41639-83-2

Usage

Uses

Used in Pharmaceutical Industry:
Latanoprost acid is used as an ocular hypotensive drug for the treatment of open-angle glaucoma and ocular hypertension. It acts as a potent FP receptor agonist, with an EC50 of 3.6 nM for human FP receptors, which is twice the potency of PGF2α. The efficacy of PG analog esters for the treatment of glaucoma correlates closely with the FP receptor binding affinity of the free acid form, Latanoprost acid.
However, it is important to note that Latanoprost acid is more irritating and less effective than the prodrug Latanoprost when applied directly to the eyes of human glaucoma patients. Therefore, the isopropyl ester prodrug form, Latanoprost, is preferred for clinical use.

Biochem/physiol Actions

Potent, selective FP prostanoid receptor agonist, F-series prostaglandin analog. 200 times as potent as isopropyl ester form.

InChI:InChI=1/C23H34O5/c24-18(13-12-17-8-4-3-5-9-17)14-15-20-19(21(25)16-22(20)26)10-6-1-2-7-11-23(27)28/h1,3-6,8-9,18-22,24-26H,2,7,10-16H2,(H,27,28)/b6-1-/t18-,19+,20+,21-,22+/m0/s1

Synthetic route

(Z)-3-hydroxy-2-(hydroxymethyl)-2-methylpropyl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate (913258-32-9) → latanoprost acid (41639-83-2)

Conditions	Yield
With lithium hydroxide In methanol; water for 8h;	99%
Stage #1: (Z)-3-hydroxy-2-(hydroxymethyl)-2-methylpropyl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate With lithium hydroxide In methanol; water at 20℃; for 5.5 - 8h; Stage #2: With sodium hydrogen sulfate; ammonium chloride In methanol; water; ethyl acetate Product distribution / selectivity;	99%

(Z)-methyl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate (913258-31-8) → latanoprost acid (41639-83-2)

Conditions	Yield
With lithium hydroxide In methanol; water at 20℃; for 20h;	96%
Stage #1: methyl (Z)-7-{(1R,2R,3R,5S)-3,5-dihydroxy-2-[(R)-3-hydroxy-5-phenylpentyl]cyclopentyl}hept-5-enoate With lithium hydroxide In methanol; water at 20℃; for 20h; Stage #2: With sodium hydrogen sulfate; ammonium chloride In methanol; water; ethyl acetate	96%

(Z)-7-((1R,2R,3R,5S)-3-(tert-butyldimethylsilyloxy)-2-((R)-3-(tert-butyldimethylsilyloxy)-5-phenylpentyl)-5-hydroxycyclopentyl)hept-5-enoic acid (1240483-23-1) → latanoprost acid (41639-83-2)

Conditions	Yield
Stage #1: (Z)-7-((1R,2R,3R,5S)-3-(tert-butyldimethylsilyloxy)-2-((R)-3-(tert-butyldimethylsilyloxy)-5-phenylpentyl)-5-hydroxycyclopentyl)hept-5-enoic acid With hydrogenchloride; water In tetrahydrofuran at 20℃; for 18h; Stage #2: In tetrahydrofuran pH=6.8; Aqueous phosphate buffer;	91%
Stage #1: (Z)-7-((1R,2R,3R,5S)-3-(tert-butyldimethylsilyloxy)-2-((R)-3-(tert-butyldimethylsilyloxy)-5-phenylpentyl)-5-hydroxycyclopentyl)hept-5-enoic acid With hydrogenchloride In tetrahydrofuran; water at 20℃; for 18h; Stage #2: In tetrahydrofuran; water pH=6.8; Aqueous phosphate buffer;	91%

latanoprost (130209-82-4) → latanoprost acid (41639-83-2)

Conditions	Yield
Stage #1: latanoprost With lithium hydroxide; water In tetrahydrofuran for 16h; Stage #2: With hydrogenchloride In tetrahydrofuran; water	90%

(3aR,4R,5R,6aS)-4-[(3R)-(tert-butyldimethylsilyl)oxy-5-phenylpentyl]perhydrocyclopenta[b]furan-2,5-diol → latanoprost acid (41639-83-2)

Conditions	Yield
With hydrogenchloride; water In tetrahydrofuran at 20℃; for 17h;	87%
With hydrogenchloride In methanol; water for 3.33333h;

(8aR,9R,10R,14aS,Z)-10-hydroxy-9-((3R)-3-hydroxy-5-phenylpentyl)-4,5,8,8a,9,10,11,11a-octahydrocyclopenta[b]oxecin-2(3H)-one → latanoprost acid (41639-83-2)

Conditions	Yield
With water; potassium hydroxide In water; isopropyl alcohol at 50℃; for 2h; Reagent/catalyst; Temperature;	68%
With potassium hydroxide In water; isopropyl alcohol at 50℃; for 2h;

(4-carboxybutyl)triphenylphosphonium bromide (17814-85-6) + (1S,5R,6R,7R)-6-<(3R)-3-hydroxy-5-phenyl-1-pentyl>-7(R)-hydroxy-2-oxabicyclo<3.3.0>octan-3-ol → latanoprost acid (41639-83-2)

Conditions	Yield
With potassium tert-butylate 1.) THF, RT, 30 min, 2.) THF, -15 to -10 deg C, 4 h; Multistep reaction;

(S)-4-phenyl-1-iodo-2-(triethylsiloxy)butane (913258-20-5) → latanoprost acid (41639-83-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 99 percent / LiOH*H2O / methanol; H2O / 8 h View Scheme

(S)-4-phenyl-1-(p-tolylsulfonyloxy)-2-(triethylsiloxy)butane (913258-19-2) → latanoprost acid (41639-83-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 89 percent / NaI; pyridine / dimethylformamide / 2.5 h / 75 - 80 °C 2: 99 percent / LiOH*H2O / methanol; H2O / 8 h View Scheme

methyl (Z)-7-[(1R,2R,3R,5S)-2-((3S)-3-triethylsilyloxy-5-phenyl-1-(phenylsulfonyl)pentyl)-3,5-bis(triethylsilyloxy)cyclopentyl]hept-5-enoate (930118-48-2) → latanoprost acid (41639-83-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 45 mg / PPTS / acetone; H2O / 6 h / 20 °C 2: 96 percent / LiOH*H2O / methanol; H2O / 20 h / 20 °C View Scheme

1-{(Z)-6-[(1R,2R,3R,5S)-2-[(R)-3-(triethylsilyloxy)-5-phenylpentyl]-3,5-bis(triethylsilyloxy)cyclopentyl]hex-4-enyl}-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane (913258-28-3) → latanoprost acid (41639-83-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 95 percent / PPTS / acetone; H2O / 5 h / 18 °C 2: 99 percent / LiOH*H2O / methanol; H2O / 8 h View Scheme

1-{(Z)-6-[(1R,2R,3R,5S)-2-[(3S)-3-(triethylsilyloxy)-5-phenyl-1-(phenylsulfonyl)pentyl]-3,5-bis(triethylsilyloxy)cyclopentyl]hex-4-enyl}-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane → latanoprost acid (41639-83-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 99 percent / Na2HPO4; Na/Hg / methanol / 0 - 20 °C 2: 95 percent / PPTS / acetone; H2O / 5 h / 18 °C 3: 99 percent / LiOH*H2O / methanol; H2O / 8 h View Scheme

2,2-bis(hydroxymethyl)propyl-(Z)-7-[(1R,2R,3R,5S)-2-[(3S)-3-triethylsilyloxy-5-phenyl-1-(phenylsulfonyl)pentyl]-3,5-bis(triethylsilyloxy)cyclopentyl]hept-5-enoate (913258-25-0) → latanoprost acid (41639-83-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 227 mg / Na2HPO4; Na/Hg / methanol / 2 h 2: 45 mg / PPTS / acetone; H2O / 6 h / 20 °C 3: 96 percent / LiOH*H2O / methanol; H2O / 20 h / 20 °C View Scheme

4-Phenyl-1-butene (768-56-9) → latanoprost acid (41639-83-2)

Conditions	Yield
Multi-step reaction with 6 steps 1: (K3Fe(CN)6; K2OsO2(OH)4; K2CO3 / (DHQ)2AQN / 2-methyl-propan-2-ol; H2O / 17 h / 0 °C 2: 67.4 percent / Bu2SnO; Et3N / CH2Cl2 / 0 - 20 °C 3: 99.5 percent / imidazole; Et3N / dimethylformamide / 1.33 h / 0 - 20 °C 4: 89 percent / NaI; pyridine / dimethylformamide / 2.5 h / 75 - 80 °C 5: 99 percent / LiOH*H2O / methanol; H2O / 8 h View Scheme
Multi-step reaction with 10 steps 1.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 25.5 h / 0 - 20 °C 2.1: [(S,S)-N,N’-bis(3,5-di-tertbutylsalicylidene)-1,2-cyclohexanediaminato(2-)]cobalt(II); acetic acid / tetrahydrofuran; water / 24 h / 0 - 20 °C 3.1: n-butyllithium / tetrahydrofuran / -20 °C 3.2: -20 - 20 °C 4.1: 1H-imidazole / dichloromethane / 16 h / 0 - 20 °C 5.1: 9-bora-bicyclo[3.3.1]nonane / tetrahydrofuran / 3 h / 20 °C / Inert atmosphere 5.2: 2 h / 20 °C / Inert atmosphere 6.1: iodine; triphenylphosphine; 1H-imidazole / dichloromethane / 1 h / 20 °C / Inert atmosphere 7.1: tert.-butyl lithium / diethyl ether / 4 h / -78 - -40 °C / Inert atmosphere 7.2: 1 h / -78 - -20 °C / Inert atmosphere 8.1: ozone / methanol; dichloromethane / -78 °C 8.2: 3.25 h / -78 - 20 °C / Inert atmosphere 9.1: hydrogenchloride; water / tetrahydrofuran / 16 h / 20 °C 10.1: potassium tert-butylate / tetrahydrofuran / 0.67 h / 0 °C / Inert atmosphere 10.2: 1.5 h / 0 - 20 °C / Inert atmosphere View Scheme

benzyltriphenylphosphonium bromide (1449-46-3) → latanoprost acid (41639-83-2)

Conditions

Yield

Multi-step reaction with 8 steps 1.1: hexyllithium / tetrahydrofuran; hexane / 1.5 h / 5 - 15 °C 1.2: 62 percent / tetrahydrofuran; hexane / 2 h / 20 °C 2.1: 98.8 percent / H2 / Pd/C / methanol / 24 h / 30 °C / 7500.6 Torr 3.1: 99 percent / PTSA / methanol / 4 h / 40 °C 4.1: 67.4 percent / Bu2SnO; Et3N / CH2Cl2 / 0 - 20 °C 5.1: 99.5 percent / imidazole; Et3N / dimethylformamide / 1.33 h / 0 - 20 °C 6.1: 89 percent / NaI; pyridine / dimethylformamide / 2.5 h / 75 - 80 °C 7.1: 99 percent / LiOH*H2O / methanol; H2O / 8 h View Scheme

(S)-4-phenyl-1,2-butanediol (124988-64-3) → latanoprost acid (41639-83-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: 67.4 percent / Bu2SnO; Et3N / CH2Cl2 / 0 - 20 °C 2: 99.5 percent / imidazole; Et3N / dimethylformamide / 1.33 h / 0 - 20 °C 3: 89 percent / NaI; pyridine / dimethylformamide / 2.5 h / 75 - 80 °C 4: 99 percent / LiOH*H2O / methanol; H2O / 8 h View Scheme

(S)-2-hydroxy-4-phenylbutyl 4-methylbenzenesulfonate (118629-73-5) → latanoprost acid (41639-83-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: 99.5 percent / imidazole; Et3N / dimethylformamide / 1.33 h / 0 - 20 °C 2: 89 percent / NaI; pyridine / dimethylformamide / 2.5 h / 75 - 80 °C 3: 99 percent / LiOH*H2O / methanol; H2O / 8 h View Scheme

(4S)-2,2-dimethyl-4-styryl-1,3-dioxolane (152203-65-1) → latanoprost acid (41639-83-2)

Conditions

Yield

Multi-step reaction with 7 steps 1: 98.8 percent / H2 / Pd/C / methanol / 24 h / 30 °C / 7500.6 Torr 2: 99 percent / PTSA / methanol / 4 h / 40 °C 3: 67.4 percent / Bu2SnO; Et3N / CH2Cl2 / 0 - 20 °C 4: 99.5 percent / imidazole; Et3N / dimethylformamide / 1.33 h / 0 - 20 °C 5: 89 percent / NaI; pyridine / dimethylformamide / 2.5 h / 75 - 80 °C 6: 99 percent / LiOH*H2O / methanol; H2O / 8 h View Scheme

(4S)-2,2-dimethyl-4-(2-phenylethyl)-1,3-dioxolane (157732-87-1) → latanoprost acid (41639-83-2)

Conditions	Yield
Multi-step reaction with 6 steps 1: 99 percent / PTSA / methanol / 4 h / 40 °C 2: 67.4 percent / Bu2SnO; Et3N / CH2Cl2 / 0 - 20 °C 3: 99.5 percent / imidazole; Et3N / dimethylformamide / 1.33 h / 0 - 20 °C 4: 89 percent / NaI; pyridine / dimethylformamide / 2.5 h / 75 - 80 °C 5: 99 percent / LiOH*H2O / methanol; H2O / 8 h View Scheme

(-)-Corey lactone 5-(4-phenylbenzoate) (31752-99-5) → latanoprost acid (41639-83-2)

Conditions

Yield

Multi-step reaction with 7 steps 1: DCC, phosphoric acid / 1,2-dimethoxy-ethane / a) 18 deg C, 30 min, b) RT, 2 h 2: 1.) NaH / 1.) DME, RT, 1 h, 2.) DME, a) 0 deg C, 30 min, b) RT, 2 h 3: 52 percent / lithium tri-sec-butylborohydride (lithium selectride) / tetrahydrofuran; diethyl ether / 1 h / -78 - -75 °C 4: 78.4 percent / H2, 1 M NaOH / 10percent Pd/C / ethanol / 6 h 5: 85 percent / K2CO3 / methanol / 6 h / Ambient temperature 6: 65 percent / diisobutylaluminium hydride (DIBAL) / toluene; tetrahydrofuran / 1 h / -80 - -72 °C 7: 1.) t-BuOK / 1.) THF, RT, 30 min, 2.) THF, -15 to -10 deg C, 4 h View Scheme

benzyl bromide (100-39-0) + alcoholic potash → latanoprost acid (41639-83-2)

Conditions

Yield

Multi-step reaction with 7 steps 1: 1.) NaH, 2.) n-BuLi 2: 1.) NaH / 1.) DME, RT, 1 h, 2.) DME, a) 0 deg C, 30 min, b) RT, 2 h 3: 52 percent / lithium tri-sec-butylborohydride (lithium selectride) / tetrahydrofuran; diethyl ether / 1 h / -78 - -75 °C 4: 78.4 percent / H2, 1 M NaOH / 10percent Pd/C / ethanol / 6 h 5: 85 percent / K2CO3 / methanol / 6 h / Ambient temperature 6: 65 percent / diisobutylaluminium hydride (DIBAL) / toluene; tetrahydrofuran / 1 h / -80 - -72 °C 7: 1.) t-BuOK / 1.) THF, RT, 30 min, 2.) THF, -15 to -10 deg C, 4 h View Scheme

(1S,5R,6R,7R)-6-(3-oxo-5-phenyl-1E-pentenyl)-7-<(4-phenylbenzoyl)oxy>-2-oxabicyclo<3.3.0>octan-3-one (41639-72-9) → latanoprost acid (41639-83-2)

Conditions

Yield

Multi-step reaction with 5 steps 1: 52 percent / lithium tri-sec-butylborohydride (lithium selectride) / tetrahydrofuran; diethyl ether / 1 h / -78 - -75 °C 2: 78.4 percent / H2, 1 M NaOH / 10percent Pd/C / ethanol / 6 h 3: 85 percent / K2CO3 / methanol / 6 h / Ambient temperature 4: 65 percent / diisobutylaluminium hydride (DIBAL) / toluene; tetrahydrofuran / 1 h / -80 - -72 °C 5: 1.) t-BuOK / 1.) THF, RT, 30 min, 2.) THF, -15 to -10 deg C, 4 h View Scheme

(1S,5R,6R,7R)-6-<(3S)-3-hydroxy-5-phenyl-1-pentenyl>-7-<(4-phenylbenzoyl)oxy>-2-oxabicyclo<3.3.0>octan-3-one (41639-23-0) → latanoprost acid (41639-83-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: 78.4 percent / H2, 1 M NaOH / 10percent Pd/C / ethanol / 6 h 2: 85 percent / K2CO3 / methanol / 6 h / Ambient temperature 3: 65 percent / diisobutylaluminium hydride (DIBAL) / toluene; tetrahydrofuran / 1 h / -80 - -72 °C 4: 1.) t-BuOK / 1.) THF, RT, 30 min, 2.) THF, -15 to -10 deg C, 4 h View Scheme

dimethyl (2-oxo-4-phenylbutyl)phosphonate → latanoprost acid (41639-83-2)

Conditions

Yield

Multi-step reaction with 6 steps 1: 1.) NaH / 1.) DME, RT, 1 h, 2.) DME, a) 0 deg C, 30 min, b) RT, 2 h 2: 52 percent / lithium tri-sec-butylborohydride (lithium selectride) / tetrahydrofuran; diethyl ether / 1 h / -78 - -75 °C 3: 78.4 percent / H2, 1 M NaOH / 10percent Pd/C / ethanol / 6 h 4: 85 percent / K2CO3 / methanol / 6 h / Ambient temperature 5: 65 percent / diisobutylaluminium hydride (DIBAL) / toluene; tetrahydrofuran / 1 h / -80 - -72 °C 6: 1.) t-BuOK / 1.) THF, RT, 30 min, 2.) THF, -15 to -10 deg C, 4 h View Scheme

(1S,5R,6R,7R)-6-<(3R)-3-hydroxy-5-phenyl-1-pentyl>-7(R)-hydroxy-2-oxabicyclo<3.3.0>octan-3-one (145773-21-3) → latanoprost acid (41639-83-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 65 percent / diisobutylaluminium hydride (DIBAL) / toluene; tetrahydrofuran / 1 h / -80 - -72 °C 2: 1.) t-BuOK / 1.) THF, RT, 30 min, 2.) THF, -15 to -10 deg C, 4 h View Scheme

(1S,5R,6R,7R)-6-<(3R)-3-hydroxy-5-phenyl-1-pentyl>-7-<(4-phenylbenzoyl)oxy>-2-oxabicyclo<3.3.0>octan-3-one (145773-20-2) → latanoprost acid (41639-83-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 85 percent / K2CO3 / methanol / 6 h / Ambient temperature 2: 65 percent / diisobutylaluminium hydride (DIBAL) / toluene; tetrahydrofuran / 1 h / -80 - -72 °C 3: 1.) t-BuOK / 1.) THF, RT, 30 min, 2.) THF, -15 to -10 deg C, 4 h View Scheme

(3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl biphenyl-4-carboxylate (38754-71-1) → latanoprost acid (41639-83-2)

Conditions

Yield

Multi-step reaction with 6 steps 1: 1.) NaH / 1.) DME, RT, 1 h, 2.) DME, a) 0 deg C, 30 min, b) RT, 2 h 2: 52 percent / lithium tri-sec-butylborohydride (lithium selectride) / tetrahydrofuran; diethyl ether / 1 h / -78 - -75 °C 3: 78.4 percent / H2, 1 M NaOH / 10percent Pd/C / ethanol / 6 h 4: 85 percent / K2CO3 / methanol / 6 h / Ambient temperature 5: 65 percent / diisobutylaluminium hydride (DIBAL) / toluene; tetrahydrofuran / 1 h / -80 - -72 °C 6: 1.) t-BuOK / 1.) THF, RT, 30 min, 2.) THF, -15 to -10 deg C, 4 h View Scheme

C38H70O5Si3 (943315-69-3) + C38H70O5Si3 → latanoprost acid (41639-83-2)

Conditions	Yield
With hydrogenchloride; water In acetone at 0 - 25℃; pH=1 - 3;

(4-carboxybutyl)triphenylphosphonium bromide (17814-85-6) + (1S,5R,6R,7R)-6-<(3S)-3-hydroxy-5-phenyl-1-pentyl>-7(R)-hydroxy-2-oxabicyclo<3.3.0>octan-3-ol (352276-28-9) → latanoprost acid (41639-83-2)

Conditions	Yield
Stage #1: (4-carboxybutyl)triphenylphosphonium bromide With potassium tert-butylate In tetrahydrofuran at 0℃; Stage #2: (1S,5R,6R,7R)-6-<(3S)-3-hydroxy-5-phenyl-1-pentyl>-7(R)-hydroxy-2-oxabicyclo<3.3.0>octan-3-ol In tetrahydrofuran at -17℃; for 20h; Wittig Reaction; Stage #3: With aminosulfonic acid In tert-butyl methyl ether; water pH=1.5 - 2.0;
Stage #1: (4-carboxybutyl)triphenylphosphonium bromide With potassium tert-butylate In tetrahydrofuran at 0℃; for 0.5 - 0.666667h; Wittig Reaction; Stage #2: (1S,5R,6R,7R)-6-<(3S)-3-hydroxy-5-phenyl-1-pentyl>-7(R)-hydroxy-2-oxabicyclo<3.3.0>octan-3-ol In tetrahydrofuran at -15℃; for 4 - 5h; Wittig Reaction;
Stage #1: (4-carboxybutyl)triphenylphosphonium bromide With potassium tert-butylate In tetrahydrofuran at 0℃; for 0.75h; Inert atmosphere; Stage #2: (1S,5R,6R,7R)-6-<(3S)-3-hydroxy-5-phenyl-1-pentyl>-7(R)-hydroxy-2-oxabicyclo<3.3.0>octan-3-ol In tetrahydrofuran at -15 - -10℃; Wittig Reaction; Inert atmosphere;

L-arginine (74-79-3) + latanoprost acid (41639-83-2) → latanoprost L-arginine salt (1224443-39-3)

Conditions	Yield
In methanol; water for 0.5h; Product distribution / selectivity;	100%
In methanol; water for 0.5h; Product distribution / selectivity;

2-iodo-propane (75-30-9) + latanoprost acid (41639-83-2) → isopropyl (E)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate + latanoprost (130209-82-4)

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetone at 20℃; for 14h;	A n/a B 99.83%

latanoprost acid (41639-83-2) + isopropyl alcohol (67-63-0) → latanoprost (130209-82-4)

Conditions	Yield
With Lipase Novozym 435 at 30℃; for 18h; Enzymatic reaction;	92%
Novozym 435 at 30℃; for 18h;	92%
With 2-chloro-1,3-dimethyl imidazolium chloride; potassium tert-butylate; triethylamine at 0 - 70℃; for 2h;

2-iodo-propane (75-30-9) + latanoprost acid (41639-83-2) → latanoprost (130209-82-4)

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	84%
With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 14h;	72%
With potassium carbonate In N,N-dimethyl-formamide at 50℃;	68%

isobutylamine (78-81-9) + latanoprost acid (41639-83-2) → 17-phenyl-13,14-dihydro-trinor-prostaglandin F2α isobutylamide (1131798-26-9)

Conditions	Yield
With dicyclohexyl-carbodiimide In tetrahydrofuran at 0 - 20℃;	70%

desmethyl anethole trithione (18274-81-2) + latanoprost acid (41639-83-2) → (5Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoic acid 4-(3H-1,2-dithiole-3-thione-5-yl)phenyl ester (1088434-86-9)

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	65%
Stage #1: desmethyl anethole trithione; latanoprost acid; dmap In tetrahydrofuran at 0℃; Inert atmosphere; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 15h; Inert atmosphere;
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap In tetrahydrofuran at 0 - 20℃; for 15h;

2-iodo-propane (75-30-9) + latanoprost acid (41639-83-2) → isopropyl (E)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate + isopropyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((S)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate + latanoprost (130209-82-4)

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetone at 20℃; for 5.5 - 14.2167h; Product distribution / selectivity;	A n/a B n/a C 63.2%

5,7-Dihydroxy-3-(4-methoxy-phenyl)-chromen-4-on (491-80-5) + latanoprost acid (41639-83-2) → (Z)-5-hydroxy-3-(4-methoxyphenyl)-4-oxo-4H-chromen-7-yl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate

Conditions	Yield
In dichloromethane at 20℃;	60%

2-(prop-2-yn-1-yl)pent-4-yn-1-ol (432027-96-8) + latanoprost acid (41639-83-2) → (Z)-2-(prop-2-yn-1-yl)pent-4-yn-1-yl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate

Conditions	Yield
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In dichloromethane at 20℃; Inert atmosphere; Darkness;	45%

tert-butyldimethylsilyl chloride (18162-48-6) + latanoprost acid (41639-83-2) → (Z)-7-((1R,2R,3R,5S)-3,5-bis((tert-butyldimethylsilyl)oxy)-2-((R)-3-((tert-butyldimethylsilyl)oxy)-5-phenylpentyl)cyclopentyl)hept-5-enoic acid

Conditions	Yield
With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 24h;

Upstream product

• 17814-85-6 (4-carboxybutyl)triphenylphosphonium bromide 
• 145773-21-3 (1S,5R,6R,7R)-6-<(3R)-3-hydroxy-5-phenyl-1-pentyl>-7(R)-hydroxy-2-oxabicyclo<3.3.0>octan-3-one 
• 38754-71-1 (3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl biphenyl-4-carboxylate 
• 130209-82-4 latanoprost 
• 352276-28-9 (1S,5R,6R,7R)-6-<(3S)-3-hydroxy-5-phenyl-1-pentyl>-7(R)-hydroxy-2-oxabicyclo<3.3.0>octan-3-ol 
• 41162-19-0 dimethyl(2-oxo-4-phenylbutyl)phosphonate 
• 61263-22-7 (3aR,4R,5R,6aS)-4-((3R)-5-phenyl-3-((tetrahydro-2H-pyran-2-yl)oxy)pentyl)-5-((tetrahydro-2H-pyran-2-yl)oxy)hexahydro-2H-cyclopenta[b]furan-2-one 
• 145667-75-0 (1S,5R,6R,7R)-6-<(3S)-3-hydroxy-5-phenyl-1-pentyl>-7(R)-hydroxy-2-oxabicyclo<3.3.0>octan-3-one 
• 856453-29-7 (3aR,4R,5R,6aS)-4-((3R)-5-phenyl-3-((tetrahydro-2H-pyran-2-yl)oxy)pentyl)-5-((tetrahydro-2H-pyran-2-yl)oxy)hexahydro-2H-cyclopenta[b]furan-2-ol 
• 37904-38-4 (3S)-5-phenyl-1-penten-3-ol 
• 5307-99-3 (+/-)-7,7-dichlorobicyclo[3.2.0]hept-2-en-6-one 
• 26054-46-6 (-)-(1S,5R)-2-oxabicyclo[3.3.0]oct-6-en-3-one 
• 542-92-7 cyclopenta-1,3-diene 
• 87422-39-7 (3aR,6aS)-3,3-dichloro-3,3a,6,6a-tetrahydro-2H-cyclopenta[b]furan-2-one 

Downstream Products

• 145773-22-4 isopropyl (E)-7-{(1R,2R,3R,5S)-3,5-dihydroxy-2-[(R)-3-hydroxy-5-phenylpentyl]cyclopentyl}hept-5-enoate 
• 130209-82-4 latanoprost 
• 860006-34-4 [1R-[1α (Z), 2β (R*), 3α, 5α]]-7-[3,5-dihydroxy-2-(3-hydroxy-5-phenylpentyl)cyclopentyl]-5-heptenoic acid 4-(bromomethyl) benzyl ester 
• 860005-21-6 4-(nitrooxy)butyl [1α(Z),2β(R),3α,5α]-7-[3,5-dihydroxy-2-((3R)-3-hydroxy-5-phenylpentyl)cyclopentyl]-5-heptenoate 
• 145773-22-4 isopropyl (Z)-7-{(1R,2R,3R,5S)-3,5-dihydroxy-2-[(S)-3-hydroxy-5-phenylpentyl]cyclopentyl}hept-5-enoate 
• 1088434-90-5 (5Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoic acid 2-(methylsulfonylthio)ethylamide 
• 1088434-86-9 (5Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoic acid 4-(3H-1,2-dithiole-3-thione-5-yl)phenyl ester 
• 1131798-26-9 17-phenyl-13,14-dihydro-trinor-prostaglandin F2α isobutylamide 
• 1131798-23-6 17-phenyl-13,14-dihydro-trinor-prostaglandin F2α isobutyl ester 
• 913258-31-8 methyl (Z)-7-{(1R,2R,3R,5S)-3,5-dihydroxy-2-[(R)-3-hydroxy-5-phenylpentyl]cyclopentyl}hept-5-enoate 
• 1224443-39-3 latanoprost L-arginine salt 

Relevant academic research and scientific papers

HETERODIMER COMPOSITIONS AND METHODS FOR THE TREATMENT OF OCULAR DISORDERS

Described herein are processable compositions comprising at least one moiety that is processable in its free form. Also described herein are compositions and methods for the treatment of ocular diseases or disorders including glaucoma, blepharitis, ocular inflammation, diabetic macular edema, posterior inflammation, anterior inflammation, macular degeneration (e.g., wet macular degeneration (AMD) or dry AMD), post-cataract surgery, and retinal vein occlusion. Said compositions and methods comprise steroids and prostaglandins which demonstrate anti-inflammatory activity, intraocular pressure (IOP) lowering, and/or other desirable activities. Injection of said compositions in the eye provides therapeutic benefit to patients suffering from ocular disorders.

Asymmetric Synthesis of Corey Lactone and Latanoprost

Corey lactone was synthesized in a single pot within 152 minutes in a 50 % overall yield via pot and time economical manner. Latanoprost, an antiglaucoma blockbuster drug, was also synthesized via seven pot reaction with five purifications in a 25 % total yield. One of the key reactions is asymmetric domino Michael/Michael reaction, formal [3+2] cycloaddition reaction, of 3-(dimethylphenylsilyl)propenal and ethyl 4-oxo-2-pentenoate, catalyzed by diphenylprolinol silyl ether, which constructed the core substituted cyclopentanone derivative with nearly optically pure form.

Access to a Key Building Block for the Prostaglandin Family via Stereocontrolled Organocatalytic Baeyer–Villiger Oxidation

A new protocol for the construction of a crucial bicyclic lactone of prostaglandins using a stereocontrolled organocatalytic Baeyer–Villiger (B-V) oxidation was developed. The key B-V oxidation of a racemic cyclobutanone derivative with aqueous hydrogen peroxide has enabled an early-stage construction of a bicyclic lactone skeleton in high enantiomeric excess (up to 95 %). The generated bicyclic lactone is fully primed with two desired stereocenters and enabled the synthesis of the entire family of prostaglandins according to Corey′s route. Furthermore, the reactivity and enantioselectivity of B-V oxidation of racemic bicyclic cyclobutanones were evaluated and 90–99 % ee was obtained, representing one of the most efficient routes to chiral lactones. This study further facilitates the synthesis of prostaglandins and chiral lactone-containing natural products to promote drug discovery.

High-purity Latanoprost, preparation method therefor and use of Latanoprost

The invention discloses high-purity Latanoprost, a preparation method therefor and use of the Latanoprost. According to the high-purity Latanoprost disclosed by the invention, the content of an impurity with a structure represented by a formula II shown in the description in the high-purity Latanoprost is not higher than 0.1%. The preparation method comprises the steps: (1) subjecting a compound represented by a formula IV shown in the description (an intermediate 1 of the Latanoprost) to a wittig reaction, so as to obtain a compound represented by a formula V shown in the description (an intermediate 2 of the Latanoprost); (2) subjecting the compound V to washing and purifying by a ammonium chloride solution, then, carrying out dehydroxylation protection or not, and carrying out a reaction with iodo-isopropane, so as to obtain a crude raw pharmaceutical material of the Latanoprost; and (3) loading a sample of the raw pharmaceutical material of the Latanoprost to a silica-gel column, carrying out eluting with an eluate, and carrying out chromatographic purification, thereby obtaining the high-purity Latanoprost.

Compound And Method

A compound of formula (I): (I) wherein Y is, Z is OR10, NR11R11 SR11, S(0)R11 S02R11, R10 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, CO—R11, or a protecting group, and R11 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or alkoxyl; a process for making a compound of formula (I); and a process for making a prostaglandin or a prostaglandin analogue using a compound of formula (I). wherein Y is

Synthesis of prostaglandin analogues, latanoprost and bimatoprost, using organocatalysis via a key bicyclic enal intermediate

Two antiglaucoma drugs, bimatoprost and latanoprost, which are analogues of the prostaglandin, PGF2?±, have been synthesized in just 7 and 8 steps, respectively. The syntheses employ an organocatalytic aldol reaction that converts succinaldehyde into a key bicyclic enal intermediate, which is primed for attachment of the required lower and upper side chains. By utilizing the crystalline lactone, the drug molecules were prepared in >99% ee.

Processes for the preparation of isomer free prostaglandins

Novel processes for the preparation of a compound of Formula I-2 substantially free of the 5,6-trans isomer: wherein R2, R3 and R4 are as defined in the specification are provided. Novel intermediates for the preparations of isomer free Prostaglandins and derivatives thereof are also provided.

PROCESSES AND INTERMEDIATES FOR THE PREPARATIONS OF ISOMER FREE PROSTAGLANDINS

Novel processes for the preparation of a compound of Formula I-2 substantially free of the 5,6-trans isomer: wherein R2, R3 and R4 are as defined in the specification are provided. Novel intermediates for the preparations of isomer free Prostaglandins and derivatives thereof are also provided.

COMPOUND AND METHOD

A compound of formula (I): (I) wherein Y is, Z is OR10, NR11R11 SR11, S(0)R11 S02R11, R10 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, CO-R11, or a protecting group, and R11 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or alkoxyl; a process for making a compound of formula (I); and a process for making a prostaglandin or a prostaglandin analogue using a compound of formula (I).

PROCESS FOR THE PREPARATION OF PROSTAGLANDIN DERIVATIVES

The invention concerns a new process for the preparation of prostaglandin derivatives, in particular prostaglandin F2α derivatives, for example bimatoprost, latanoprost and travoprost, the new intermediates of said process and their use in the preparation of prostagblandin derivatives.