130209-82-4

Basic information

• Product Name: Latanoprost
• Synonyms: XALATAN;ISOPROPYL (5Z, 9A,11A,15R)-9,11,15-TRIHYDROXY-17-PHENYL-18,19,20-TRINOR-PROST-5Z-EN-1-OATE;LATANOPROST;17-PHENYL-13,14-DIHYDRO TRINOR PROSTAGLANDIN F2ALPHA ISOPROPYL ESTER;9ALPHA,11ALPHA,15R-TRIHYDROXY-17-PHENYL-18,19,20-TRINOR-PROST-5Z-EN-1-OIC ACID, ISOPROPYL ESTER;9ALPHA, 11ALPHA, 15S-TRIHYDROXY-17-PHENYL-18,19,20-TRINOR-PROS-5Z-EN-1-OIC ACID, ISOPROPYL ESTER;(1r-(1-alpha(z),2-beta(r*),3-alpha,5-alpha))--methylethyleste;7-(3,5-dihydroxy-2-(3-hydroxy-5-phenylpentyl)cyclopentyl)-5-heptenoicaci1
• CAS NO: 130209-82-4
• Molecular Formula: C₂₆H₄₀O₅
• Molecular Weight: 432.59
• EINECS: 1806241-263-5
• Product Categories: Active Pharmaceutical Ingredients;Prostaglandins;Prostaglandin;Aromatics;Chiral Reagents;Intermediates & Fine Chemicals;Pharmaceuticals;Other APIs;Inhibitors;Key Products
• Mol File: 130209-82-4.mol

Chemical Properties

• Boiling Point: 583.8 °C at 760 mmHg
• Flash Point: 188.3 °C
• Appearance: pale yellow/oil
• Density: 1.093 g/cm³
• Refractive Index: 1.537
• Storage Temp.: −20°C
• Solubility: DMSO: freely soluble
• PKA: 14.84±0.70(Predicted)
• Water Solubility: DMSO: freely soluble
• Merck: 14,5376
• CAS DataBase Reference: Latanoprost(CAS DataBase Reference)
• NIST Chemistry Reference: Latanoprost(130209-82-4)
• EPA Substance Registry System: Latanoprost(130209-82-4)

Safety Data

• WGK Germany: 3
• RTECS: MJ9669550
• Hazardous Substances Data: 130209-82-4(Hazardous Substances Data)

Usage

a prostaglandin F2a analogue

Latanoprost is a prostaglandin F2a analogue.It is a prostanoid selective FP receptor agonist that is believed to reduce the intraocular pressure (IOP) by increasing the outflow of aqueous humor. It is used to treat certain kinds of glaucoma(open-angle glaucoma ocular hypertension). It is also used to treat a condition called hypertension of the eye. Latanoprost is used to increase the natural outflow of fluid (aqueous humor) from inside the eye into the bloodstream. It appears to work by increasing the outflow of fluid from the eye. This lowers the pressure in the eye. Latanoprost may make your eyesight blurred for a short length of time. if this happens do not drive or operate machine or use any tools until your eye sight becomes clear again.

Latanoprost ophthalmic solution

Latanoprost ophthalmic solution is a topical medication used for controlling the progression of glaucoma or ocular hypertension, by reducing intraocular pressure. It is a prostaglandin analogue that works by increasing the outflow of aqueous fluid from the eyes. It is also known by the brand name of Xalatan manufactured by Pfizer.For the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. Latanoprost ophthalmic solution contain a preservative called benzalkonium chloride which can be absorbed onto the surface of contact lenses and may discolour soft contact lenses.

Side effects

Between 6% and 10% (between 1 in 20 and 1 in 6) of persons receiving latanoprost for 6 months report at least one side effect localized to the eyes. These side effects included Temporary blurred vision after application, eyelid redness, permanently darken eyelashes,Swelling or erosions of the cornea,a sensation of a foreign body, discoloration of the iris, itching, a temporary burning sensation during use, and stinging. Discoloration of the iris begins happens slowly. It is caused by an increase in the amount of brown pigment in the iris and may be permanent. Other side effects which have been reported less frequently include dryness of the eyes, increased tearing, herpes simplex keratitis, eye pain and other eye-related discomfort.

Molecular Structure

Latanoprost contains a pentene ring which has α-and ω-carbon chain with the ester of the α-carbon chain termini in the structure can facilitate its penetration through the cornea. At the corneal stroma, latanoprost can be decomposed into free acid which can bind to the FP receptor as the active part. It has hydroxyl group in C15, and has a short ω-chain and a benzene ring which are important for the efficacy of the drug.

Adverse reactions and side effects

Topical administration can result in mild to moderate conjunctival or scleral hyperemia. Occasionally slight redness on eyes can be observed. During the treatment of the first 2-3 days, the eyes will have a slight foreign body sensation; a small number of patients may get rash.

Production method

First dissolve the compound (Ⅰ) in toluene, cool to 18 °C, further add dicyclohexyl carbodiimide (DCC) and phosphoric acid, followed by addition of (4-phenyl-3-oxobutyl) triphenylphosphonium iodide with condensation being converted to compound (II) which is further converted to the product through the six-step reaction.

Originator

Pharmacia & pjohn (UK)

Manufacturing Process

Manufacturing process for Latanoprost includes these steps as follows: Synthesis of [3aR-[3aα,4α(E),5β,6aα]]-5-(benzoyloxy) hexahydro-4-(3-oxo-5-phenyl-1-pentenyl)-2H-cyclopenta[b]furan-2-one, synthesis of [3aR-[3aα,4a(1E,3S),5β,6aα]]-5-(benzoyloxy)hexahydro- 4-(3 -hydroxy-5-phenyl-1-pentenyl)-2H-cyclopenta[b]furan-2-one, synthesis of [3aR-[3aα,4a(1E,3S),5β,6aα]]- 5-(benzoyloxy)hexahydro-4-(3-hydroxy-5-phenyl-1-pentyl)-2Hcyclopenta[b]furan-2-one, synthesis of 2-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5- phenylpentyl]cyclopentyl]acetic acid, synthesis of [3aR-[3aα,4α(R),5β,6aα]]-hexahydro-5-hydroxy-4-(3-hydroxy-5- phenylpentyl)-2H-cyclopenta[b]furan-2-one, synthesis of [3aR-[3aα,4α(R),5β,6aα]]- hexahydro-5-hydroxy-4-(3-hydroxy-5-phenylpentyl)-2H-cyclopenta[b]furan-2-one;synthesis of (3aR,4R,5R,6aS)-5- (1-ethoxyethoxy)-4-[(3R)-3-(1-ethoxyethoxy)-5-phenylpentyl]hexahydro-2Hcyclopenta[b]furan-2-ol;synthesis of 7-[(1R,2R,3R,5S)-3-(1-ethoxyethoxy)-5- hydroxy-2-[(3R)-3-(1-ethoxyethoxy)-5- phenylpentyl]cyclopentyl-5-heptenoic acid; synthesis of (5Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5- phenylpentyl]cyclopentyl]-5-heptenoic acid (Latanoprost Acid); At last, Latanoprost acid is dissolved in DMF (10 mL) and added to a slurry of cesium carbonate (1.6 g) in DMF (10 mL). 2-Iodopropane (0.49 mL) is added and the slurry is heated to 45°C for about 6 hours. When the reaction is complete, MTBE (40 mL) and water (50 mL) are added and the mixture is stirred for 15 min. The phases are separated and the aqueous phase is washed with MTBE (20 mL). The organic phases are combined and concentrated. The concentrate is chromatographed (silica gel) eluting with MTBE. The appropriate fractions are pooled and concentrated to give (5Z)-(9CI)-7-[(1R,2R,3R,5S)-3,5- Dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl ]cyclopentyl]-5-heptenoic acid 1- methylethyl ester (Latanoprost).

Therapeutic Function

Antiglaucoma

Biochem/physiol Actions

Latanoprost is a potent, selective prostaglandin F2α?analog receptor agonist. It is hydrolyzed by esterases into its biologically active form latanoprost acid in the cornea. Latanoprostplays a role in reducing the intraocular pressure (IOP) due to which it has therapeutic effects in treating glaucoma.

Safety Profile

A poison by ingestion and intravenous route. Human systemic effects. When heated to decomposition it emits acrid smoke and irritating vapors.

InChI:InChI=1/C26H40O5/c1-19(2)31-26(30)13-9-4-3-8-12-22-23(25(29)18-24(22)28)17-16-21(27)15-14-20-10-6-5-7-11-20/h3,5-8,10-11,19,21-25,27-29H,4,9,12-18H2,1-2H3/t21-,22+,23+,24-,25+/m0/s1

Synthetic route

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;

isopropyl 11,15-bistetrahydropyranyloxy-13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2α → latanoprost (130209-82-4)

Conditions	Yield
With pyridinium p-toluenesulfonate In methanol at 52℃; for 4h; Product distribution / selectivity;	90%
pyridinium p-toluenesulfonate In methanol at 52℃; for 4h;	90%
With pyridinium p-toluenesulfonate In dichloromethane at 40℃; Inert atmosphere;	86.1%
With toluene-4-sulfonic acid In isopropyl alcohol at 40℃; for 5h;
With ethanol; pyridinium p-toluenesulfonate at 20 - 50℃; for 3h;

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%

C41H64O8 (856453-33-3) → latanoprost (130209-82-4)

Conditions	Yield
With pyridinium p-toluenesulfonate In methanol at 45℃; for 6h; Product distribution / selectivity;	83.7%
pyridinium p-toluenesulfonate In methanol at 45℃; for 6h;	83.7%

C39H46O7 → latanoprost (130209-82-4)

Conditions	Yield
Stage #1: C39H46O7 With hydrogen In ethyl acetate at 20℃; for 4h; Inert atmosphere; Stage #2: With 2,3-dicyano-5,6-dichloro-p-benzoquinone In dichloromethane; water at 0℃; for 0.5h; Inert atmosphere; Stage #3: With sodium tetrahydroborate In methanol; dichloromethane; water at 0℃; for 2.5h; Inert atmosphere;	83%

C26H38O5 (141074-06-8) → latanoprost (130209-82-4)

Conditions	Yield
Stage #1: C26H38O5 With 2,6-di-tert-butyl-4-methyl-phenol; diisobutylaluminium hydride In toluene at -70 - -20℃; Stage #2: With hydrogenchloride In water; toluene	75%

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%

2-iodo-propane (75-30-9) + C23H32O4 → latanoprost (130209-82-4)

Conditions	Yield
Stage #1: C23H32O4 With sodium hydride In isopropyl alcohol; mineral oil at 20 - 35℃; for 18h; Stage #2: 2-iodo-propane With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; for 18h;	49%

(3aR,4R,5R,6aS)-hexahydro-5-triethylsilyoxy-4-[5-phenyl-(3R)-3-triethylsilyloxy-pentanyl]-2H-cyclopenta[β]furan-2-one (477884-73-4) → 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
Purification / work up;	A n/a B n/a C 45%

(-)-Corey lactone 5-(4-phenylbenzoate) (31752-99-5) → latanoprost (130209-82-4)

Conditions

Yield

Multi-step reaction with 8 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 8: 38 percent / DBU / acetone / 4 h / Ambient temperature View Scheme

benzyl bromide (100-39-0) + alcoholic potash → latanoprost (130209-82-4)

Conditions

Yield

Multi-step reaction with 8 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 8: 38 percent / DBU / acetone / 4 h / Ambient temperature 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 (130209-82-4)

Conditions

Yield

Multi-step reaction with 6 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 6: 38 percent / DBU / acetone / 4 h / Ambient temperature 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 (130209-82-4)

Conditions	Yield
Multi-step reaction with 5 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 5: 38 percent / DBU / acetone / 4 h / Ambient temperature View Scheme

dimethyl (2-oxo-4-phenylbutyl)phosphonate → latanoprost (130209-82-4)

Conditions

Yield

Multi-step reaction with 7 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 7: 38 percent / DBU / acetone / 4 h / Ambient temperature View Scheme

(1S,5R,6R,7R)-6-<(3R)-3-hydroxy-5-phenyl-1-pentyl>-7(R)-hydroxy-2-oxabicyclo<3.3.0>octan-3-ol → latanoprost (130209-82-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) t-BuOK / 1.) THF, RT, 30 min, 2.) THF, -15 to -10 deg C, 4 h 2: 38 percent / DBU / acetone / 4 h / Ambient temperature 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 (130209-82-4)

Conditions	Yield
Multi-step reaction with 3 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 3: 38 percent / DBU / acetone / 4 h / Ambient temperature 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 (130209-82-4)

Conditions	Yield
Multi-step reaction with 4 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 4: 38 percent / DBU / acetone / 4 h / Ambient temperature View Scheme

(3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl biphenyl-4-carboxylate (38754-71-1) → latanoprost (130209-82-4)

Conditions

Yield

Multi-step reaction with 7 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 7: 38 percent / DBU / acetone / 4 h / Ambient temperature View Scheme

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

Conditions	Yield
With caesium carbonate In water; N,N-dimethyl-formamide

C41H76O5Si3 + C41H76O5Si3 → latanoprost (130209-82-4)

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

C38H68O5Si2 (477884-76-7) → latanoprost (130209-82-4)

Conditions	Yield
With hydrogenchloride; water In tetrahydrofuran at 20℃; for 0.5h;

C38H68O5Si2 (477884-76-7) + C38H68O5Si2 → 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 hydrogenchloride; water In tetrahydrofuran at 20℃; for 0.5h;

2-iodo-propane (75-30-9) + latanoprost L-arginine salt (1224443-39-3) → latanoprost (130209-82-4)

Conditions	Yield
In methanol; water
In methanol; water

(Z)-isopropyl 7-((1R,2R,3R,5S)-3-(tert-butyldimethylsilyloxy)-2-((R)-3-(tert-butyldimethylsilyloxy)-5-phenylpentyl)-5-hydroxycyclopentyl)hept-5-enoate (474944-22-4) → latanoprost (130209-82-4)

Conditions	Yield
With hydrogenchloride; water In isopropyl alcohol at 25 - 30℃;

latanoprost acid (41639-83-2) + isopropyl bromide (75-26-3) → latanoprost (130209-82-4)

Conditions	Yield
Stage #1: latanoprost acid With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetone at 20 - 25℃; for 0.166667h; Stage #2: isopropyl bromide In acetone for 0.5h;

tert-butyl[(1S)-3-iodo-1-phenethylpropyl]oxydimethylsilane (876953-73-0) → latanoprost (130209-82-4)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: tert.-butyl lithium / hexane; diethyl ether / 4 h / -78 °C / Inert atmosphere 1.2: 0.92 h / -78 - -50 °C / Inert atmosphere 2.1: diisobutylaluminium hydride / toluene / 3 h / -78 °C 2.2: -50 °C 3.1: dmap; diisopropyl-carbodiimide / tetrahydrofuran / 24 h / 20 - 40 °C 4.1: Grubbs catalyst first generation / dichloromethane / 18 h / 20 - 40 °C / Inert atmosphere 5.1: tetrabutyl ammonium fluoride; ammonium hydrogen difluoride / tetrahydrofuran / 24 h / 20 - 40 °C 6.1: sodium hydride / isopropyl alcohol; mineral oil / 18 h / 20 - 35 °C 6.2: 18 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: tert.-butyl lithium / diethyl ether; pentane / 4 h / -78 - -40 °C / Inert atmosphere; Schlenk technique 1.2: 0.5 h / -30 °C / Inert atmosphere; Schlenk technique 2.1: ozone / methanol; dichloromethane / -78 °C 2.2: -78 - 20 °C 3.1: hydrogenchloride; water / tetrahydrofuran / 16 h / 20 °C 4.1: potassium tert-butylate / tetrahydrofuran / 0.67 h / 0 °C / Inert atmosphere; Schlenk technique 4.2: 0 - 20 °C / Inert atmosphere; Schlenk technique 5.1: caesium carbonate / N,N-dimethyl-formamide / 18 h / 20 °C View Scheme
Multi-step reaction with 6 steps 1.1: tert.-butyl lithium / diethyl ether; pentane / 4 h / -78 - -40 °C / Inert atmosphere; Schlenk technique 1.2: 0.5 h / -30 °C / Inert atmosphere; Schlenk technique 2.1: ozone / methanol; dichloromethane / -78 °C 2.2: -78 - 20 °C 3.1: diisobutylaluminium hydride / dichloromethane / 2 h / -78 °C 4.1: valerianate de potassium / tetrahydrofuran / 0.5 h / 0 °C / Inert atmosphere; Schlenk technique 4.2: 0 - 20 °C / Inert atmosphere; Schlenk technique 5.1: hydrogenchloride; water / tetrahydrofuran / 17 h / 20 °C 6.1: caesium carbonate / N,N-dimethyl-formamide / 18 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: tert.-butyl lithium / diethyl ether / 4 h / -78 - -40 °C / Inert atmosphere 1.2: 1 h / -78 - -20 °C / Inert atmosphere 2.1: ozone / methanol; dichloromethane / -78 °C 2.2: 3.25 h / -78 - 20 °C / Inert atmosphere 3.1: hydrogenchloride; water / tetrahydrofuran / 16 h / 20 °C 4.1: potassium tert-butylate / tetrahydrofuran / 0.67 h / 0 °C / Inert atmosphere 4.2: 1.5 h / 0 - 20 °C / Inert atmosphere 5.1: caesium carbonate / N,N-dimethyl-formamide / 18 h / 20 °C View Scheme

C31H54O3Si2 (1261926-67-3) → latanoprost (130209-82-4)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: diisobutylaluminium hydride / toluene / 3 h / -78 °C 1.2: -50 °C 2.1: dmap; diisopropyl-carbodiimide / tetrahydrofuran / 24 h / 20 - 40 °C 3.1: Grubbs catalyst first generation / dichloromethane / 18 h / 20 - 40 °C / Inert atmosphere 4.1: tetrabutyl ammonium fluoride; ammonium hydrogen difluoride / tetrahydrofuran / 24 h / 20 - 40 °C 5.1: sodium hydride / isopropyl alcohol; mineral oil / 18 h / 20 - 35 °C 5.2: 18 h / 20 °C View Scheme

tert-butyldimethylsilyl chloride (18162-48-6) + latanoprost (130209-82-4) → (Z)-isopropyl 7-((1R,2R,3R,5S)-3,5-bis((tert-butyldimethylsilyl)oxy)-2-((R)-3-((tert-butyldimethylsilyl)oxy)-5-phenylpentyl)cyclopentyl)hept-5-enoate

Conditions	Yield
With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 16h;	94%

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%

butylboronic acid (4426-47-5) + latanoprost (130209-82-4) → (Z)-isopropyl 7-((1R,5S,6R,7R)-3-butyl-7-((R)-3-hydroxy-5-phenylpentyl)-2,4-dioxa-3-borabicyclo[3.2.1]octan-6-yl)hept-5-enoate

Conditions	Yield
In dichloromethane at 45℃; for 20h; Inert atmosphere;	80%
In dichloromethane at 45℃; for 22h; Inert atmosphere;

(S)-2-{(S)-2-[(S)-2-((S)-2-acetoxypropionyloxy)propionyloxy]propionyloxy}propionic acid + latanoprost (130209-82-4) → C68H94O32

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 30℃; for 28h; Inert atmosphere;	60%

(S)-2-((S)-2-{(S)-2-[(S)-2-((S)-2-acetoxypropionyloxy)propionyloxy]propionyloxy}propionyloxy)propionic acid + latanoprost (130209-82-4) → propan-2-yl (5Z)-7-[3,5-bis({[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-(acetyloxy)propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy})-2-(3-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-(acetyloxy)propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}-5-phenylpentyl)cyclopentyl]hept-5-enoate

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 30℃; for 48h; Inert atmosphere;	54%

(2S)-2-{[(2S)-2-{[(2S)-2-(acetyloxy)propanoyl]oxy}propanoyl]oxy}propanoic acid + latanoprost (130209-82-4) → propan-2-yl (5Z)-7-[3,5-bis({[(2S)-2-{[(2S)-2-{[(2S)-2-(acetyloxy)propanoyl]oxy}propanoyl]oxy}propanoyl]oxy})-2-(3-{[(2S)-2-{[(2S)-2-{[(2S)-2-(acetyloxy)propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}-5-phenylpentyl)cyclopentyl]hept-5-enoate

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 30℃; for 48h; Inert atmosphere;	37%

(S)-2-[(S)-2-((S)-2-{(S)-2-[(S)-2-((S)-2-acetoxypropionyloxy)propionyloxy]propionyloxy}propionyloxy)propionyloxy]-propionic acid + latanoprost (130209-82-4) → propan-2-yl (5Z)-7-[3,5-bis({[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-(acetyloxy)propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy})-2-(3-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-(acetyloxy)propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}propanoyl]oxy}-5-phenylpentyl)cyclopentyl]hept-5-enoate

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 30℃; for 48h; Inert atmosphere;	35%

Upstream product

• 75-30-9 2-iodo-propane 
• 41639-83-2 latanoprost acid 
• 31752-99-5 (-)-Corey lactone 5-(4-phenylbenzoate) 
• 38754-71-1 (3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl biphenyl-4-carboxylate 
• 856453-33-3 C₄₁H₆₄O₈ 
• 1224443-39-3 latanoprost L-arginine salt 
• 67-63-0 isopropyl alcohol 
• 141074-06-8 C₂₆H₃₈O₅ 
• 474944-22-4 (Z)-isopropyl 7-((1R,2R,3R,5S)-3-(tert-butyldimethylsilyloxy)-2-((R)-3-(tert-butyldimethylsilyloxy)-5-phenylpentyl)-5-hydroxycyclopentyl)hept-5-enoate 
• 75-26-3 isopropyl bromide 
• 876953-73-0 tert-butyl[(1S)-3-iodo-1-phenethylpropyl]oxydimethylsilane 
• 1261926-67-3 C₃₁H₅₄O₃Si₂ 
• 1261926-68-4 C₃₁H₅₆O₃Si₂ 
• 1261926-69-5 C₃₇H₆₄O₄Si₂ 

Downstream Products

• 41639-83-2 latanoprost acid 

Relevant articles and documents

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.

Enantio- and Diastereoselective Synthesis of Latanoprost using an Organocatalyst

An enantioselective total synthesis of latanoprost was achieved. Its chiral cyclopentane core structure was constructed through an organocatalyst-mediated [3+2]-cycloaddition reaction, and chirality in the ω-side chain was generated by prolinate-anion-mediated α-aminoxylation of an aldehyde. Highly diastereoselective domino acetalization and an oxy-Michael reaction were key steps for the generation of C9 chirality.

NOVEL LATANOPROST INTERMEDIATE AND METHOD FOR PREPARING LATANOPROST WITH HIGH PURITY

The present invention provides a novel latanoprost intermediate represented by chemical formula 1. In chemical formula 1, R is hydrogen or C_1-C_4 alkyl, P is hydrogen or a hydroxy protecting group, at least one P is a hydroxy protecting group. The hydroxy protecting group is represented by chemical formula 2. In chemical formula 2, R^1 is each independently -NO_2 or C_6-C_18 aryl, and R^1 is fused to a phenyl ring to form a C_10-C_18 aromatic ring.COPYRIGHT KIPO 2021

An improved synthesis of latanoprost involving effective control on 15(S) diastereomer

An improved process for the synthesis of latanoprost having excellent optical purity (de 99.9%, [α]D20 = +35.37° (c = 0.90, acetonitrile)) without use of preparative HPLC is described. This process involves effective purification of hydroxyl intermediate (5A) through solvent crystallization followed by inhibition of inversion of the chiral center at C-15 position. This was possible due to judicious use of diol intermediate (6) for double bond reduction prior to hydroxyl protection.

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.

A Facile and Efficient Synthesis of (15R)-Latanoprost from Chiral Precursor Corey Lactone Diol

An efficient asymmetric synthetic route for the synthesis of anti-glaucoma agent, (15R)-latanoprost using Corey lactone diol as chiral substrate under Swern oxidation, allylic reduction and Wittig reaction conditions has been developed. In this method, reduction of keto and alkene functional groups has been achieved in a single step using low cost catalyst NiCl2/NaBH4 in methanol. This new synthetic protocol is a good alternative for the synthesis of latanoprost with high stereo selectivity and improved yield. [Figure not available: see fulltext.]

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.