, 4H), 1.38-1.24(m, 2H), 0.98(s, 9H)ppm.MS(m / z): 543(M + +1).

[0086] Compound Synthesis

[0087] The method is the same as before. 1 H NMR (400MHz, CDCl3) δ7.60-7.36 (m, 10H), 7.32-7.26 (m, 2H), 7.21-7.15 (m, 3H), 3.63 (quint, J=5.6Hz, 1H), 2.83-2.76 (m, 1H), 2.71-2.6 6 (m, 1H), 2.31-2.25 (m, 5H), 2.15-2.11 (m, 2H), 1.87-1.82 (m, 2H), 1.80-1.51 (m, 4H), 1.38-1.24 (m, 2H), 0.98 (s, 9H)ppm. MS (m / z): 545 (M + +1).

[0088] Compound Synthesis

[0089] The method is the same as before. 1H NMR (400MHz, CDCl3) δ7.60-7.36 (m, 10H), 7.31-7.28 (m, 2H), 7.22-7.17 (m, 3H), 5.48 -5.33 (m, 2H), 5.00 (quint, J=6.4Hz, 1H), 3.66 (quint, J=5.6Hz, 1H), 2.81-2.77 (m, 1H ), 2.71-2.66(m, 1H), 2.31-2.25(m, 5H), 2.15-2.12(m, 2H), 1.87-1.82(m, 2H), 1.80-1 .58(m, 9H), 1.36-1.24(m, 2H), 1.22(d, J=6.0Hz, 6H), 0.98(s, 9H)ppm.MS(m / z): 672(M + +1).

[0090] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0091] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the patent. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the patent for this invention shall be determined by the appended claims.

Claims

1. A method for synthesizing latanoprost, characterized in that: The following steps are involved: (1) In an organic solvent, core lactone 1 reacts with alkyl silicon chloride in the presence of a base for 1 to 10 hours, followed by the addition of a weak acid to obtain compound 2. The reaction temperature is -10°C to 50°C, and the molar ratio of core lactone 1 to alkyl silicon chloride is 1.0:1.0 to 10.

0. (2) Compound 2 and an oxidant are reacted in an organic solvent for 1 to 20 hours to obtain Compound 3, the reaction temperature is 0°C to 50°C, and the molar ratio of Compound 2 to the oxidant is 1.0:1.0 to 5.0; the oxidant is a Dess-Martin agent, activated manganese dioxide, sodium hypochlorite, PCC or PDC; (3) Compound 3 is reacted with dimethyl 2-oxo-4-phenylbutylphosphonate in an organic solvent under the action of a base for 1 to 10 hours to obtain compound 4. The reaction temperature is -78°C to 0°C, and the molar ratio of compound 3, dimethyl 2-oxo-4-phenylbutylphosphonate, and the base is 1.0:1.0-5.0:1.0-5.0; (4) Compound 4 is reacted with a chiral reducing agent in an organic solvent for 1 to 20 hours to obtain compound 5, the reaction temperature is -78°C to room temperature, and the molar ratio of compound 4 to the chiral reducing agent is 1.0:1.0 to 5.0; (5) In an organic solvent, compound 5 is reacted with a reducing agent for 1 to 24 hours to obtain a reduced product, compound 6, wherein the reaction temperature is 0°C to room temperature, the molar ratio of compound 5 to the reducing agent is 1.0:1.0 to 5.0, and the reducing agent is 10% palladium on carbon; (6) Compound 6 and a reducing agent are reacted in an organic solvent for 1 to 10 hours to obtain a reduced product, Compound 7, at a reaction temperature of -78 to 0°C, and a molar ratio of Compound 6 to the reducing agent of 1.0:1.0 to 5.0; (7) Compound 7 and isopropyl bromopentanoate triphenylphosphine are reacted in an organic solvent for 1 to 15 hours to obtain Compound 8. The reaction temperature is -78°C to 0°C, and the molar ratio of Compound 7 to isopropyl bromopentanoate triphenylphosphine is 1.0:1.0 to 5.0; (8) Compound 8 is reacted in an organic solvent under the action of an acid for 1 to 10 hours to remove the silicon protecting group to obtain compound 9. The reaction temperature is 0°C to 40°C, and the molar ratio of compound 8 to the acid is 1.0:1.0 to 5.0; The product 9, raw material 1 and compounds 2-8 respectively have the following structures:

2. The method for synthesizing latanoprost according to claim 1, wherein 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 latanoprost according to claim 2, wherein The organic solvent in steps (1), (2) and (8) is dichloromethane, the organic solvent in (3), (4) and (7) is tetrahydrofuran, the organic solvent in step (6) is toluene, and the organic solvent in step (5) is ethanol.

4. The method for synthesizing latanoprost according to any one of claims 1 to 3, characterized in that The alkylsilyl chloride in step (1) is tert-butyldimethylsilyl chloride, or triethylsilyl chloride, or trimethylsilyl chloride, or tert-butyldiphenylsilyl chloride.

5. The method for synthesizing latanoprost according to any one of claims 1 to 3, characterized in that The reaction in step (3) is carried out under inert gas protection, and the base is sodium hydrogen hydride, potassium tert-butoxide, tert-butyl lithium, imidazole, triethylamine, diisopropylethylamine, piperidine, lutidine, sodium hexamethyldisilazide, potassium hexamethyldisilazide, N-methylmorpholine, 1,4-diazabicyclo[2.2.2]octane or pyridine.

6. The method for synthesizing latanoprost according to any one of claims 1 to 3, characterized in that The reducing agent in step (6) is lithium borohydride, sodium borohydride, potassium borohydride, diisopropylaluminum hydride or lithium aluminum tetrahydride.

7. The method for synthesizing latanoprost according to any one of claims 1 to 3, characterized in that The acid in step (8) is trifluoroacetic acid, aluminum chloride, hydrochloric acid, p-toluenesulfonic acid, hydrofluoric acid, pyridine hydrofluoride, sulfuric acid or nitric acid.

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