Intermediate useful in the preparation of prostaglandin f2 compounds

Abstract

A process for the preparation of intermediates of cloprostenol and other prostaglandin compounds with high yields and increase atom efficiency and it use in the preparation of cloprostenol and other prostaglandin F2α compounds.

Description

[0001] A NOVEL INTERMEDIATE USEFUL IN THE PREPARATION OF PROSTAGLANDIN F2a COMPOUNDS

[0002] TECHNICAL FIELD

[0003] The present invention relates to novel intermediates and an improved process for the preparation of prostaglandin F2a compounds.

[0004] BACKGROUND

[0005] Prostaglandins are tissue hormones of which there are four groups based on structure and function, A, B, E and F. PGF2a and Prostaglandin E are the most important having a direct effect on reproductive organs and fertility. Fluprostenol, cloprostenol, dinoprost, tiaprost and luprostiol are synthetic PGF2a analogues. These compounds are used to improve breeding efficiency. See Dudhatra et al, Vet. World, 2012, Vol. 5(6) pp 378-384.

[0006] Cloprostenol ((Z)-7-[(17?,27?,37?,5S)-2-[(£,37?)-4-(3-chlorophenoxy)-3-hydroxybut-l-enyl]-3,5- dihydroxycyclopentyl]hept-5-enoic acid) is a synthetic prostaglandin, structurally related to prostagladin F2a (PGF2-alpha), that produces PGF2-alpha effects. Cloprostenol has been used in cattle to induce luteolysis (beef and dairy cattle) to manipulate the timing of the estrus cycle to benefit breeding management practices. Saunders Handbook of Veterinary Drugs (Fourth Edition), 2016, pl78. Cloprostenol is a synthetic racemic analogue of prostaglandin F2a. Normally a racemic mixture of both the enantiomers R-cloprostenol and S-cloprostenol is obtained by the chemical synthesis. See European Medicines Agency Veterinary Medicines and Inspections EMEA / MRL / 202 / 97-FINAL April 1997. Racemic cloprostenol sodium is described as (±)-(5Z)-7- (l / ?,3 / ?,5tS)-2-[( LE,3 / ?)-4-(3-chlorophenoxy)-3-hydroxybut-l-enyl]-3,5-dihydroxy cyclopentylhept- 5-enoate in British Pharmacopoeia (September 24, 2021), 5-Heptenoic acid, 7-[2-[4-(3- chlorophenoxy)-3-hydroxy-l-butenyl]-3,5-dihydroxycyclopentyl]-, [la(Z),2P(lE,3A*),3a,5a]-, sodium salt, (±)-; or (±)-Sodium (Z)-7-[(lA*,2A*,3A*,55*)-2-[(E)-(3A*)-4-(mchlorophenoxy)-3- hydroxy-l-butenyl]-3,5-dihydroxycyclopentyl]-5-heptenoate [55028-72-3] in US Pharmacopoeia (September 24, 2021).

[0007] Zhang, et al. discloses enantioselective and divergent synthesis of prostaglandins (see Nature Chemistry, Vol 13, July 2021, 692-697). Specifically, the below transformation from the Corey lactone to an PGF2-alpha intermediate utilizing a Hoveyda-Grubbs 2nd generation catalyst is shown. Zhang also discloses that cloprostenol can be made using similar reactions.

[0008] Chen et al., CHIRALITY 27:392-396 (2015) discloses that a synthesis of (+)-cloprostenol that has been accomplished in nine steps and 26% overall yield from commercially available (-)-Corey lactone 4-phenylbenzoate alcohol. Chen also discloses the following scheme to transform the Corey lactone phenyl benzoate starting material to the corresponding alcohol.

[0009] The co-side chain of cloprostenol was introduced via a Horner-Wadsworth-Emmons (HWE) reaction of aldehyde 2 with phosphonate ester 12. The atom efficiency of this route from compound 2 to 4 in the scheme above is 80% (Atom Efficiency = 518 / (350 +292) x 100 = 80 %).

[0010] There is a need for high yielding alternative processes to make key intermediates which in turn can be converted to prostaglandin compounds such as cloprostenol with higher atom efficiency or economy. SUMMARY OF INVENTION

[0011] The present invention relates to a novel compound of Formula III and process to produce the compound of Formula VI comprising reacting a compound of Formula III in the presence of a catalyst to yield the compound of Formula VI.

[0012] DESCRIPTION OF EMBODIMENTS

[0013] The present invention relates to a novel compound of Formula III.

[0014] The compound of Formula III can be used in a cost-effective novel route for the preparation of advanced intermediate of prostaglandin compounds, compound of Formula VI as shown in Scheme 1A.

[0015] This approach can be extended to other prostaglandins as the current method for the synthesis of prostaglandins suffer from low yields and lengthy steps. The novel route to prepare intermediate VI from compound III (a novel intermediate) and VII will reduce the process steps compared to conventional synthesis with high throughput and reduce waste. A novel route to prepare intermediate VII is also presented and can be easily scaled up from commercially available basic raw materials with very high yield. An advantage in the current route is the product compound VI can be obtained without going through an intermediate (e,g, Compound 3 of the route disclosed in Chen above). It means more atom efficient with less waste generation leading to a lower number of operations on scale.

[0016] For example as shown in Scheme IB below, the compound of Formula (V), a key intermediate for the preparation of cloprostenol , a prostaglandin analogue, can be prepared from the compounds of Formulas (III) and (IV). The invention further relates to a route for the preparation of compound (V) via cross metathesis reaction using a catalyst such as a 2ndgeneration Hoveyda Grubbs catalyst. The purpose of this route is to manufacture prostaglandin and prostaglandin analogues such as cloprostenol sodium an active materials of superior quality to be used in the Animal Health industry at low cost.

[0017] Scheme IB Preparation of the compound of Formula V Sustainable green chemistry principles aim to develop and promote chemical processes that minimize the negative impact on the environment and human health while maximizing efficiency and economic viability. These principles guide the creation of environmentally friendly and resource-efficient chemical products and processes. One important tool used to assess the efficiency of these processes is Process Mass Intensity (PMI). PMI is a metric that quantifies the amount of input materials used per unit of product output, including raw materials, energy, and water. By measuring the PMI, researchers and industry professionals can evaluate and optimize the efficiency of a chemical process, thereby reducing waste and minimizing the environmental footprint. This approach aligns with the broader goals of sustainable green chemistry, which seeks to advance the field of chemistry by incorporating scientific innovation and principles of environmental stewardship and resource conservation. See Zimmerman, J.B., & Anastas, P.T. (2016). Process Efficiency Metrics for Green Chemistry: A Tutorial Review. Chemical Society Reviews, 45(18), 5040-5054 or Chaudhari, R. V., & Chaudhari, P. A. (2015). Design and development of green and sustainable chemical processes: A practical approach. Organic Process Research & Development, 19(7), 932-942. DOI: 10.1021 / acs.oprd.5b00159.

[0018] The American Chemical Society, Green Chemistry Institute Pharmaceutical Round Table (ACS GCI PR) has developed a PMI Calculator that enables a PMI value to be quickly determined, https: / / www.acs.org / content / dani / acsorg / greencheniistry / industriainnovation / roundtabl e / convergent-pmi -tool . xl sx

[0019] By applying the chemistry which relates to preparation and use of Formula III the PMI score can be significantly reduced as a number of chemical transformations are removed as well as a large volume of different solvents.

[0020] The PMI for the process to transform the Corey lactone phenyl benzoate starting material to the corresponding alcohol as disclosed by Chen (see above) has a PMI of 306. In contrast, the inventive process of the Scheme IB to convert Compound III to Compound V has a PMI of 90.

[0021] Atom efficiency or economy is another extremely useful tool for rapid evaluation of the amount of waste generated by alternative routes to a specific product. It is calculated by dividing the molecular weight of the desired product by the sum of the molecular weights of all substances produced in the stoichiometric equation for the reaction(s) involved. The comparison is made on a theoretical basis (i.e., 100% chemical yield). See R. Shelton, Pure Appl. Chem., Vol. 72, No. 7, pp. 1233-1246, 2000. The Atom Efficiency of the Scheme IB process from Compound III to Compound V is 94% (518.15 / (348 +198) x 100 = 94 %).

[0022] Furthermore, this process proceeds directly from Compound III to Compound V.

[0023] Scheme 2 Preparation of Compound IV

[0024] In the reaction of the compound of Formula I with the compound of Formula II to form the compound of Formula III in Scheme IB, an oxidizing agent is used. Examples of oxidizing agents are TEMPO, EDCI and DMP.

[0025] TEMPO is a member of the class of aminoxyls that is piperidine that carries an oxidanediyl group at position 1 and methyl groups at positions 2, 2, 6, and 6, respectively. It has a role as a ferroptosis inhibitor, a catalyst and a radical scavenger. It is a member of piperidines and a member of aminoxyls. (See https: / / pubchem.ncbi.nlm.nih.gov / compound / Tempo, accessed February 27, 2024).

[0026] EDCI is l-Ethyl-3 -(3 -dimethyl aminopropyl)carbodiimide.

[0027] Dess-Martin periodinane (DMP) is a chemical reagent used in the Dess-Martin oxidation, oxidizing primary alcohols to aldehydes and secondary alcohols to ketones. D. B. Dess & J. C. Martin, J. Org. Chem. 1983, 48, 4155-4156.

[0028] Hovey da-Grubbs 2nd generation catalyst or (l,3-Bis-(2,4,6-trimethylphenyl)-2- imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium, CAS Number 635679-24- 2, is an organometallic ruthenium complex often used in olefin metathesis reactions. See Scholl, et al., Organic Letters 1999 Vol. 1 No. 6 pp 953-956. See also Umicore Catalog No. M722.

[0029] Other catalyst that are useful in the inventive processes: (l,3-Bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(2- isopropoxybenzylidene)ruthenium(II), CAS Number 301224-40-8, Umicore Catalog No. M720.

[0030] (l,3-Bis-(2-tolyl)-2-imidazolidinylidene]dichloro(2-isopropoxybenzylidene)ruthenium(II), CAS Number 927429-61-6, Umicore Catalog No. M721. (l,3-Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro[5-(isobutoxycarbonylamido)-2- isopropoxybenzylidene]ruthenium(II), CAS Number 1025728-57-7, Umicore Catalog No. M730.

[0031] (l,3-Bis(2,6-diisopropylphenyl)-2-imidazolidinylidene]dichloro[5-(isobutoxycarbonylamido)-2- isopropoxybenzylidene]ruthenium(II), CAS Number: 1212009-05-6, Umicore Catalog No. M731.

[0032] Lithium bis(trimethylsilyl)amide is a organosilicon lithium compound with the formula LiN(Si(CH3)3)2. It is commonly abbreviated as LiHMDS.

[0033] Sodium bis(trimethylsilyl)amide is the organosilicon compound with the formula NaN(Si(CH3)3)2.

[0034] This species, usually called NaHMDS (sodium hexamethyldisilazide), is a strong base.

[0035] Formula III as presented in the application is actual a racemic mixture of the following two enantiomer in a 1:1 ratio

[0036]

[0037] Accordingly, Formulas II, III and V are also 1 : 1 racemic mixtures of their analogous structures.

[0038] Formula I as presented in the application is actual a racemic mixture of the following two enantiomer in a 1 : 1 ratio.

[0039] Formula II as presented in the application is actual a racemic mixture of the following two enantiomer in a 1 : 1 ratio.

[0040] Formula V as presented in the application is actual a racemic mixture of the following two enantiomer in a 1 : 1 ratio.

[0041]

[0042] As noted above, the inventive process can be extended to a broader range of prostaglandin compounds. For example, compounds such as PGF2a, latanoprost, carboprost, fluprostenol, travoprost, and PGE2 can be made with the inventive process.

[0043] The compound of Formula VI as presented in the application is also a racemic mixture of the following two enantiomer in a 1 : 1 ratio. The compound of Formula VII is wherein

[0044] Ri is C2-C5 alkyl, -O-phenyl, wherein the alkyl or phenyl are optionally substituted with one or more halo, haloalkyl, hydroxy, alkyloxy, or haloalkyoxy and

[0045] R2 is H or CH3.

[0046] In another embodiment, Ri is -(CFb^CFb and R2 is H.

[0047] In another embodiment, Ri is -O-mCFsphenyl and R2 is H.

[0048] In another embodiment, Ri is -(CH2)4CH3 and R2 is CH3. In another embodiment, Ri is -O-m-Cl-phenyl and R2 is H.

[0049] Another embodiment of the invention is a process to produce the compound of Formula VI comprising reacting a compound of Formula III with a compound of Formula VII in the presence of a catalyst to yield the compound of Formula VI wherein

[0050] Ri is C2-C5 alkyl, -O-phenyl, wherein the alkyl or phenyl are optionally substituted with one or more halo, haloalkyl, hydroxy, alkyloxy, or haloalkyoxy and

[0051] R2 is H or CH3.

[0052] In an embodiment of the invention, the catalyst is a Hovey da-Grubbs 2nd generation catalyst.

[0053] In an embodiment of the invention, the catalyst is (l,3-Bis-(2,4,6-trimethylphenyl)-2- imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene) ruthenium, (l,3-Bis-(2,4,6- trimethylphenyl)-2-imidazolidinylidene]dichloro(2-isopropoxybenzylidene)ruthenium(II), (1,3-Bis-

[0054] (2-tolyl)-2-imidazolidinylidene]dichloro(2-isopropoxybenzylidene)ruthenium(II), (1,3-Bis(2,4,6- trimethylphenyl)-2-imidazolidinylidene]dichloro[5-(isobutoxycarbonylamido)-2- isopropoxybenzylidene]ruthenium(II), or (l,3-Bis(2,6-diisopropylphenyl)-2- imidazolidinylidene]dichloro[5-(isobutoxycarbonylamido)-2-isopropoxybenzylidene]ruthenium(II).

[0055] In an embodiment of the invention, the catalyst is (l,3-Bis-(2,4,6-trimethylphenyl)-2- imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene) ruthenium.

[0056] In an embodiment of the invention, the catalyst is (l,3-Bis-(2,4,6-trimethylphenyl)-2- imidazolidinylidene]dichloro(2-isopropoxybenzylidene)ruthenium(II).

[0057] In another embodiment, the compound of Formula III is produced by a) reacting a compound of Formula I with an oxidizing agent to produce a compound of Formula II

[0058] ; and b) reacting the compound of Formula II with methyltriphenyl phosphonium halide to form the compound of Formula III.

[0059] In an embodiment, the oxidizing agent of step a) is TEMPO, EDCI or DMP, preferably EDCI. In an alternative embodiment, the methyltriphenyl phosphonium halide of step b) is methyltriphenyl phosphonium bromide, methyltriphenyl phosphonium chloride, or methyltriphenyl phosphonium iodide, preferably methyltriphenyl phosphonium bromide.

[0060] In another embodiment, step b) of the process further comprise a base and the base is selected from potassium tertiary butoxide, NaHMDS or LiHMDS.

[0061] In another aspect of the invention, the compound of Formula IV is produced by a) reacting a compound of Formula VIII de dialkyl acetal to form a compound of Formula IX b) combing the compound of Formula IX with an acid and heating to produce a compound of

[0062] Formula X c) reacting the compound of Formula X with a vinyl magnesium halide to yield the compound of Formula IV.

[0063] In an embodiment, the halo acetaldehyde dialkyl acetal of step a) is bromo acetaldehyde diethyl acetal, bromo acetaldehyde dimethyl acetal, iodo acetaldehyde diethyl acetal, or iodo acetaldehyde dimethyl acetal.

[0064] In an embodiment, the acid of step a) is hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid, preferably hydrochloric acid. In an aspect of the invention, the vinyl magnesium halide of step c) is selected from vinyl magnesium bromide or vinyl magnesium chloride, preferably vinyl magnesium bromide.

[0065] An aspect of the invention is a compound of Formula III In another aspect of the invention is a process to produce a compound of Formula III comprising a) reacting a compound of Formula I with an oxidizing agent to produce a compound of Formula II

[0066] b) reacting the compound of Formula II with methyltriphenyl phosphonium halide to form the compound of Formula III.

[0067] In an alternative embodiment, the oxidizing agent of step a) is TEMPO, DMP or EDCI, preferably EDCI.

[0068] In an alternative embodiment, the methyltriphenyl phosphonium halide of step b) is methyltriphenyl phosphonium bromide, methyltriphenyl phosphonium chloride, or methyltriphenyl phosphonium iodide, preferably methyltriphenyl phosphonium bromide.

[0069] Another embodiment is a process to produce a compound of Formula IX comprising a) reacting a compound of Formula VIII dialkyl acetal to form a compound of Formula IX b) combining the compound of Formula IX with an acid and heating to produce a compound of

[0070] Formula X c) reacting the compound of Formula X with vinyl magnesium halide to yield the compound of Formula IV.

[0071] In an alternative embodiment, the halo acetaldehyde dialkyl acetal of step a) is bromo acetaldehyde diethyl acetal, bromo acetaldehyde dimethyl acetal, iodo acetaldehyde diethyl acetal, or iodo acetaldehyde dimethyl acetal, preferably bromo acetaldehyde diethyl acetal.

[0072] In an alternative embodiment, the vinyl magnesium halide of step c) is selected from vinyl magnesium bromide or vinyl magnesium chloride, preferably vinyl magnesium bromide.

[0073] An additional embodiment is a process to produce cloprostenol comprising a) reacting a compound of Formula III in the presence of a catalyst to yield the compound of Formula V.

[0074] b) further transforming the compound of Formula V to yield cloprostenol.

[0075] In an additional embodiment, the compound of Formula V is transformed into cloprostenal according to Scheme 3. Scheme 3 Preparation of cloprostenol from the compound of Formula V See Chen et al., CHIRALITY 27:392-396 (2015).

[0076] The compound of Formula III can also be used to prepare other prostaglandin compounds, dinoprast and bimatrprost are examples.

[0077] Pharmaceutically acceptable carriers are known to one skilled in the art. A non-limiting list of examples is given in WO 2018 / 025753 on pages 9-18. Another aspect of the invention is a pharmaceutical composition comprising a compound produced by of the above processes and a pharmaceutical acceptable excipient.

[0078] EXAMPLES

[0079] EXAMPLE 1 - Preparation of a racemic mixture of Formula II

[0080] (±)- Corey lactone 5-(4-phenylbenzoate) of Formula I, di chloromethane (2000 mL), and methanol (1000 mL) were added to a round bottom flask (1) at 25°C and stirred for 10-20 minutes to get a clear solution. In another round bottom flask (2) were added potassium bromide (4.73 g), sodium bicarbonate (22.4 g), water (270 mL) and was stirred for 30 minutes to get a clear solution. The contents from round bottom flask (2) were transferred to (1) at 25°C, cooled to -9°C and added Tempo (0.44g) under stirring. In a separate round bottom flask (3) were added sodium bicarbonate (7.63 g) and sodium hypochlorite (253.5 g) at room temperature and were stirred for 30 minutes at 5°C to get a clear solution. The contents from round bottom flask (3) were transferred to (1) at - 9°C over 2 hours and stirred for additional one hour at the same temperature. After reaction completion, sodium thiosulphate solution (dissolve 80 g of sodium thiosulphate pentahydrate in 100 mL of water) and isopropyl alcohol were added at below 10 °C. The layers were separated. To the aqueous layer was added di chloromethane (400 mL) and stirred for 15 minutes. The layers were separated. The combined organic layers were washed with sodium bicarbonate solution (18 g in 300 mL), cooled to 5°C, and proceeded to the next step.

[0081] EXAMPLE 2 - Preparation of a racemic mixture of Formula II

[0082] Corey lactone 5-(4 phenylbenzoate)

[0083] To a solution of (±)- Corey lactone 5-(4-phenylbenzoate) of Formula I (100 g), dimethyl sulphoxide (177 mL) and dimethoxy ethane (1.00 L) was added l-Ethyl-3 -(3 -dimethyl aminopropyl)carbodiimide (163 g) at 25 °C in one portion. The mixture was cooled to 0°C under nitrogen atmosphere. Phosphoric acid (13.9 g) was added dropwise at 0 °C over 10 minutes. The reaction mixture was stirred at 25 °C for 2 hrs. After the completion of the reaction, added water (1000 mL) and extracted with ethyl acetate (800 mL x 3). The combined organic layers was washed with 10 % citric acid (1000 mL) solution. The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to give a residue; The residue was triturated with isopropyl ether (300 mL) at 20 °C for 30 min. Obtained (±) compound II (90.0 g, 257 mmol, 90.5% yield) as off-white solid.

[0084] EXAMPLE 3 A - Preparation of a racemic mixture of Formula III

[0085] To a solution of methyltriphenylphosphonium bromide (15.3 g) in THF (200 mL) was added a solution of potassium tertiary butoxide (4.80 g) in THF (100 mL) dropwise at -60 °C, over 5 min under nitrogen and was stirred for 10 minutes. A solution of (±) Formula II (10.0 g) in THF (200 mL) was added dropwise at -60 °C, over 10 min under nitrogen. The reaction was stirred at 0 °C for 30 min and was poured into saturated ammonium chloride solution (600 mL). The reaction mixture was extracted with ethyl acetate (200 mL x 2) and washed with brine (500 mL). The combined organic layers were dried over sodium sulphate, filtered and concentrated under reduced pressure to give a residue. The residue was dissolved in tetrahydro furan (70.0 mL) and calcium bromide (17.1 g) was added in one portion at 20 °C. The mixture was stirred at 20 °C for 12 hrs and filtered over celite. The organic layer was concentrated under reduced pressure to give a residue and was purified by column chromatography over silica gel to obtain 6 g (60 % yield) of (±) compound III as white solid.

[0086] EXAMPLE 3B - Preparation of a racemic mixture of Formula III

[0087] To a solution of methyltriphenylphosphonium bromide (138 g) in THF (1.8 L) was added a solution of 2 M NaHMDS (96 mL) in THF dropwise at -60 to -70°C over 30 min under nitrogen and was stirred for 60 minutes. The temperature was raised to 0-5°C. A solution of (±) Formula II (90.0 g) in THF (900 mL) was added dropwise at 0-5°C, over 10-15 min under nitrogen. The reaction was stirred at 0 °C for 30 min and poured into 20 % ammonium chloride solution (900 mL) over 30 minutes at 10-15°C. The reaction mixture was extracted with ethyl acetate (900 mL) and was filtered through a celite bed under vacuum at 30-40°C. The organic layers were separated and concentrated under reduced pressure to give a residue. The residue was dissolved in acetonitrile (900 mL), charged calcium bromide (77 g), and stirred for 18 h at 20-30°C. The precipitate thus formed was filtered. The filtrate was concentrated under vacuum at 40-45°C to get the crude compound III, purified by column chromatography over neutral alumina using ethyl acetate and hexane as eluent to obtain 100 g (±) compound III as a white solid.

[0088] EXAMPLE 3C - Preparation of a racemic mixture of Formula III

[0089] To a solution of, methyltriphenylphosphonium bromide (30.58 g) in dry THF (500 mL) was added a solution of 2 M NaHMDS (42.8 mL) in THF dropwise at -60 to -70°C over 30-45 min under argon and stirred for 2 hours. The temperature was raised to 0-5°C. Formula II (20.0 g) was added portion wise at 0-5°C, over 10-15 min under argon. The reach on was stirred at 0 °C for 60 minutes and poured into precooled mixture (-40 °C to -50 °C) of ethyl acetate and 20 % ammonium chloride solution (900 mL) over a period of 30-45 minutes. The reaction mixture temperature was raised to 0-5 °C and was filtered through a celite bed. The organic layer was separated from filtrate and filtered through neutral alumina bed under vacuum below 40 °C and concentrated partially under reduced pressure. The residue was triturated and recrystallized using isopropyl alcohol (290 mL) to obtain 10.1 g (±) compound III as an off-white solid.

[0090] EXAMPLE 4 - Preparation of a racemic mixture of Formula V In an argon-filled glovebox, a 125 mL 3 -neck round bottom flask with a stir bar was charged with

[0091] Formula III (2.50 g), compound IV (1.57 g) and anisole (20 mL). In a 20 mL vial, Hovey da-Grubbs 2nd generation catalyst (45 mg) was dissolved in anisole (5 mL). The catalyst solution was transferred to the flask via cannula. The green solution was sparged while heating at 40 °C for 4 h. The reaction was cooled to room temperature and ethyl vinyl ether (2 mL) was added to quench any remaining active metathesis catalyst. Solvent was removed in vacuum on a rotovap (bath temp. 60 °C). Toluene (30 mL) was added to the oil and concentrated in vacuum to remove residual anisole and was repeated twice. The product was separated via flash chromatography to give Compound V. Yield 65 %.

[0092] Example 5 - Preparation of Formula VII Step 1

[0093] To a solution of Formula VI (98.0 g) and NaOH (60.9 g) in Dimethyl acetamide (1500 mL) was added bromoacetaldehyde dimethyl acetal (225 g) at 20 °C and was heated to 85 - 90 °C for 12 hours. The reaction was quenched with water (3000 mL) and the product was extracted into n-heptane (800 mL). The organic layer was separated, washed with 5 % sodium hydroxide solution (2 x 1000 mL), brine (1 x 500 mL) and concentrated under reduced pressure to give the product VII in quantitative yield. 1HNMR (CDC13, 400 MHz): 5 7.17-7.21 (m, 1H),6.93 (d, J = 4.4 Hz, 2H), 6.83 (d, J = 2.4 Hz, 1H), 4.82 (t, J = 4.8 Hz, 1H), 3.99 (d, J =5.2 Hz, 2H) 3.75-3.78 (m, 2H), 3.61-3.66 (m, 2H), 1.25 (t, J = 6.8 Hz, 6H).

[0094] Example 6 - Preparation of Formula VIII

[0095] To a solution of VII (20 g) in tetrahydrofuran (100 mL) was added hydrochloric acid (2 M, 110 mL) dropwise at 20 °C for 10 minutes under nitrogen and was heated to 80 °C for 2 hours. The reaction was cooled and the product was extracted into toluene (200 mL). The combined organic layers was washed with water (4 x 100 mL) and concentrated to ~ 65 mL and used for next step without further purification.

[0096] 1HNMR (CDC13, 400 MHz): 5 9.66 (s, 1H), 6.89 (d, J= 8.0 Hz, H), 7.79 (t, J= 4 Hz, 2H), 4.36 (s, 2H)

[0097] Example 7 - Preparation of Formula IV

[0098] To the above solution of Formula VIII was added Vinyl magnesium bromide (1 M in THF, 117 mL) dropwise at -65 °C to - 60 °C for 30 min under nitrogen and stirred for 1 hr at the same temperature. The temperature was warmed up to 20 °C and stirred for 12 hrs. The reaction mixture was quenched by addition saturated ammonium chloride (270 mL) and extracted with ethyl acetate (70 mL). The combined organic layers were washed with brine (130 mL x 2), dried over sodium sulphate, filtered and concentrated under reduced pressure to give a residue. The crude product was distilled in vacuum (80 - 135 °C, 33 pa pressure / oil pump) to give compound of Formula IV with 80 % yield as yellow oil.

[0099] 1HNMR (CDC13, 400 MHz): 5 7.31 (t, = 8.0 Hz, 1H), 7.01-7.04 (m, 2H), 5.46 (d, J= 16.8 Hz, 1H), 5.91-5.97 (m, 1H), 5.38 (dt, Ji = 20 Hz, J2= 20 Hz, 1H), 5.25 (d, J= 4.8 Hz, 1H), 5.16 (d, J =12.4 Hz, 1H), 4.30-4.32 (m, 1H), 3.93-3.96 (m, 1H), 3.85-3.87 (m, 1H).

[0100] Example 8 - Preparation of cloprostenol from Compound V

[0101] Cloprostenol is prepared from Compound V by the process described in Chen et al., CHIRALITY 27:392-396 (2015) from bottom of the left-hand column of page 393 to the top of right-hand column and Scheme 1 of page 394.

Claims

CLAIMS1. The compound of Formula IIIcomprising reacting a compound of Formula IIIin the presence of a catalyst to yield the compound of Formula VI, whereinRi is C2-C5 alkyl, -O-phenyl, wherein the alkyl or phenyl are optionally substituted with one or more halo, haloalkyl, hydroxy, alkyloxy, or haloalkyoxy andR2 is H or CH3.

3. The process of claim 2, wherein the compound of Formula VI is a compound of Formula Vthe compound of Formula VII is a compound of Formula IV4. The process of anyone of claims 2-3 wherein the catalyst is (l,3-Bis-(2,4,6-trimethylphenyl)-2- imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene) ruthenium, (l,3-Bis-(2,4,6- trimethylphenyl)-2-imidazolidinylidene]dichloro(2-isopropoxybenzylidene)ruthenium(II), (1,3-Bis- (2-tolyl)-2-imidazolidinylidene]dichloro(2-isopropoxybenzylidene)ruthenium(II), (1,3-Bis(2,4,6- trimethylphenyl)-2-imidazolidinylidene]dichloro[5-(isobutoxycarbonylamido)-2- isopropoxybenzylidene]ruthenium(II), or (l,3-Bis(2,6-diisopropylphenyl)-2- imidazolidinylidene]dichloro[5-(isobutoxycarbonylamido)-2-isopropoxybenzylidene]ruthenium(II).

5. A process to produce a compound of Formula IIIcomprising a) reacting a compound of Formula Iwith an oxidizing agent to produce a compound of Formula II; and b) reacting the compound of Formula II with a methyltriphenyl phosphonium halide to form the compound of Formula III.

6. The process of claim 5, wherein the oxidizing agent of step a) is TEMPO, DMP or EDCI preferably EDCI.

7. The process of claims 5 or 6, wherein the methyltriphenyl phosphonium halide of step b) is methyltriphenyl phosphonium bromide, methyltriphenyl phosphonium chloride, or methyltriphenyl phosphonium iodide, preferably methyltriphenyl phosphonium bromide.

8. The process of anyone of claims 5-7, wherein step b) further comprisings a base and the base is selected from potassium tertiary butoxide, NaHMDS or LiHMDS.

9. The process of anyone of claims 5-8, wherein the compound of Formula III is isolated by recrystallization with a solvent, preferably an alkyl alcohol.

10. The process of claim 9, wherein the solvent is isopropyl alcohol.

11. A process to produce a compound of Formula VII, d of Formula VII is a compound of Formula IVcomprising a) reacting a compound of Formula VIII dialkyl acetal to form a compound of Formula IXb) combining the compound of Formula IX with an acid and heating to produce a compound ofFormula Xc) reacting the compound of Formula X with a vinyl magnesium halide to yield the compound of Formula IV.

12. The process of claim 11, wherein the halo acetaldehyde dialkyl acetal of step a) is bromo acetaldehyde diethyl acetal, bromo acetaldehyde dimethyl acetal, iodo acetaldehyde diethyl acetal, or iodo acetaldehyde dimethyl acetal, preferably bromo acetaldehyde diethyl acetal.

13. The process of claimsl 1 and 12, wherein the acid of step b) is hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid, preferably hydrochloric acid.

14. The process of anyone of claims 11-13, wherein the vinyl magnesium halide of step c) is selected from vinyl magnesium bromide or vinyl magnesium chloride, preferably vinyl magnesium bromide.

15. A process to make a prostaglandin compound comprising a) comprising reacting a compound of Formula IIIin the presence of a catalyst to yield the compound of Formula VI, whereinRi is C2-C5 alkyl, -O-phenyl, wherein the alkyl or phenyl are optionally substituted with one or more halo, haloalkyl, hydroxy, alkyloxy, or haloalkyoxy andR2 is H or CH3, to yield a compound of Formula VIand b) further transforming the compound of Formula VI to a prostaglandin compound.

16. The process of claim 15, wherein the compound of Formula VI is a compound of Formula Vthe compound of Formula VII is a compound of Formula IVthe prostaglandin compound is cloprostenol.

17. A pharmaceutical composition comprising a compound produced by the process of any one of claims 15-16 and a pharmaceutical acceptable excipient.

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