Name: 155206-00-1|(Z)-7-((1R,2R,3R,5S)-3,5-Dihydroxy-2-((S,E)-3-hydroxy-5-phenylpent-1-en-1-yl)cyclopentyl)-N-ethylhept-5-enamide|98%
Brand: Ambeed
SKU: A147258
Price: 8.0 USD
Availability: InStock
Rating: 90 (40 reviews)

2
[ 75-04-7 ]
[ 38315-47-8 ]
[ 155206-00-1 ]

Yield	Reaction Conditions	Operation in experiment
< 80%	In methanol; at 24 - 27℃; for 72h;Product distribution / selectivity;	A mixture of ester 2 [9.0 g, 22.4 mmol, contain (by HPLC) 3.5% of 5-trans isomer], 70% aq EtNH2 (40 mL, 503 mmol) and MeOH (45 mL) was stirred in a well closed flask at 24 to 27 C. for 72 h and concentrated in vacuo. The residue was portioned between EtOAc (100 mL) and water (60 mL). The phases were separated, the aqueous one was extracted with EtOAc (30 mL) and the combined organics were washed with 10% NaHCO3 (2×30 mL) and brine, dried over Na2SO4, filtered and concentrated in vacuo to give 8.0 g (86%) of crude bimatoprost containing 3.5% (by HPLC) of 5-trans isomer 1b. The crude bimatoprost was crystallized from a mixture of EtOAc (27 mL) and MTBE (54 mL) as follows: dissolving the crude bimatoprost at or near the boiling point and allowing the hot solution to cool to rt. Additional MTBE (40 mL) was added and the mixture was stirred for 2 h at 0 to 5 C. The precipitate was filtered off, washed on the filter with cold MTBE (2×20 mL) and dried in vacuo for 1 h at 0 to 5 C., for 0.5 h at rt and for 2 h at 30 to 40 C. to give 7.5 g (80%) of bimatoprost crystalline form I as white solid with 98% purity by HPLC, less than 1% of 5-trans isomer 1b. The bimatoprost (7.5 g) was crystallized from EtOAc (75 mL) as follows: dissolving the bimatoprost at or near the boiling point, allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5 C. The precipitate was filtered off and dried in vacuo for 1 h at 0 to 5 C., for 0.5 h at rt and for 2 h at 30 to 40 C. to give 6.7 g (90% recovery) of bimatoprost crystalline form I as white powder with 99% purity by HPLC, 0.6% 5-trans isomer 1b, NMT 0.1% of 15R-isomer 1a, and NMT 0.1% of 15-keto bimatoprost 1c; mp 64-66 C.; [alpha]D20+36 (c 1, MeOH).The x-ray powder diffraction pattern of bimatoprost crystalline form I has characteristic peaks expressed in degrees 2theta at approximately 5.4, 6.2, 10.9, 11.3, 13.7, 16.6, 17.5, 18.3, 18.6, 18.9, 19.4, 19.7, 19.9,20.7, 20.9, 21.6, 22.7 and 28.2.IR DRIFTS (KBr): 3426.6, 3390.7, 3320.8, 3083.3, 3059.3, 3010.8, 2911.8, 2863.8, 1618.1, 1544.8, 1495.6, 1453.5, 1370.0, 1344.6, 1316.0, 1289.1, 1259.9, 1247.9, 1150.6, 1096.4, 1053.4, 1026.3, 975.0, 919.7, 767.4, 746.0, 728.1, 697.7, 607.2 and 597.6 cm-1.IR (KBr): 3414.9, 3326.6, 3085.5, 3025.1, 3011.5, 2929.6, 2914.2, 2864.9, 1644.8, 1619.2, 1546.2, 1496.2, 1454.6, 1372.9, 1346.0, 1317.3, 1290.4, 1260.9, 1249.3, 1229.4, 1203.6, 1151.9, 1097.2, 1054.5, 1028.6, 975.4, 920.5, 767.6, 747.5, 721.7, 698.9, 596.2, 545.9, 491.2 and 463.0 cm-1.IR (Nujol): 3418.5, 3328.2, 3085.2, 3062.4, 2953.1, 2925.4, 2854.7, 1619.6, 1545.3, 1496.3, 1456.5, 1376.5, 1346.2, 1316.5, 1290.0, 1261.0, 1248.7, 1229.1, 1203.3, 1151.1, 1122.6, 1097.5, 1054.6, 1027.1, 975.9, 961.0, 920.3, 768.1, 721.8, 697.8, 595.7 and 545.4 cm-1.Crystalline form I of bimatoprost was characterized by powder x-ray diffractometry, DSC, IR DRIFTS (KBr), IR (KBr) and IR (Nujol) spectroscopy as set forth above and illustrated in FIGS. 1-5.
62%	In water; at 20℃; for 60h;	[106] Example 7: Preparation of Bimatoprost Ethylamine; [108] Compound (1-1) (155 g) was added to a 70% aqueous solution of ethylamine (3.0 L), followed by stirring at room temperature for 60 hours. After the reaction was completed, the resulting reaction solution was concentrated to be its half level under reduced pressure, neutralized with a 2M aqueous solution of sodium hydrogensulfate (3.0 L, pH = 4-5) and extracted with ethyl acetate (3.0 L). The organic layer was dried over sodium sulfate (1 kg), filtered and concentrated. The resulting residue was subjected to preparative HPLC (eluent: n-hexane: anhydrous ethanol = 90:10), concentrated, and crystallized with diethyl ether (1.5 L). The resulting solid was filtered and dried under vacuum to give highly pure bimatoprost (100 g, Purity: 99.5% or more, Yield: 62%).
	In methanol; water; at 90℃; for 45h;	Example 9: Amidation; A 21 thick-walled glass vessel equipped with a magnetic stirring bar was charged with a solution of ester (49) (85.2g, 212.7mmol) in methanol (0.41) and 70% aqueous solution of ethylamine (0.41). The vessel was sealed, heated and stirred in an oil bath maintained at 90C for 45h. TLC analysis showed consumption of ester (49). The volatiles were removed under reduced pressure, and the residue was partitioned between ethyl acetate (1.51) and saturated brine (0.71). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 0. 51). The combined organic layers were dried (Na2SO4), filtered, and concentrated to dryness. The residue was chromatographed on silica gel (lkg) eluting successively with 80: 20 ethyl acetate-heptane (41), ethyl acetate (121), 1: 99 methanol-ethyl acetate (161), and 2: 99 methanol-ethyl acetate (161). The resulting product (55.6g) was triturated with tert-butyl methyl ether to give Bimatoprost (22) as a white solid (47. 2g). 1H and 13C NMR conformed to structure.

	In water; at 23℃; for 48h;	56g of ethylamine (MW = 45.08; 47.9 equivalents) in 24mL of water were added to 8.08g of crude (Z)-7 [(1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenyl-pent-1-enyl)-cyclo-pentyl]-hept-5-enoic acid methylester (MW = 402.54; 1 equivalents) and the resulting solution was stirred for 48h at 23C. The excess of ethylamine was removed by distillation in vacuo (25, 100mbar) after complete conversion. To the residue were added 400mL of methylenechloride and 100mL of water and the pH was adjusted to 1.5 by addition of 1 M aqueous hydrochloric acid. After separation of the layers the organic layers were washed with 100mL of saturated aqueous sodium bicarbonate, 100mL of water, and 100mL of brine. The solution was filtered and concentrated in vacuo yielding 8.33g of oily bimatoprost crude. To the residue were added 25mL of acetonitrile. After adding seeds the mixture was stirred for 30 minutes at ambient temperature, cooled to 0C and stirred for two hours at this temperature. The crystal suspension was cooled to -20C. After stirring for 14 hours at -20C the crystals were isolated by filtration, washed with cold acetonitrile and then dried in vacuo yielding 5.47g crystalline bimatoprost (mp 70-74C).
	at 25℃;Inert atmosphere;	Compound 14 (17 g) was charged with ethylaminesolution (185 mL, 5 vol) and stirred solution for 36 h at roomtemperature. After completion of reaction, solvent was removedunder vacuum, treated with ethyl acetate and water and allowedto stand for separation of aqueous and organic layers. Theorganic layer was dried over Na 2 SO 4 and concentration ofsolvent results solid compound which stirred in methyl tertiarybutyl ether. The desired solid compound further purified in ethylacetate. 1 H NMR (300 MHz, CDCl 3 ): delta 1(J/Hz = 7.1, t, 3H),1.3 (m, 4H), 1.6 (m, 2H), 2.0 (m, 8H), 2.5 (m, 2H), 3.0 (m, 2H),3.6 (m, 1H), 3.9 (m, 2H), 4.3 (J/Hz = 4.8, d, 1H), 4.5 (J/Hz = 5.7,d, 1H), 4.6 (J/Hz = 4.8 Hz, d, 1H), 5.3 (m, 4H), 7.2 (m, 5H),7.6 (s, 1H). 13 C NMR (300 MHz, CDCl 3 ): delta 14.89, 25.49, 25.69,26.76, 31.97, 34.46, 35.92, 38.84, 43.01, 50.49, 55.69, 72.27,72.59, 77.95, 125.86, 128.44, 128.54 , 129.22, 129.82, 133.13,135.08, 142.1, 173.32. IR (Neat, cm -1 ): lambda max 1626.66, 2925.48,3336.25, 3418.21. MS (ESI) m/z: 415.43 (M+1); HRMS (ESI):m/z calcd for C 25 H 37 NO 4 . [M] 415.43. SOR: 34.3.
	In water; at 20 - 25℃;	The resulting crude (1 .05 g) was solved without further purification in 10,0 ml a 70.0 % aqueous solution of EtNH2 and the solution was stirred at 20-25 C for 2-3 days until the reaction was complete. The completion of the reaction was checked by TLC. A reaction crude containing about 10.0% by weight of acid bimatoprost (depending on the reaction temperature) was obtained. After extracting the product with 10.0 ml of toluene, Then, the obtained organic phase is washed with water until the washing water is substantially neutral, and then, it was concentrated at vacuum to obtain crude bimatoprost (0.82 g to 0.92) g with a overall yield from 76.5% to 85.5% calculated from acid bimatoprost.

Reference： [1]Patent: US2009/163596,2009,A1 .Location in patent: Page/Page column 18
[2]Patent: WO2010/104344,2010,A2 .Location in patent: Paragraph 106-108
[3]Patent: WO2005/58812,2005,A2 .Location in patent: Page/Page column 46-47
[4]Patent: EP2135860,2009,A1 .Location in patent: Page/Page column 15-16
[5]Asian Journal of Chemistry,2017,vol. 29,p. 2767 - 2770
[6]Patent: WO2017/182465,2017,A1 .Location in patent: Page/Page column 29; 30

3
[ 856240-62-5 ]
[ 1163135-95-2 ]
[ 155206-00-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hexamethyldisilazane;	This step of the synthesis produces the crude bimatoprost API by introduction of the upper side chain. The lactone moiety is first reduced to the lactol under standard diisobutylaluminum hydride conditions. The lactol is not isolated, but is treated directly in situ with Wittig reagent. The crude bimatoprost is a mixture of cis and trans isomers about the 5,6-double bond. The cis isomer is the major project. The trans isomer is controlled in the crude bimatoprost specifications by a limit of NMT 8% on each individual impurity.

Reference： [1]Patent: WO2003/74481,2003,A2 .Location in patent: Page/Page column 7

4
[ 108-30-5 ]
[ 155206-00-1 ]
[ 1043914-34-6 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; triethylamine; In dichloromethane; at 20℃; for 0.333333h;	200 mg of <strong>[155206-00-1]bimatoprost</strong>, 48 mg of succinic anhydride, 147 mg of 4-dimethylamino pyridine, 74 muL of triethyl amine and 4 mL dichloromethane are mixed together and placed on a shaker for 20 minutes at room temperature. Four mL of hexane were added to the solution to precipitate the linker- modified <strong>[155206-00-1]bimatoprost</strong>. After precipitation, the solvents were evaporated under reduced pressure until only a thick oily layer was left. 10 mL of 0.1 M calcium chloride (pH = 8) was added and the solution volume reduced to near dryness under reduced pressure. 10 mL of deionized (DI) water was added to redissolve all material. The redissolved sample was then placed in a 50 mL centrifuge vial and acidified with 1 M HCl to a pH 4. The solution turned a milky white as the product precipitated. The product was collected by centrifugation for 10 minutes at 3850 xG.
	With dmap; triethylamine; In dichloromethane; at 20℃; for 1h;Product distribution / selectivity;	200 mg of <strong>[155206-00-1]bimatoprost</strong> (0.48mmol), 48 mg of succinic anhydride (0.48mmol), 147 mg of 4- dimethylamino pyridine (DMAP) (1.2mmol), 74 muL of triethyl amine (TEA) (0.53mmol), 1 g of DEAE Sephadex (40-125 mum particle size) were weighed out. Next, 4 mL of dichloromethane were added to a vial. The succinic anhydride was added to the vial and dissolved in the dichloromethane by vortexing. Next, the DMAP was added and dissolved by vortexing. Next, the <strong>[155206-00-1]bimatoprost</strong> was added and dissolved by vortexing. Next, the TEA was added and dissolved by vortexing. Finally, the DEAE was added and mixed by vortexing and the vial was tightly capped. The capped vial was then placed on a wrist action shaker and shaken for 1 hour at room temperature. As the reaction was proceeding, the plunger from a 10 mL syringe was removed. Small circles of filter paper were cut out and wetted. The wet filter paper circles were used to plug the syringe opening. The filter paper is designed to retard the flow of the DEAE gel. The syringe was filled to the 1 mL line with dry DEAE beads. The beads were wetted using water and then methanol. The reaction mixture was then pipetted into the syringe. The gel was washed with 40 mL of 75% methanol and 40 mL of water to remove any impurities or unreacted material. The gel was then washed with 40 mL of IM NaCl to elute the product.

Reference： [1]Patent: WO2008/94659,2008,A2 .Location in patent: Page/Page column 68
[2]Patent: WO2008/94659,2008,A2 .Location in patent: Page/Page column 69-70

5
[ 155206-00-1 ]
[ 1163135-96-3 ]

Yield	Reaction Conditions	Operation in experiment
63%	With 2,3-dicyano-5,6-dichloro-p-benzoquinone; In 1,4-dioxane; dichloromethane; at 40℃; for 24h;	Example 20 15-keto <strong>[155206-00-1]Bimatoprost</strong> 1c A mixture of <strong>[155206-00-1]bimatoprost</strong> 1 (0.33 g, 0.8 mmol), DDQ (0.68 g, 3.0 mmol), CH2Cl2 (5 mL) and 1,4-dioxane (5 mL) was stirred for 24 h at 40 C. and evaporated in vacuo. The residue was purified by chromatography on a silica gel (20 g, eluent EtOAc then EtOAc/MeOH 20:1) to give 0.21 g (63%) of 15-keto <strong>[155206-00-1]bimatoprost</strong> 1c as yellow oil.
50%	With 2,3-dicyano-5,6-dichloro-p-benzoquinone; In 1,4-dioxane; at 20℃;Inert atmosphere;	Using a method from Taber, D. F.; Kanai, K. Tetrahedron 1998, 54, 11767- 11782, to a stirred solution of <strong>[155206-00-1]bimatoprost</strong> (100 rng, 0.240 mmol) in 1,4-dioxane (20 mL) was added portionwise DDQ (224 mg, 0.96 mmol). The resultant mixture was stirred at ambient temperature over night and then was washed with water (2 x 20 mL) and brine (2 x 20 mL). The organic layer was dried with Na2SO4, filtered and concentrated in vacuo leading to 15-keto-<strong>[155206-00-1]bimatoprost</strong> s-1 (54 mg, 0.13 mmol) in 50% yield as a reddish solid, which was used in the next step without further purification. 1H NMR (300 MHz, CDCI3): delta.1.14 (t, J=7.3 Hz, 3H), 1.35 (d, J=10.5 Hz, 1H),2.80-2.98 (m, 4H)1 3.20-3.35 (m, 2H), 4.05 (bm, 1 H), 4.10 (m, 1H), 5.36-5.42 (m, 2H), 6.16 (d, J=15.7 Hz, 1H), 6.68 (dd, J= 8.8, 15.7 Hz, 1 H).LCMS ESI (M+Na+): m/z 437.20.

Reference： [1]Patent: US2009/163596,2009,A1 .Location in patent: Page/Page column 18
[2]Patent: WO2009/136281,2009,A1 .Location in patent: Page/Page column 77

6
[ 107-10-8 ]
[ 130209-76-6 ]
[ 155206-00-1 ]

Yield	Reaction Conditions	Operation in experiment
62%	In methanol; at 90℃;	A solution of compound (11c) (about 40 g) prepared in EXAMPLE 21 in MeOH (44 mL) and 45% EtNH2 in MeOH (800 mL) was heated to about 90 C. The reaction mixture was cooled to about 30 C. and concentrated under vacuum to remove MeOH to provide 45 g of crude product. This was purified by column chromatography to furnish 27 g (94.8% HPLC purity, 73% yield) of crude Bimatoprost. A solution of Bimatoprost (27 g) in MeOH (about 26 mL) and MTBE (about 800 mL) was heated until the solution became clear, and then was cooled down. The resulting crystals were filtered and the filter cake was washed twice with MTBE (150 mL each) and dried under reduced pressure to give 22 g (99.7% HPLC purity, 62% yield based on compound 11c) of Bimatoprost. This could be further purified to 99.9% HPLC purity Bimatoprost by re-crystallization.Characterization of Bimatoprost:1H NMR (300 MHz, CD3OD): delta 1.09 (t, J=7.2 Hz, 3H), 1.50 (m, 1H), 1.62 (m, 3H), 1.83 (m, 2H), 2.11 (m, 8H), 2.68 (septet, J=7.5 Hz, 2H), 3.15 (q, J=7.2 Hz, 2H), 3.83 (m, 1H), 4.03 (t, J=6.45 Hz, 1H), 4.09 (m, 1H), 5.36 (m, 1H), 5.50 (m, 2H), 5.62 (d, J=6.3 Hz, 1 H), 7.20 (m, 5H), 7.89 (br, 1H).m/z (API-ES, Neg): 460 ([M+HCOO]-, 100%).

Reference： [1]Patent: US2009/259058,2009,A1 .Location in patent: Page/Page column 22-23

7
C₂₈H₄₀O₆ [ No CAS ]
[ 75-04-7 ]
[ 155206-00-1 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; at -10℃; for 2h;Inert atmosphere;	Under an atmosphere of nitrogen 250mL methylenechloride were added to 12.34g of (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenyl-pent-1-enyl)-cyclopentyl]-hept-5-enoic acid (compound (7), MW = 402.54; 26.1mmol; 1 equivalents) and the solution was cooled to -10C. At this temperature 5.1g of triethylamine (MW = 101.19; 50.4mmol; 1.9 equivalents) and 5.8g of pivalic acid chloride (MW = 120.58; 48.1mmol; 1.8 equivalents) were added. The reaction mixture was stirred for two hours. Then a solution of 2.3g ethylamine (MW = 45.08; 2.0 equivalents) in 10mL of methylene chloride was added. After stirring the reaction mixture for two hours at -10C, the mixture was warmed to room temperature. The reaction was quenched by adding 250mL of water and adjusting the pH to 2.0 with 1 M aqueous hydrochloric acid. After separation of the layers, the organic layers was washed with 250mL of saturated aqueous sodium bicarbonate, water and brine. After filtration the solution was concentrated under reduced pressure to give 18.4g of bimatoprost crude (yield: 95%; as determined by NMR). Bimatoprost crude was purified as described below.

Reference： [1]Patent: EP2135860,2009,A1 .Location in patent: Page/Page column 16-17

8
C₂₆H₃₆O₇ [ No CAS ]
[ 75-04-7 ]
[ 155206-00-1 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; at -10℃; for 2h;	250mL of methylene chloride were added to 12.3g of (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenyl-pent-1-enyl)-cyclopentyl]-hept-5-enoic acid (compound (7), MW = 402.54; 26.1mmol; 1 equivalents). The solution is cooled to -10C. At this temperature 5.1g of triethylamine (MW = 101.19; 50.4mmol; 1.9 equivalents) and 5.1g of ethyl chloroformate (MW = 108.52; 48.1mmol; 1.8 equivalents) were added and the mixture was stirred for two hours. A solution of 2.3g of ethylamine (MW = 45.08; 2.0 equivalents) in 10mL methylenchloride was added. After stirring the reaction mixture for two hours at -10C, the mixture was warmed to room temperature. The reaction was quenched by addition of 250mL of water and the pH is adjusted to 2.0 with 1 M aqueous hydrochloric acid. After separation of the layers, the organic layer was washed with 250mL of saturated aqueous sodium bicarbonate, water and brine. After filtration the solution was concentrated under reduced pressure to give 13.1g of bimatoprost crude (yield: 89%; as determined by NMR). Bimatoprost crude was purified as described below.

Reference： [1]Patent: EP2135860,2009,A1 .Location in patent: Page/Page column 17

Yield	Reaction Conditions	Operation in experiment
96%	In dichloromethane; Petroleum ether; at 10 - 30℃; for 10h;Purification / work up;	The crystalline form B of <strong>[155206-00-1]Bimatoprost</strong> (0.50g) obtained in Example 2 and isopropanol (25ml) were added to a 100ml eggplant-type flask, dissolved at 30C, and then decompressed and concentrated at 30C to dryness to obtain oily <strong>[155206-00-1]Bimatoprost</strong>; dichloromethane (20ml) was added and heated at 30C for dissolution; petroleum ether (60ml) was added dropwise at 30C under the condition of magnetic stirring, cooled to 10C, then continuously stirred at this temperature for 10h and filtered; and dichloromethane and petroleum ether (1:3) at 10C were washed for twice to three times and dried, thus obtaining 0.48g crystalline solid. An X-ray powder diffraction pattern is the same as that of Fig. 2, differential scanning calorimetry (DSC) is the same as that of Fig. 3 and infrared spectrogram is the same as that of Fig. 4. (Yield: 96%)
	With silica gel; In ethanol; n-heptane;preparative HPLC;Purification / work up;	<strong>[155206-00-1]Bimatoprost</strong> crude, as obtained by examples 2, 3, and 4 contained 4-5% of 15R-<strong>[155206-00-1]bimatoprost</strong> (29) and 2-3% of 5,6-trans-<strong>[155206-00-1]bimatoprost</strong> (30) relative to <strong>[155206-00-1]bimatoprost</strong>. The remaining impurities were Wittig reagent derived compounds. The assay of <strong>[155206-00-1]bimatoprost</strong> in the individual <strong>[155206-00-1]bimatoprost</strong> crude samples was in the range of 30% to 90%.a) chromatography 10g of <strong>[155206-00-1]bimatoprost</strong> crude (as obtained in example 3b) were dissolved in 50mL of heptane / EtOH 1 /1. The crude product was purified on a preparative HPLC system using silica as stationary phase and heptane / EtOH 5 / 95 as eluent. 7g of <strong>[155206-00-1]bimatoprost</strong> pure were obtained after evaporation of the solvent. The assay of <strong>[155206-00-1]bimatoprost</strong> after chromatography was 99.5% with impurity levels of <0.15%. The above HPLC procedure is preferably carried out on a silica gel column. Examples of suitable columns include WatersRT" Spherisorb, PhenomenexRTM Luna Cyano and Phenomenex"Luna Silica or YMC-Pack-Silica.b) crystallisation <strong>[155206-00-1]Bimatoprost</strong> as obtained in example 5a with an assay of 99.5% and impurity levels of <0.15% was further purified by crystallisation from acetonitrile or MTBE to give <strong>[155206-00-1]bimatoprost</strong> with 99.9% purity and impurity levels of <0.10%. The purity of <strong>[155206-00-1]bimatoprost</strong> was determined using a Chiracel OD-RH 4.6x150mm (5mum) column. Eluant A: 2.62g sulfamic acid in 1000g H2O; eluant B: 40:60 H2O/ acetonitrile, flow rate 1.1mL / min; 35C; 210nm.
	In dichloromethane; di-isopropyl ether; at 20 - 25℃;Purification / work up;	Step 8: Purification of <strong>[155206-00-1]Bimatoprost</strong>The crude <strong>[155206-00-1]Bimatoprost</strong> (1.2 g) was dissolved in dichloromethane (15 ml) at 20-25C to get clear solution. The reaction mass was filtered through micron filter to make particle free. Charged filtrate to RB flask and slowly added diisopropyl ether (90 ml) over a period of 30-45 minutes. The product was filtered and washed with diisopropyl ether to obtain 0.8-0.9 g pure <strong>[155206-00-1]Bimatoprost</strong>.

In hexane; ethyl acetate; at 25 - 70℃; for 2.25h;Purification / work up;

Into a 1 liter 4 necked round bottom flask fitted with a mechanical stirrer and a reflux condenser was charged crude <strong>[155206-00-1]bimatoprost</strong> (2 gms, obtained from Example 6 above) and ethyl acetate (30 ml). Heated the solution to about 65C to about 70C and stirred for 15 minutes at the same temperature. Added hexane (30 ml) at temperature about 65C to about 70C and cooled the solution to about 25C to about 30C over a period of 2 hours.Filtered the resultant product and washed with chilled ethyl acetate (10 ml) and hexane (10 ml). ). The wet product was dried at 35C to 40C under reduced pressure to provide the title compound Yield: 1.2 gms.HPLC purity (chiral): 99.61%Formula A: 0.35%Formula D: 0.03%Formula G: 0.01%.

10
[ 856240-62-5 ]
[ 1201226-16-5 ]
[ 155206-00-1 ]

Yield	Reaction Conditions	Operation in experiment
65%		Step 7: Preparation of the Bimatoflost {((Z) -7 - ((1R, 2R, 3R, 5S) -3,5-dihydroxy- 5-phenylpent-1-enyl) cyclopentyl) -N-ethylhept-5-enamide To a 50 ml 3-neck flask was added the compound of Formula VI (3.27 g, 6.56 mmol, 2 eq) prepared in Step 3, and 10 ml of THF was added and stirred. After cooling to 0 C, potassium tert-butoxide (1.47 g, 13.12 mmol, 8 eq) was added and stirred for 10 min. The mixture was stirred at 0 C for 30 minutes, slowly warmed to room temperature and stirred. To a solution of the compound of formula V (0.5 g, 1.64 mmol, 1 eq) prepared in step 6 at 0 C in 5 ml of THF Dissolve it slowly and cool it at room temperature Then, 10 ml of H2O and 10 ml of ethyl acetate were added to separate layers. The aqueous layer was extracted with 5 ml of ethyl acetate. The organic layer was washed with 20 ml of a 10% aqueous NaCl solution. The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was then subjected to column chromatography with methylene chloride: MeOH = 9: 1 to obtain a white crystalline compound (0.45 g, 65%).
41%		7O. (Z)-7-((1R,2R,3R,5S)-3,5-Dihydroxy-2-((S,E)-3-hydroxy-5-phenylpent-1-enyl)cyclopentyl)-N-ethylhept-5-enamide, bimatoprost, 97 (5-(Ethylamino)-5-oxopentyl)triphenylphosphonium bromide 96 (1.37 g, 2.91 mmol, 6 eq.) was added to a flame dried Schlenk flask, under N2, and anhydrous THF (10 ml) added. The resulting suspension was cooled to 0 C. KOt-Bu (653.0 mg, 5.82 mmol, 12 eq.) was added in one portion and the resulting orange mixture stirred at 0 C. for 40 min. A solution of crude triol 94 (0.485 mmol, 1 eq.) in anhydrous THF (2.5 ml) was added dropwise via syringe. After complete addition the mixture was stirred at r.t. for 1 h. The reaction was quenched with saturated aq. NH4Cl (10 ml) and extracted with EtOAc (510 ml). The combined organic phases were dried (MgSO4), filtered, and concentrated to give the crude material as solids. These were triturated with EtOAc (10 ml) and the solids filtered and washed with EtOAc (410 ml). The filtrate was concentrated under vacuum and purified by column chromatography on silica, eluting with EtOAc/MeOH (97.5:2.5 to 95:5) to give 97 (99.2 mg) as a yellowish oil which was further purified by preparative TLC (EtOAc/MeOH 5%) to give 97 (82.6 mg, 41% over 2 steps) as a clear, colourless oil. Analytical data consistent with the literature (Zanoni, G. et al., Tetrahedron 66, 7472-7478 (2010); Gutman, A. et al., US 20090163596 (2009)). numax (film)/cm-1 3300 (broad), 2930, 1643, 1550, 1453, 1332, 1293, 1048, 1029, 968, 729, 698 1H NMR (400 MHz; CDCl3) deltaH=1.09 (t, J=7.1 Hz, 3H, CH3), 1.42-2.40 (m, 14H, 6CH2, 2CH), 2.67 (m, 2H, CH2), 3.22 (dq, J=7.1, 6.3 Hz, 2H, CH2NH), 3.41 (broad s, 3H, 3OH), 3.80-4.30 (broad m, 3H, 3CHOH), 5.37 (m, 2H, 2=CH), 5.47 (dd, J=15.2, 7.9 Hz, 1H, =CH), 5.59 (dd, J=15.2, 7.9 Hz, 1H, =CH), 5.90 (broad s, 1H, NH), 7.17 (m, 3H, ArCH's), 7.26 (m, 2H, ArCH's) 13C NMR (100 MHz; CDCl3) deltaC=14.8 (CH3), 25.4 (CH2), 25.6 (CH2), 26.7 (CH2), 31.9 (CH2), 34.4 (CH2NH), 35.8 (CH2C=O), 38.8 (CH2), 42.9 (CH2), 50.2 (CH), 55.5 (CH), 72.3 (CHOH), 72.4 (CHOH), 77.7 (CHOH), 125.8 (ArCH), 128.4 (2ArCH), 128.5 (2ArCH), 129.1 (=CH), 129.7 (=CH), 133.7 (=CH), 135.1 (=CH), 142.0 (ArC), 173.4 (C=O) m/z (ESI+) 438.2 [MNa]+ HRMS (ESI+) calcd for C25H37NO4Na [MNa]+ 438.2614. found 438.2615. [alpha]D22 +41.1 (c. 0.35, CH2Cl2) (lit.-Zanoni, G. et al., Tetrahedron 66, 7472-7478 (2010), +32.7 (c. 0.33, CH2O2)) (lit.-Gutman, A. et al., US 20090163596 (2009), +36 (c. 1, MeOH))
		A suspension of 15.0g of (4-ethylcarbamoyl- butyl)triphenylphosphonium bromide (MW = 470.39; 3.2 equivalents) in 50mL of THF was cooled to 0C. At this temperature 11.9g of a 2M solution of potassium-tert butoxide (MW = 112.21; 3.3 equivalents) in THF were added drop wise over 30min and stirring was continued at 0C for 30min. The resulting orange red suspension was cooled to a mass temperature of -17C. To the red suspension of the ylide a solution of 3.57g of (3alphaR,4R,5R,6alphaS)-4-((R)-3-hydroxy-5-phenyl-pent-1-enyl)-hexahydro-cyclopenta[b]furan-2,5-diol (compound (6), MW = 306.41; 1 equivalents) in 24mL of THF was added over 30min and the reaction mixture was stirred at -17C for about 20h. To the slightly orange suspension 180mL of brine and 80mL of MTBE were added and the pH was adjusted to 2.0 by addition of 20% aqueous sulfamic acid. After stirring for 5min the layers were separated. The aqueous layer was extracted once with 80mL of MTBE. The MTBE layers were combined and washed with 80mL of brine and the pH was adjusted to 7.5 by addition of saturated aqueous sodium bicarbonate. The filtered organic layer was concentrated at 45C and 100mbar to give 15.0g of crude bimatoprost (yield -80% as estimated by NMR), which was purified as described below.

82.6 mg

(5-(Ethylamino)-5-oxopentyl)triphenylphosphonium bromide 96 (1.37 g, 2.91 mmol, 6 eq.) was added to a flame dried Schlenk flask, under N2, and anhydrous THF (10 ml) added. The resulting suspension was cooled to 0 C. KOt-Bu (653.0 mg, 5.82 mmol, 12 eq.) was added in one portion and the resulting orange mixture stirred at 0 C for 40 min. A solution of crude triol 94 (0.485 mmol, 1 eq.) in anhydrous THF (2.5 ml) was added dropwise via syringe. After complete addition the mixture was stirred at r.t. for 1 h. The reaction was quenched with saturated aq. NH4CI (10 ml) and extracted with EtOAc (5 x 10 ml). The combined organic phases were dried (MgS04), filtered, and concentrated to give the crude material as solids. These were triturated with EtOAc (10 ml) and the solids filtered and washed with EtOAc (4 x 10 ml). The filtrate was concentrated under vacuum and purified by column chromatography on silica, eluting with EtOAc/MeOH (97.5:2.5 to 95:5) to give 97 (99.2 mg) as a yellowish oil which was further purified by preparative TLC (EtOAc/MeOH 5%) to give 97 (82.6 mg, 41% over 2 steps) as a clear, colourless oil. Analytical data consistent with the literature (Zanoni, G. et al., Tetrahedron 66, 7472-7478 (2010); Gutman, A. et al., US 20090163596 (2009)). max (filmVcm-1 3300 (broad), 2930, 1643, 1550, 1453, 1332, 1293, 1048, 1029, 968, 729, 698 *H NMR (400 MHz; CDCI3) deltaEta = 1.09 (t, J = 7.1 Hz, 3H, CH3), 1.42-2.40 (m, 14H, 6 x CH2, 2 x CH), 2.67 (m, 2H, CH2), 3.22 (dq, J = 7.1, 6.3 Hz, 2H, CH2NH), 3.41 (broad s, 3H, 3 x OH), 3.80-4.30 (broad m, 3H, 3 x CHOH), 5.37 (m, 2H, 2 x =CH), 5.47 (dd, J = 15.2, 7.9 Hz, 1H, =CH), 5.59 (dd, J = 15.2, 7.9 Hz, 1H, =CH), 5.90 (broad s, 1H, NH), 7.17 (m, 3H, ArCH's), 7.26 (m, 2H, ArCH's) 13C NMR ( 100 MHz; CDCI3) 5C = 14.8 (CH3), 25.4 (CH2), 25.6 (CH2), 26.7 (CH2), 31.9 (CH2), 34.4 (CH2NH), 35.8 (CH2C=0), 38.8 (CH2), 42.9 (CH2), 50.2 (CH), 55.5 (CH), 72.3 (CHOH), 72.4 (CHOH), 77.7 (CHOH), 125.8 (ArCH), 128.4 (2 x ArCH), 128.5 (2 x ArCH), 129.1 (=CH), 129.7 (=CH), 133.7 (=CH), 135.1 (=CH), 142.0 (ArC), 173.4 (C=0) m/z (ESI+) 438.2 [MNa]+ HRMS (ESI+) calcd for Q^IV^Na [MNa]+ 438.2614, found 438.2615 [a]D22 +41.1 (c. 0.35, CH2CI2) (lit. - Zanoni, G. et al., Tetrahedron 66, 7472-7478 (2010), +32.7 (c. 0.33, CH2CI2)) (lit. - Gutman, A. et al., US 20090163596 (2009), +36 (c. 1, MeOH))

Reference： [1]Patent: KR2017/25682,2017,A .Location in patent: Paragraph 0090; 0093; 0128-0130
[2]Patent: US2015/158837,2015,A1 .Location in patent: Paragraph 0591-0598
[3]Patent: EP2135860,2009,A1 .Location in patent: Page/Page column 17
[4]Patent: WO2013/186550,2013,A1 .Location in patent: Page/Page column 111; 112
[5]Angewandte Chemie - International Edition,2019,vol. 58,p. 9923 - 9927
Angew. Chem.,2019,vol. 131,p. 10028 - 10032,5

11
[ 927-58-2 ]
[ 155206-00-1 ]
[ 1194047-71-6 ]

Yield	Reaction Conditions	Operation in experiment
6%	With dmap; In dichloromethane; at 0℃; for 72h;Inert atmosphere;	To a suspension of <strong>[155206-00-1]bimatoprost</strong> (Cayman Chemicals; 540 mg, 1.30 mmol) in anhydrous dichloromethane (5.2 ml_) at 0C was added DMAP (850 mg, 1.33 mmol) and 4-bromobutyryl chloride (0.154 ml, .32 mmol) and allowed to stir for 72h. The resultant mixture was filtered and solvent removed by nitrogen flow. The residue was redissolved in dichloromethane, washed with saturated NaHCO3 and brine, and dried over MgSO4 to give a crude mixture, which was submitted to preparative reverse phase HPLC to give as a major separable pure component, 11-bromoester h-1 as a colorless oil, 42 mgO).1H NMR (400 MHz, DMSO-d6) delta 7.70 (bs., 1 H), 7.22 - 7.32 (m, 2 H), 7.10 - 7.21 (m, 3 H), 5.37 - 5.54 (m, 3 H), 5.20 - 5.35 (m, 1 H), 4.72 - 4.86 (m, 2 H), 4.57 - 4.66 (m,1 H), 3.84 - 4.01 (m, 2 H), 3.51 (t, J=6.57 Hz, 2 H), 2.96 - 3.10 (m, 2 H), 2.54 - 2.66 (m,2 H)1 2.21 - 2.45 (m, 4 H), 2.05 - 2.21 (m, 1 H), 1.89 - 2.04 (m, 7 H), 1.57 - 1.73 (m, 2 H), 1.30 - 1.54 (m, 4 H), 0.98 (t, J=7.33 Hz, 3 H). <n="53"/>LCMS (ESI): m/z 588.2 (M+Na)+HRMS: Calcd for C29H42BrNO5Na [M+Na]+: 586.2138. Found: 586.2132.

Reference： [1]Patent: WO2009/136281,2009,A1 .Location in patent: Page/Page column 51-52

12
[ 37693-18-8 ]
[ 155206-00-1 ]
[ 1194047-69-2 ]

Yield	Reaction Conditions	Operation in experiment
15%	With dmap; In dichloromethane; at 20℃; for 72h;Inert atmosphere;	To a solution of <strong>[155206-00-1]bimatoprost</strong> (Cayman Chemicals 16820, Lot 188757; 123 mg,0.30 mmol) in DCM (3 mL) at 00C was added DMAP (39 mg, 0.31 mmol) followed by the slow addition of 4-chlorobutyl chloroformate (43 uL, 0.31 mmol). After 3 days at ambient temperature, the mixture was diluted with DCM and washed with water (1x) and brine (1x). The DCM layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude mixture of regioisomers and diacylated products was submitted to column chromatography (ethyl acetate-hexane 25-100%, followed by methanol-dichloromethane (5-15%) to provide as the major component isolated, 11- acylated chloride g-1 (25 mg, 15%) as a colorless oil. LCMS (ES-API): m/z 572.2 (M+Na)+.

Reference： [1]Patent: WO2009/136281,2009,A1 .Location in patent: Page/Page column 48

13
[ 907625-06-3 ]
[ 155206-00-1 ]
[ 1194047-41-0 ]
[ 1194047-42-1 ]
[ 1194047-44-3 ]
[ 1194047-43-2 ]

Yield	Reaction Conditions	Operation in experiment
12.4%; 1.7%	With DMAP resin (PS-DMAP); In dichloromethane; at 0 - 20℃; for 18.3333h;Inert atmosphere;	6-(Nitrooxy)hexanoic acid (1.77 g, 10.0 mmol) was dissolved in anhydrous dichloromethane (80 ml_) under nitrogen at ambient temperature. The solution was cooled to 0C, successively added 4 drops of anhydrous DMF and oxalyl chloride (870 uL, 10 mmol), and allowed to warm to ambient temperature. After 12h, the mixture was filtered through a silica plug, which was washed with anhydrous dichloromethane (50 mL). The solvent was evaporated to give 1.71g (88%) of crude presumed acid chloride (6-nitroxy-hexanoyl chloride) as a yellow oil, which was immediately used without further purification. To a suspension of bimataprost (Cayman Chemicals; 831 mg, 2.00 mmol) in dichloromethane (10 mL) at 0C were added DMAP resin (Argonaut (Biotage "PS- DMAP"); 2.75 g of 1.60 mmol/g, 4.20 mmol) and the above crude 6-nitroxy-hexanoyl chloride (822 mg, 2.1 mmol) under nitrogen. After 20 min at 0C, the cooling bath was removed and stirred at ambient temperature 18 hours. The resin was filtered off, and the filtrate concentrated, then the crude mixture was separated by preparative reverse phase HPLC to provide 15-ester F-1 (142 mg, 12.4%) as colorless oil, 9-ester F-2 (20 mg, 1.7%) as a white solid, 9,11-diacyl nitrate F-3 as colorless oil, and 11.15-diacyl ester F-4 as colorless oil, respectively.; Example F-11H NMR (700 MHz, DMSO-d6) delta 0.98 (t, J=7.30 Hz, 3 H), 1.31 (dq, J=7.74, 7.59 Hz, 2 H), 1.42 (dd, J=15.48, 3.98 Hz, 1 H), 1.45 - 1.50 (m, 2H), 1.50 - 1.54 (m, 2 H), 1.57 - 1.63 (m, J=7.35, 7.35, 7.19, 6.86 Hz, 2 H), 1.63 - 1.70 (m, 2 H), 1.95 (d, J=7.08 Hz, 2 H), 1.98 (t, J=7.52 Hz, 3 H), 2.11 (t, J=15.70 Hz, 1 H), 2.25 (t, J=7.30 Hz, 2 H), 2.33 (ddd, J=14.82, 9.29, 5.53 Hz, 1 H), 2.45 (t, J=8.18 Hz, 1 H), 2.55 - 2.64 (m, 2 H), 2.98 - 3.06 (m, 2H), 3.91 (qd, J=5.68, 5.53 Hz, 1 H), 3.95 (d, J=3.98 Hz, 1 H), 4.46 (t, J=6.63 Hz, 2 H), 4.61 (d, J=3.98 Hz1 1 H), 4.75 (d, J=4.87 Hz, 1 H), 4.77 (dd,J=7.74, 4.64 Hz, 1 H), 5.24 - 5.32 (m, 1 H), 5.38 - 5.49 (m, 3 H), 7.16 (d, J=7.52 Hz, 3 H), 7.25 (t, J=7.74 Hz, 2 H), 7.70 (t, J=4.64 Hz, 1 H). 13C NMR (176 MHz, DMSO-cfe): delta 14.78, 24.04, 24.34, 24.49, 25.29, 25.67,26.31, 31.14, 33.20, 33.40, 34.90, 40.00, 41.30, 48.67, 50.77, 69.27, 69.92, 73.88, 78.27, 125.54, 128.17, 128.22, 128.94, 129.24, 129.84, 136.07, 142.23, 171.57, 172.62.Confirmed the structure as depicted, based upon detailed inspection of proton chemical shifts, integration, couplings, as well as key homo and hetero-nuclear correlation observed in 2D spectra. The absence of carbon correlations in the HSQC spectrum allowed for the identification of hydroxyl protons. The observation of correlations from the hydroxyl protons to neighboring methine and methylene protons in the COSY spectrum enabled the determination of substitution of the cyclopentyl ring.Key COSY correlations observed: <n="45"/> Key HMBC correlations observed : A key correlation for the site of attachment was found in the HMBC spectrum for proton at C-11 (numbered 1 above) assigned to resonance at delta 4.77 (dd, J=7.74, 4.64 Hz1 1 H) to the carbonyl of the ester (numbered 7 above) at delta 172.62.LCMS ESI: m/z 597.2 (M+Na+). HRMS. Calcd for C29H42BrNO5Na [M+Na]+: 597.3146. Found: 597.3134 <n="46"/>Example F-2 1H NMR (700 MHz, DMSO-d6) delta 0.98 (t, J=7.30 Hz, 3 H), 1.17 - 1.30 (m, 2 H), 1.33 - 1.41 (m, 4 H), 1.47 (dt, J=15.48, 7.74 Hz, 2 H), 1.56 (qd, J=7.67, 7.52 Hz, 2 H), 1.59 - 1.74 (m, 5 H), 1.86 (dd, J=13.71 , 7.96 Hz, 1 H), 1.90 - 1.96 (m, 1 H), 1.98 (t, J=7.52 Hz, 2 H)1 2.02 (t, J=5.09 Hz, 2 H), 2.17 (dt, J=11.94, 7.96 Hz, 1 H), 2.29 (q,J=7.08 Hz, 2 H), 2.36 (ddd, J=14.82, 8.62, 6.19 Hz, 1 H), 2.56 - 2.66 (m, 2 H), 3.03 (dd, J=7.30, 5.53 Hz, 2 H), 3.76 (dd, J=13.71 , 2.65 Hz, 1 H), 3.88 - 3.95 (m, 1 H), 4.50 (t, J=6.63 Hz, 2 H), 4.73 (d, J=4.42 Hz, 1 H), 4.75 (d, J=5.75 Hz, 1 H), 4.91 (t, J=4.64 Hz, 1 H), 5.29 (d, J=4.42 Hz, 1 H), 5.36 - 5.44 (m, 1 H), 5.46 - 5.53 (m, 1 H), 7.10 - 7.20 (m, 3 H), 7.26 (t, J=7.52 Hz, 2 H), 7.70 (qd, J=5.68, 5.53 Hz, 1 H).13C NMR (176 MHz, DMSO-d6) delta 14.78, 24.00, 24.58, 24.64, 25.23, 25.73, 26.33, 31.32, 33.19, 33.57, 34.85, 40.01, 41.45, 46.55, 54.70, 70.30, 73.67, 73.76, 75.04, 125.57, 128.05, 128.23, 128.26, 129.73, 130.77, 136.00, 142.27, 171.43, 172.27.Confirmed the structure as depicted based upon detailed inspection of proton chemical shifts, integration, couplings, as well as key homo and hetero-?uclear correlation observed in 2D spectra. The absence of carbon correlations in the HSQC spectrum allowed for the identification of hydroxyl protons. The observation of correlations from the hydroxyl protons to neighboring methine and methylene protons in the COSY spectrum enabled the determination of substitution of the cyclopentyl ring. Key COSY correlations observed: <n="47"/> The COSY and HSQC helped assign the hydroxyl protons to resonances at delta 4.73 (d, J=4.42 Hz, 1 H), 4.75 (d, J=5.75 Hz, 1 H) and methine protons; C-9 (numbered 4 above) to delta 4.91 (t, J=4.64 Hz, 1 H), C-11 (numbered 1 above) to ...

Reference： [1]Patent: WO2009/136281,2009,A1 .Location in patent: Page/Page column 41-47

14
[ 4426-47-5 ]
[ 155206-00-1 ]
[ 1194047-63-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	In dichloromethane; at 42℃; for 1h;Inert atmosphere;Product distribution / selectivity;	Following an analogous procedure from Bundy, G. L.; Peterson, D. C; Cornette, J. C; Miller, W. L; Spilman, C. H.; Wilks, J. W. J. Med. Chem. 1983, 26, 1089-1099, to <n="31"/>a solution of <strong>[155206-00-1]bimatoprost</strong> (Cayman Chemicals 16820, Lot 188757; 679 mg, 1.63 mmol) in DCM (10.9 mL) was added butylboronic acid (187 mg, 1.84 mmol). After 1 hour at 42C, solvent was removed under reduced pressure and dried under high vacuum pump for 2 hours. Fresh DCM was added and stirred at 42C for another hour. Solvent was removed and dried under high vacuum pump for 1.5 hour. Fresh DCM was added again and stirred at 42C for 16 hours. Solvent was evaporated and dried in vacuum oven at 45C for 3 hours to give 904 mg (100%) of boronate b-1 as an oil, which was used directly in the next step without further purification.1H NMR (400 MHz, DMSO-cfe) delta 0.50 - 0.66 (m, 2 H), 0.76 - 0.91 (m, 3 H)1 0.98 (t, J=7.20 Hz, 3 H), 1.16 - 1.35 (m, 4 H), 1.52 (quin, J=7.39 Hz, 2 H), 1.57 - 1.71 (m, 2 H),1.74 (br. s., 1 H), 1.78 - 2.09 (m, 6 H), 2.08 - 2.23 (m, 2 H), 2.23 - 2.32 (m, 1 H), 2.52 - 2.65 (m, 2 H), 2.95 - 3.12 (m, 2 H), 3.79 - 3.93 (m, 1 H), 4.02 (s, 1 H), 4.25 (br. s., 1 H),4.75 (d, J=4.55 Hz, 1 H), 5.26 - 5.54 (m, 4 H)1 7.09 - 7.22 (m, 3 H), 7.26 (t, J=7.45 Hz, 2 H)1 7.62 - 7.82 (m, 1 H).
	In tert-butyl methyl ether; at 40℃; for 1h;	Methyltertbutyl ether (2800mL, l4vol.) was charged in a flask. <strong>[155206-00-1]Bimatoprost</strong> (200 g, 1 eq.) was added and the equipment was rinsed with methyltertbutyl ether (200 mL, 1 vol.). Butyl boronic acid (58.94 g, 1.13 eq.) was added to the resulting suspension in one portion, the equipment was rinsed with methyltertbutyl ether (200 mL, 1 vol.). The mixture was heated to 40C for 1 hour. The reaction was monitored by 1 H (0091) NMR till conversion >97%. (0092) The reaction mixture was cooled to 20C to 25C, clarified on a glass filter and washed with methyltertbutyl ether (200 mL, 1 vol.). The filtrate was charged in the 4L three-neck round bottomed flask, the equipment was rinsed with methyltertbutyl ether (100 mL, 0.5 vol.) and the media was heated at a temperature about 40C under vacuum for azeotropic distillation. Rinsing with methyltertbutyl ether and azeotropic distillation was continued till the water content of (Z)-7-[(lS,5R,6R,7R)-3-butyl-6-[((E,3S)-3- hydroxy-5 -phenyl-pent- 1 -enyl]-2,4-dioxa-3-borabicyclo[3.2.1 )octan-7-yl]-N-ethyl-hept- 5-enamide (compound (II)) was equal to or below 0.25%. Compound of formula (II) was obtained with quantitative yield (281.22 g).

Reference： [1]Patent: WO2009/136281,2009,A1 .Location in patent: Page/Page column 29-30
[2]Patent: WO2019/162149,2019,A1 .Location in patent: Page/Page column 13; 16-17

15
[ 935472-60-9 ]
[ 155206-00-1 ]
[ 1194047-46-5 ]
[ 1194047-45-4 ]
[ 1194047-56-7 ]
[ 1194047-57-8 ]
[ 1194047-55-6 ]

Yield	Reaction Conditions	Operation in experiment
2%; 15%; 18%; 4%; 5%	With dmap; In dichloromethane; at 20℃; for 60h;Inert atmosphere;	<strong>[155206-00-1]Bimatoprost</strong> (1.00 g, 2.41 mmol) was dissolved in DCM (24.1 mL), treated with 4- (nitrooxy)butyl 4-nitrophenyl carbonate (p-1; 1.45 g, 4.82 mmol) and DMAP (607 mg, <n="69"/>4.82 mmol), and allowed to stir at ambient temperature for 6Oh. The resultant mixture was diluted with DCM, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to a crude mixture, which was purified via successive cycles of chromatography: MPLC (10-100% EA/hexane, followed with 5-15% methanol in DCM), then preparative HPLC to afford several pure compounds as follows:11 -Carbonate G-1: 210 mg (15%) pale yellow oil15-Carbonate G-2: 30 mg (2%) pale yellow oil. P-1 tri-Nitrate P-1 : 124 mg (5%) pale yellow oil.1H NMR (400 MHz, DMSO-cfe) delta 0.98 (t, J=7.20 Hz, 3 H), 1.41 - 1.55 (m, 2 H), 1.59 - 1.78 (m, 13 H), 1.80 - 2.15 (m, 9 H), 2.43 - 2.50 (m, 1 H), 2.54 - 2.65 (m, 3 H), 2.96 - 3.10 (m, 2 H), 3.99 - 4.18 (m, 6 H), 4.33 - 4.33 (m, 0 H), 4.45 - 4.62 (m, 6 H), 4.81 (ddd, J=8.91 , 7.26, 3.79 Hz, 1 H)1 4.87 (t, J=4.67 Hz, 1 H), 4.93 - 5.04 (m, 1 H), 5.25 - 5.41 (m, 2 H), 5.59 - 5.72 (m, 2 H), 7.13 - 7.23 (m, 3 H), 7.23 - 7.34 (m, 2 H), 7.69 (t, J=5.18 Hz, 1 H).Anal. Calcd for C40H58N4Oi9O^SH2O: C, 62.00; H, 7.72; N, 4.82. Found C, 62.06; H, 7.76; N, 4.90. P-211, 15-di-Nitrate P-2: 320 mg (18%) pale yellow oil.1H NMR (400 MHz, DMSO-d6): delta 0.97 (t, J=7.20 Hz, 3 H), 1.38 - 1.58 (m, 4 H), 1.58 - 1.77 (m, 8 H), 1.79 - 2.03 (m, 7 H), 2.05 - 2.17 (m, 1 H), 2.34 (ddd, J=14.78, 9.09, <n="70"/>5.43 Hz, 1 H)1 2.44 - 2.48 (m, 1 H), 2.52 - 2.63 (m, 2 H), 2.96 - 3.07 (m, 2 H)1 3.95 (d, J=4.04 Hz, 1 H), 3.98 - 4.15 (m, 4 H), 4.51 (ddd, J=12.88, 6.32, 6.06 Hz, 4 H), 4.64 - 4.76 (m, 2 H), 4.96 (q, J=6.48 Hz, 1 H), 5.28 (dt, J=10.93, 7.17 Hz, 1 H), 5.34 - 5.46 (m, 1 H), 5.48 -5.69 (m, 2 H), 7.11 - 7.21 (m, 3 H), 7.22 - 7.32 (m, 2 H), 7.69 (t, J=5.31 Hz, 1 H).LCMS (M+Na+): m/z 760.2.The critical aspect of confirming this structure was assignment of methine signals (H-8,H-9,H-11, H-12.H-15 - see non-conventional numbering and structure below) and hydroxyl signals through inspection of 1D proton, 2D HSQC1COSY and HMBC spectra. The hydroxyl group at C-9 was identified through inspection of HSQC spectrum, looking for signals in the proton spectrum with an absence of a cross peak in the HSQC. The hydroxyl group was located relative to methine H-8 and methylene H-5 through inspection of COSY spectrum. Clear and distinct coupling from H-15 to H-10a and H-12 to H-9a also observed in COSY spectrum. HMBC spectrum allowed for the assignment of methine protons H-9 and H-15 relative to distinct carbonyls C-7 and C-13a, as shown in the picture below. NMR correlations for P-2 P-Z9, 11-di-Nitrate P-3: 78 mg (4%) pale yellow oil.1H NMR (400 MHz, DMSO-d6): delta 0.97 (t, J=7.20 Hz, 3 H), 1.41 - 1.51 (m, 2 H), 1.58 - 1.76 (m, 11 H), 1.76 - 2.12 (m, 7 H), 2.38 - 2.48 (m, 1 H), 2.52 - 2.65 (m, 3 H), 2.96 - 3.08 (m, 2 H), 3.88 - 3.98 (m, 1 H), 4.00 - 4.15 (m, 4 H), 4.52 (dt, J=17.62, 6.09 <n="71"/>Hz1 4 H)1 4.73 -4.83 (m, 2 H), 4.86 (t, J=4.93 Hz, 1 H), 5.25 - 5.39 (m, 2 H), 5.43 - 5.63 (m, 2 H), 7.10 - 7.20 (m, 3 H), 7.21 - 7.30 (m, 2 H), 7.69 (s, 1 H).LCMS (M+Na+): m/z 760.2.The critical aspect that confirmed this structure by NMR was assignment of the methine signals (H-8, H-9, H-11 , H-12, H-15- see non-conventional numbering and structure below) and hydroxyl signals through inspection of 1D proton, 2D HSQC, COSY, and HMBC spectra. The hydroxyl group at C-15 was identified through inspection of HSQC spectrum, looking for signals in the proton spectrum with an absence of a cross peak in the HSQC. This hydroxyl group was located relative to methines H-14 and H-16 through inspection of COSY spectrum showing clear and distinct coupling from H-15 to H-14. COSY spectrum also indicated relative position of H-8 to H-9 and H-12. HMBC spectrum allowed for the assignment of methine protons H-9 and H-11 relative to distinct carbonyls C-7 and C-22. HMBC correlations also indicated position of hydroxyl proton H-12a relative to C-14. NMR Correlations for P-3

Reference： [1]Patent: WO2009/136281,2009,A1 .Location in patent: Page/Page column 67-70

16
[ 1194047-73-8 ]
[ 155206-00-1 ]
[ 1194047-48-7 ]

Yield	Reaction Conditions	Operation in experiment
30%	With DMAP resin (PS-DMAP); In dichloromethane; at 0 - 20℃; for 72.3333h;Inert atmosphere;	Crude 4-[4-(nitrooxy)butoxy]-4-oxobutanoic acid (30 mg, 0.13 mmol) was dissolved in anhydrous dichloromethane (1.28 ml_) under N2 at room temperature. The solution was cooled to O0C and successively added anhydrous DMF (0.25 ml_) and oxalyl chloride (10 uL, 0.128 mmol). After stirring at ambient temperature for 12h, the mixture was filtered through a silica plug, which was washed with anhydrous dichloromethane (5 ml_). The solvent was removed to yield 32 mg (100%) of presumed acid chloride (4-(nitrooxy)butyl 4-chloro-4-oxobutanoate) as a colorless oil, which was immediately used without further characterization or purification.To a suspension of <strong>[155206-00-1]bimatoprost</strong> (Cayman Chemicals; 25 mg, 0.024 mmol) in dichloromethane at O0C was added DMAP resin (Argonaut (Biotage "PS-DMAP"); 30 mg of 1.6 mmol/g, 0.024 mmol) and the above crude 4-(nitrooxy)butyl 4-chloro-4- oxobutanoate. After 20 min at 00C, the cooling bath was removed, and allowed to stir at ambient temperature for 72 h. The resin was filtered off, and the filtrate was concentrated, and gave a crude mixture as an oil, which was purified by flash chromatography with a Biotage instrument, eluting with a gradient of EtOAc with CHaCI2, 25-100%, to yield 19 mg (30%) of J-1 as a colorless oil.1H NMR (400 MHz, DMSO-J6) delta 7.70 (s, 1 H), 7.26 (t, J=7.45 Hz, 2 H), 7.17 (d, J=7.83 Hz, 3 H), 5.76 (s, 2 H), 5.36 - 5.52 (m, 3 H), 5.31 (s, 1 H), 4.75 (d, J=4.80 Hz, 2 H), 4.62 (d, J=4.04 Hz, 1 H), 4.48 - 4.58 (m, 4 H), 3.93 (d, J=18.44 Hz, 2 H), 2.96 - 3.09 (m, 2 H), 2.63 - 2.71 (m, 1 H), 2.56 (d, J=1.77 Hz, 3 H), 2.22 - 2.36 (m, 2 H), 1.96 (s, 2 H), 1.56 - 1.80 (m, 10 H), 1.34 - 1.53 (m, 4 H), 0.98 (t, J=7.20 Hz, 3H). LCMS (ESI): m/z 655.2 (M+Na)+. HRMS: Calcd for C33H48N2O10Na [M+Na]+: 655.3201. Found: 655.3180

Reference： [1]Patent: WO2009/136281,2009,A1 .Location in patent: Page/Page column 54

17
[ 1224443-45-1 ]
[ 75-04-7 ]
[ 155206-00-1 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; N,N-dimethyl-formamide;Product distribution / selectivity;	Example 86 To 1.0 gram of bimataprost arginine salt (9) in DMF (20 mL) is added 2.01 equivalents of 2M ethyl amine solution in THF (Cat No.395072, Sigma-Aldrich, St. Louis, Mo.) and 1.5 eq of EDC. and the solution is stirred overnight. Added is at least 5 equivalents of a 3:1 mixture of saturated aqueous ammonium chloride and 1 M hydrochloric acid (Sigma-Aldrich, St. Louis, Mo.), and the solution is extracted with ethyl acetate, washed and purified. Isolated is bimataprost N-ethyl amide (10)
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; N,N-dimethyl-formamide;Product distribution / selectivity;	Example 86 To 1.0 gram of bimataprost arginine salt (9) in DMF (20 mL) is added 2.01 equivalents of 2M ethyl amine solution in THF (Cat No.395072, Sigma-Aldrich, St. Louis, Mo.) and 1.5 eq of EDC. and the solution is stirred overnight. Added is at least 5 equivalents of a 3:1 mixture of saturated aqueous ammonium chloride and 1 M hydrochloric acid (Sigma-Aldrich, St. Louis, Mo.), and the solution is extracted with ethyl acetate, washed and purified. Isolated is bimataprost N-ethyl amide (10)

Reference： [1]Patent: US2010/105771,2010,A1 .Location in patent: Page/Page column 17
[2]Patent: US2010/105775,2010,A1 .Location in patent: Page/Page column 19

18
[ 1240483-19-5 ]
[ 155206-00-1 ]

Yield	Reaction Conditions	Operation in experiment
91%		Preparation of the compound X (Bimatoprost)HCl 1.2 N (2 mL) is added at room temperature to a solution of the compound IX (950 mg, 1.5 mmoles) in a tetrahydrofuran/water 1:1 (50 mL) mixture, the reaction is performed under vigorous stirring and is complete after approximately 18 hours. It is quenched by adding phosphate buffer (pH = 6.8, 150 mL), then the organic phase is diluted with AcOEt, the two phases are separated, the aqueous phase is extracted with AcOEt, the re-combined organic phases are dried on magnesium sulphate and filtered, and lastly the solvent is removed at reduced pressure. The product is purified by means of column chromatography (AcOEt-methanol 95:5 v/v) . The Bimatoprost is obtained pure as a colourless oil with a yield of 91%.
91%		Preparation of the Compound X (Bimatoprost) HCl 1.2 N (2 mL) is added at room temperature to a solution of the compound IX (950 mg, 1.5 mmoles) in a tetrahydrofuran/water 1:1 (50 mL) mixture, the reaction is performed under vigorous stirring and is complete after approximately 18 hours. It is quenched by adding phosphate buffer (pH=6.8, 150 mL), then the organic phase is diluted with AcOEt, the two phases are separated, the aqueous phase is extracted with AcOEt, the re-combined organic phases are dried on magnesium sulphate and filtered, and lastly the solvent is removed at reduced pressure. The product is purified by means of column chromatography (AcOEt-methanol 95:5 v/v). The Bimatoprost is obtained pure as a colourless oil with a yield of 91%.
80%		Example 12Deprotection of Protected Bimatoprost(8)Protected BimatoprostBimatoprost Scheme 8. Deprotection of Protected Bimatoprost.As shown in Scheme 8 above, a 250 ml_ 3-necked round-bottom flask, equipped with a magnetic stirring bar, a temperature probe, rubber septa, and nitrogen inlet, was charged at room temperature, under nitrogen, with 3.Og (3.11 mmol) of protected bimatoprost from Example 12, 30 ml. of THF1 and 0.9 g (90.8 mmol) of ammonium hydrogen difluoride. The reaction mixture was heated at 40 0C for 24 h and TLC analysis (hexanes/ethyl acetate, 1 :1) indicated complete reaction. The mixture was then diluted with 30 ml. of MTBE and 25 ml_ of water followed by layer separation. The aqueous layer was back extracted with 15 ml_ of MTBE. The combined organic extracts were washed with 25 mL of brine, dried over sodium sulfate, filtered, concentrated, and chromatographically purified to afford 1.02 g (80.0% yield) of bimatoprost confirmed by 1H NMR.

With hydrogenchloride; water; In methanol; at 15 - 20℃;

Step 7: Preparation of BimatoprostIn a 100 ml round bottom flask fitted with stirrer, thermo pocket and stopper was charged methanol (20 ml) and the compound obtained in step 6 of example 2 at 25 to 300C. The resulting mixture was cooled to 15 to 200C and slowly added 2N HCI (5 ml) at 15 to 200C. The reaction mixture was maintained under stirring at 15 to 200C for 3 to 5 hours till reaction is completed by TLC. Water (40 ml) was added and cooled to 0 to 100C, the pH was adjusted to 6.5 to 7.0 with 5% sodium carbonate solution at 0 to 100C. Ethyl acetate (40 ml) was charged and stirred for 15 minutes. The organic layer was separated and aqueous layer extracted with ethyl acetate (2x 40 ml). The combined ethyl acetate fraction was washed with brine solution. The solvent was distilled out completely under vacuum below 30C. The crude product was purified by flash column chromatography/ preparative HPLC to obtained pure Bimatoprost. (0.8-1.O g)

Reference： [1]Patent: WO2010/97672,2010,A1 .Location in patent: Page/Page column 20
[2]Patent: US2012/16136,2012,A1 .Location in patent: Page/Page column 8-9
[3]Patent: WO2011/8756,2011,A1 .Location in patent: Page/Page column 65
[4]Patent: WO2010/109476,2010,A2 .Location in patent: Page/Page column 20

19
[ 960056-50-2 ]
[ 75-04-7 ]
[ 155206-00-1 ]

Reference： [1]Tetrahedron,2010,vol. 66,p. 7472 - 7478

20
C₂₃H₃₀O₄ [ No CAS ]
[ 75-04-7 ]
[ 155206-00-1 ]

Yield	Reaction Conditions	Operation in experiment
67.3%	With trimethylaluminum; In tetrahydrofuran; at 20 - 40℃; for 18h;Product distribution / selectivity;	Example 10Ring Opening of Deprotected LactonesSynthesis of Bimatoprost from 12a:As shown in Scheme 3 in Example 1 , a 250 ml_ 3-necked round-bottom flask equipped with a magnetic bar, a temperature probe, rubber septa, and a nitrogen gas inlet was charged at room temperature with 4.1 g (11.1 mmol) of deprotected lactone 12a in 20 ml_ of THF, 22.2 mi_( 44.3 mmol) of 2 M trimethylaluminum in THF, and 67 ml_ (133 mmol) of 2 M ethylamine in THF. The reaction mixture was heated at 40 C for 18 h and TLC analysis indicated complete reaction. The mixture was diluted with 50 mL of water and the pH was adjusted to 6 with 1 N HCI. The layers were separated and the aqueous layer was back extracted with 20 mL of ethyl acetate for two times. The combined organic layers were washed with 40 mL of brine, dried over sodium sulfate, filtered, and concentrated.The crude product was triturated with 20 mL of MTBE at 35 0C for 3 h, cooled to room temperature, and filtered to obtain 3.1 g (67.3% yield) of Bimatoprost, confirmed by 1H NMR.

Reference： [1]Patent: WO2011/8756,2011,A1 .Location in patent: Page/Page column 62

21
[ 329313-36-2 ]
[ 155206-00-1 ]

Reference： [1]Patent: WO2011/8756,2011,A1
[2]Patent: WO2011/8756,2011,A1
[3]Patent: WO2011/8756,2011,A1
[4]Patent: WO2011/8756,2011,A1
[5]Organic Letters,2015,vol. 17,p. 504 - 507
[6]Organic Letters,2015,vol. 17,p. 504 - 507
[7]Patent: US2015/158837,2015,A1

22
C₃₁H₅₂O₃Si₂ [ No CAS ]
[ 155206-00-1 ]

Reference： [1]Patent: WO2011/8756,2011,A1
[2]Patent: WO2011/8756,2011,A1
[3]Patent: WO2011/8756,2011,A1
[4]Patent: WO2011/8756,2011,A1

23
C₃₁H₅₄O₃Si₂ [ No CAS ]
[ 155206-00-1 ]

Reference： [1]Patent: WO2011/8756,2011,A1
[2]Patent: WO2011/8756,2011,A1

24
C₃₇H₆₂O₄Si₂ [ No CAS ]
[ 155206-00-1 ]

Reference： [1]Patent: WO2011/8756,2011,A1
[2]Patent: WO2011/8756,2011,A1

25
C₃₅H₅₈O₄Si₂ [ No CAS ]
[ 155206-00-1 ]

Reference： [1]Patent: WO2011/8756,2011,A1
[2]Patent: WO2011/8756,2011,A1

26
C₁₇H₂₇IOSi [ No CAS ]
[ 155206-00-1 ]

Reference： [1]Patent: WO2011/8756,2011,A1
[2]Patent: WO2011/8756,2011,A1
[3]Patent: WO2011/8756,2011,A1
[4]Patent: WO2011/8756,2011,A1

27
[ 98974-31-3 ]
[ 155206-00-1 ]

Reference： [1]Patent: WO2011/8756,2011,A1
[2]Patent: WO2011/8756,2011,A1
[3]Patent: WO2011/8756,2011,A1
[4]Patent: WO2011/8756,2011,A1
[5]Patent: WO2011/8756,2011,A1
[6]Patent: WO2011/8756,2011,A1
[7]Patent: WO2011/8756,2011,A1
[8]Patent: WO2011/8756,2011,A1

28
[ 17814-85-6 ]
[ 155206-00-1 ]

Reference： [1]Patent: WO2011/46569,2011,A1
[2]Patent: KR2017/25682,2017,A

29
[ 1240483-16-2 ]
[ 41723-91-5 ]
[ 75-04-7 ]
[ 155206-00-1 ]

Yield	Reaction Conditions	Operation in experiment
		Step D: Preparation of bimatoprost ethyl amide (5a-2) from a mixture of (Z)-7-((1 2fi,3 5S)-3-(te/t-butyldimethylsilyloxy)-2-((S,a-3-(te^-butyldimethylsilyloxy)-5- phenylpent-1 -enyl)-5-hvdroxycvclopentyl)-A/-ethylhept-5-enamide (9a-2a) and (Z)-7- ((1 2fi,3 5S)-5-(te/t-butyldimethylsilyloxy)-2-((S,a-3-(te^-butyldimethylsilyloxy)-5- phenylpent-1 -enyl)-3-hvdroxycvclopentyl)-A/-ethylhept-5-enamide (9a-2b) (9a-2b)To a three-necked round bottom flask equipped with a mechanical stirrer, nitrogen inlet addition funnel, and a thermocouple was charged a solution comprising a mixture of (Z)-7-((1 f?,2f?,3f?,5S)-3-(ieri-butyldimethylsilyloxy)-2-((S,£)-3-(ieri- butyldimethylsilyloxy)-5-phenylpent-1 -enyl)-5-hydroxycyclopentyl)-/V-ethylhept-5- enamide (9a-2a) and (Z)-7-((1 f?,2f?,3f?,5S)-5-(ieri-butyldimethylsilyloxy)-2-((S,£)-3-(ieri- butyldimethylsilyloxy)-5-phenylpent-1 -enyl)-3-hydroxycyclopentyl)-/V-ethylhept-5- enamide (9a-2b) (57 g, 89 mmol, 1 molar equivalent) in THF (570 mL, 10 volumes). Tetrabutylammonium fluoride (TBAF, 355 mL, 355 mmol, 4 molar equivalents) was added to the solution at once. The mixture was allowed to stir at 40 +/- 5 C overnight. After completion of the reaction, as judged by TLC, the reaction mixture was diluted with ethyl acetate (400 mL, 7 volumes) and cooled to 5 +/- 5 C. Deionized water (570 mL, 10 volumes) was added to the reaction. The layers were separated and the lower aqueous layer was treated with 1 .8 parts of sodium chloride (100 g) and re-extracted with ethyl acetate (400 mL, 7 volumes). The organic solution was concentrated under reduced pressure. The residue was redissolved in ethyl acetate (420 mL, 7.4 volumes) and with 7% sodium chloride solution (4 x 240 mL, 4 x 4.2 volumes). The organic solution was concentrated under reduced pressure to afford an oily product (52 g). The crude product was purified on AnaLogix flash silica column (600 g). Ethyl acetate and methanol were used as eluents. The product fractions were combined and concentrated to afford a white solid (23 g). The solid was further purified by dissolving in acetone (184 mL, 8 volumes) and diluted with slow addition of methyl terf-butyl ether (MTBE, 736 mL, 32 volumes). The resulting mix was stirred overnight at room temperature. The mixture was cooled to 5 +/- 5 C and was subsequently filtered and the solid was washed with MTBE (2 x 50 mL). The solid was dried under high vacuum at about 50 C to afford a white solid (21 .5 g). The obtained solid was dissolved in acetone (170 mL, 8 volumes) and diluted with slow addition of MTBE (690 mL, 32 volumes). The resulting mix was stirred overnight at room temperature. The mixture was cooled to 5 +/- 5 C and was subsequently filtered and the solid was washed with MTBE (2 x 50 mL). The solid was dried under hi vacuum at about 50 C to afford the purified title compound (18.54 g, >99.99% pure by HPLC-UV) as white solid.

Reference： [1]Patent: WO2011/46569,2011,A1 .Location in patent: Page/Page column 50-52

30
(3aR,4R,5R,6aS)-4-((E)-3-hydroxy-5-phenylpent-1-enyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl biphenyl-4-carboxylate [ No CAS ]
[ 155206-00-1 ]

Reference： [1]Patent: WO2011/46569,2011,A1

31
[ 1240483-15-1 ]
[ 155206-00-1 ]

Reference： [1]Patent: WO2011/46569,2011,A1
[2]Patent: US2012/16136,2012,A1

32
(3aR,4R,5R,6aS)-5-hydroxy-4-((E)-3-hydroxy-5-phenylpent-1-enyl)hexahydro-2H-cyclopenta[b]furan-2-one [ No CAS ]
[ 155206-00-1 ]

Reference： [1]Patent: WO2011/46569,2011,A1

33
C₃₀H₅₀O₄Si₂ [ No CAS ]
[ 155206-00-1 ]

Reference： [1]Patent: WO2011/46569,2011,A1

34
[ 1300092-89-0 ]
[ 155206-00-1 ]

Reference： [1]Patent: WO2011/55377,2011,A1

35
[ 1300093-14-4 ]
[ 155206-00-1 ]

Reference： [1]Patent: WO2011/55377,2011,A1

36
[ 1300092-91-4 ]
[ 155206-00-1 ]

Reference： [1]Patent: WO2011/55377,2011,A1

37
[ 1300092-92-5 ]
[ 155206-00-1 ]

Reference： [1]Patent: WO2011/55377,2011,A1

38
[ 1300092-94-7 ]
[ 155206-00-1 ]

Yield	Reaction Conditions	Operation in experiment
	With cerium(III) chloride heptahydrate; sodium iodide; In acetonitrile; at 80 - 85℃; for 2h;	EXAMPLE 15:; Preparation of (Z)-7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((S,E)-3- hydroxy-S-phenylpent-l-enyl)cyclopentyl)-N-ethylhept-5-enamide(Bimatoprost); Added cerium (III) chloride heptahydrate (16 g) and sodium iodide (4 g) to solution of compound(x) (26 g) in acetonitrile (260 mL) and contents were refluxed at 80-85 C for 2 h. The reaction completion was monitored by TLC. After the reaction completion the mass was concentrated under reduced pressure to remove acetonitrile. The residue was diluted with water (200 mL) and the product was extracted with ethyl acetate (500 mL). the ethyl acetate layer was washed with saturate sodium. chloride solution (100 mL), dried over sodium sulphate and filtered. The layer was concentrated under reduced pressure to obtain crude Bimatoprost. The crude Bimatoprost was purified by column chromatography method. The pure fractions from the column were pooled and concentrated to syrup stage and the product was crystallized by using diethyl ether. The product Bimatoprost obtained was of purity greater than 99 % (4 g).

Reference： [1]Patent: WO2011/55377,2011,A1 .Location in patent: Page/Page column 26; 37

39
[ 856240-62-5 ]
[ 17814-85-6 ]
[ 75-04-7 ]
[ 155206-00-1 ]

Yield	Reaction Conditions	Operation in experiment
		Into a 3 liter 4 necked round bottom flask fitted with a mechanical stirrer and a reflux condenser was charged THF (275 ml), 4-carboxybutyl triphenylphosphonium bromide (90gm) at temperature 25 to 30C. Cooled the reaction mass to -8C to -12C and added potassium tert-butoxide solution (400 ml) (1 molar solution in THF). Charged Example 5 product (15 gm in 75 ml THF) at 5C to 10C and maintained the reaction mass for 2 hours at same temperature. After completion of the reaction charged DM water (300 ml) at 5C to 10C and washed the reaction mass with ether (3 x300 ml). Separated the aqueous layer and adjusted pH to 3 with 20% citric acid solution (70 g of citric acid, water to make 350 ml). Extracted the product with ethyl acetate (3 x300 ml) and removed the solvent by distillation under vacuum at temperature 35C to 45 C. Charged acetone (600 ml) to the obtained residue and filtered the precipitated product and washed with acetone (150 ml). Combined the acetone layer and evaporated under vacuum at temperature below 45C to obtain a residue. To the resultant residue charged dimethyl formamide (150 ml) and sodium carbonate (30 gms). Heated the solution to 25C to 30C and charged methyl iodide (40 ml) and stirred for 12 hours. After completion of the reaction the solvent was removed from the solution under vacuum at 40 C to 45C and charged DM water (300 ml) and extracted the product with ethyl acetate (2x300 ml). Separated the organic layer and washed with 10% citric acid solution (450 ml) (45 g of citric acid, water to make 450 ml). Separated the organic layer and removed the solvent under vacuum at 40 C to 45C to yield the bimatoprost methyl ester as residue. To the residue added 70 % aqueous ethylamine solution (500 ml) at temperature 25C to 30C and stirred for 48 hours at same temperature. After completion of the reaction, concentrated the reaction solution to half of the volume by distillation under vacuum at 40 C to 45C. Charged DM water and adjusted the pH of the reaction mass to 3 to 5 with 30% sodium bisulphate solution (125 ml) (37.5 g of sodium bisulphate, water to make 125 ml) and extracted the product with ethyl acetate (2 125 ml). Separated the organic layer and washed with 10% sodium chloride solution (125 ml). The organic layer was removed by distillation from the reaction mass under vacuum at temperature 35C to 45C to yield title compound as residue. Charged methyl, tertiary butyl ether (125 ml) at temperature 25C to 30C and stirred for 60 minutes. Filtered the precipitated product and washed with chilled methyl tertiary butyl ether (25 ml). The wet product was dried at 35C to 40C under reduced pressure to provide the title compound.Yield: 1 1.5 gms.HPLC purity (chiral): 97.00%Formula A: 2.80%Formula B: 0.20%.Formula C: Not detected

Reference： [1]Patent: WO2012/11128,2012,A1 .Location in patent: Page/Page column 21-22

40
benzoic acid (3aR,4R,5R,6aS)-4-((E)-3-hydroxy-5-phenyl-pent-1-enyl)-2-oxo-hexahydro-cyclopenta[b]furan-5-yl ester [ No CAS ]
[ 155206-00-1 ]

Reference： [1]Patent: WO2012/11128,2012,A1

41
[ 1355995-17-3 ]
[ 155206-00-1 ]

Reference： [1]Patent: WO2012/11128,2012,A1

42
[ 41162-19-0 ]
[ 155206-00-1 ]

Reference： [1]Patent: US2012/16136,2012,A1
[2]Asian Journal of Chemistry,2017,vol. 29,p. 2767 - 2770

43
[ 64091-14-1 ]
[ 155206-00-1 ]