Method for preparing compounds containing fluorine

Abstract

This disclosure relates to methods of preparing alkenes and alkanes that contain fluorine and methods of use thereof.

Description

METHOD FOR PREPARING COMPOUNDS CONTAINING FLUORINE TECHNICAL FIELD

[0001] This disclosure relates to methods for preparing alkenes and alkanes that contain fluorine and methods of use thereof. BACKGROUND

[0002] Semifluorinated alkanes are physically, chemically and physiologically inert compounds, which find application in medicine, in particular in the ophthalmic and dermatological fields. As such, methods for the efficient productions of these compounds, particularly without one or more undesired impurities, are needed. SUMMARY

[0003] A common process for the production of semifluorinated alkanes is the free radical addition of fluoroalkyl iodides to a double bond in the presence of an azonitrile type radical generating chain initiator (e.g.2,2′-azobis(isobutyronitrile), followed by reductive dehalogenation of the resulting iodinated adduct. This reaction produces considerable amount of undesired methyl isomer impurity, which is hard to remove due to too close physical chemical properties.

[0004] The reductive dehalogenation of the adduct can be achieved with (1) zinc powder and gaseous HCl in ethanol or another alcohol, acetic acid or aqueous HCl; and (2) tributyltin hydride and LiAlH4 / ether. The process comprising reductive dehalogenation by using Zn / HCl results in low yield and low purity, due to the presence of unsaturated species in the final product. Hydrogenation of double bonds to saturated ones can be performed using catalytic (rhodium or palladium on charcoal) hydrogenation procedures under pressure. This process however requires the use of pressure reactors and long reaction time and results are not economical.

[0005] The present disclosure provides a method for preparing a compound of Formula (I):wherein m and R1are defined herein, comprising the steps of:(i) reacting a compound of Formula (II), wherein W is defined herein,with an aldehyde of Formula (III)in the presence of a base and a solvent to produce an alkene of Formula (IV)(ii) hydrogenating the alkene to yield the compound of Formula (I). The present disclosure also provides a composition comprising a compound of Formula (I):and substantially free of a compound of Formula (V)wherein m and R1are defined herein; and wherein the composition is made by a process comprising the steps: (i) reacting a compound of Formula (II), wherein X is defined herein,with a compound of Formula (III)in the presence of a base and a solvent to produce an alkene of Formula (IV);(ii) hydrogenating the alkene to yield the composition comprising the compound of Formula (I).

[0006] The disclosure provides a method for treating an ophthalmological disorder or condition comprising administering an effective amount of a composition described herein to an eye of a subject in need thereof.

[0007] In some embodiments, the methods and compositions provided herein can provide several advantages. First, in some instances, the methods provided herein can provide increased yield of the target semi-fluorinated alkanes.

[0008] Second, in some instances, the methods provided herein can result in no or low generation of one or more undesired impurities, such as methyl isomer impurities.

[0009] Additional embodiments of the present disclosure are disclosed herein. DESCRIPTION OF DRAWINGS

[0010] Fig.1 shows a gas chromatogram of 1,1,1,2,2,3,3,4,4,5,5,6,6- tridecafluorotetradecane (labelled on the chromatogram as “F6H8”) synthesized by the method of Example 1.

[0011] Fig.2 shows a gas chromatogram of 1,1,1,2,2,3,3,4,4,5,5,6,6- tridecafluorotetradecane (labelled on the chromatogram as “F6H8”) synthesized by a standard commercial process. DETAILED DESCRIPTION

[0012] The description below is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience and are not to be construed to limit the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

[0013] Unless defined otherwise, all technical and scientific terms used herein havethe same meaning as commonly understood by one of ordinary skill in the art. A dash at the front or end of a chemical group is a matter of convenience to indicate the point of attachment to a parent moiety; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a chemical structure or a dashed line drawn through a line in a chemical structure indicates a point of attachment of a group. A dashed line within a chemical structure indicates an optional bond.

[0014] As used herein, the term "about" means "approximately" (e.g., plus or minus 10% of the indicated value).

[0015] At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. A prefix such as “Cu-v” or (Cu-Cv) indicates that the following group has from u to v carbon atoms. For example, the term “C1-6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl group in the alternative.

[0016] The term “alkyl” refers to a saturated hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1-C6 alkyl indicates that the group may have from 1 to 6 (inclusive) carbon atoms in it. Any atom can be optionally substituted, e.g., by one or more substituents. Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, and tert-butyl.

[0017] The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0018] As used herein, the phrase “effective amount” or “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

[0019] As used herein, the term “4-10 membered heterocycloalkyl ether” refers to a non-aromatic ring or ring system, which optionally contain one or more alkenylene groups as part of the ring structure, which has at least one oxygen heteroatom ringmember and 4-10 ring members. Included within the term “heterocycloalkyl” are monocyclic 4-, 5-, 6- and 7-membered heterocycloalkyl groups. Examples of 4-10 membered heterocycloalkyl ether include tetrahydrofuran, tetrahydropyran, dioxane, and the like.

[0020] As used herein, the term “substantially free of” or “free of” an ingredient(s) as provided throughout the disclosure is intended to mean that the composition or compound(s) contain less than about 2 wt% (percent by weight of the total weight of the composition or compound(s)), or insignificant or negligible amounts, of said ingredient(s) unless specifically indicated otherwise. In some embodiments, the compound of Formula (I) of the present disclosure is substantially free of impurities such as a compound of Formula (V), meaning that the compound of Formula (I) contains less than about 2 wt% of an impurity such as a compound of Formula (V). In some embodiments, the compound of Formula (I) of the present disclosure is substantially free of impurities, meaning that the total amount of impurities is less than about 2 wt %.

[0021] As used herein, the term “subject” refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

[0022] As used herein the term “treating” or “treatment” refers to 1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomatology), or 2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology).

[0023] Example bases include alkali metal bases such as alkali metal hydroxides (e.g., cesium acetate, lithium acetate, sodium acetate, and potassium acetate), alkali metal carbonate (e.g., lithium carbonate, sodium carbonate, and potassium carbonate), alkali metal phosphates (e.g., cesium phosphate, lithium phosphate, sodium phosphate, potassium phosphate, and potassium phosphate dibasic), and alkali metal acetate (e.g., cesium acetate, lithium acetate, sodium acetate, and potassium acetate). Some example strong bases include, but are not limited to, hydroxide, alkoxides, metalamides, metal hydrides, metal dialkylamides and arylamines, wherein; alkoxides include lithium, sodium and potassium salts of methyl, ethyl and t-butyl oxides; metal amides include sodium amide, potassium amide and lithium amide; metal hydrides include sodium hydride, potassium hydride and lithium hydride; metal dialkylamides include sodium and potassium salts of methyl, ethyl, n-propyl, i-propyl, n-butyl, t- butyl, trimethylsilyl and cyclohexyl substituted amides; and or an organolithium base include MeLi, n-BuLi, t-BuLi, and sec-BuLi.

[0024] Suitable protic solvents can include, by way of example and without limitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, i- butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, mixtures thereof, and the like.

[0025] Suitable aprotic solvents can include, by way of example and without limitation, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl- 2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N- methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, hexamethylphosphoramide, mixtures thereof, and the like.

[0026] The instant disclosure provides a composition comprising an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, excipient or additive. The carrier(s) are “acceptable” in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament. The composition may also comprise any one of the additional therapeutic agents described herein. Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the compositions of the present disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-poly oxypropylene-block polymers, polyethylene glycol, and wool fat.

[0027] The compositions or dosage forms may contain any one of the compounds and therapeutic agents described herein in the range of 0.005% to 100% with the balance made up from the suitable pharmaceutically acceptable excipients. The contemplated compositions may contain 0.001%-100% of any one of the compounds and therapeutic agents provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%, wherein the balance may be made up of any pharmaceutically acceptable excipient described herein, or any combination of these excipients.

[0028] The compositions of the present disclosure include those suitable for any acceptable route of administration. Suitable examples of acceptable routes of administration include buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracistemal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intranasal, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal.

[0029] Compositions and formulations described herein may conveniently be presented in a unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th ed.2000). Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients. Ingeneral, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0030] In some embodiments, any one of the compounds and therapeutic agents disclosed herein are administered orally. Compositions of the present disclosure suitable for oral administration may be presented as discrete units such as capsules, sachets, granules or tablets each containing a predetermined amount (e.g., effective amount) of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a nonaqueous liquid; an oil-in-water liquid emulsion; a water-in- oil liquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption. In the case of tablets for oral use, carriers that are commonly used include lactose, sucrose, glucose, mannitol, and silicic acid and starches. Other acceptable excipients may include: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar- agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. For oral administration in a capsule form, useful diluents include lactose and dried com starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added. Compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.

[0031] Compositions suitable for parenteral administration include aqueous and non- aqueous sterile injection solutions or infusion solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, saline (e.g., 0.9% saline solution) or 5% dextrose solution, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets. The injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxy ethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant. The compositions of the present disclosure may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of the present disclosure with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.

[0032] The compositions of the present disclosure may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art. See, for example, U.S. Patent No.6,803,031. Additionalformulations and methods for intranasal administration are found in Ilium, L., J Pharm Pharmacol, 56, 3-17, 2004 and Ilium, L., Eur J Pharm Sci, 11, 1-18, 2000.

[0033] The topical compositions of the present disclosure can be prepared and used in the form of an aerosol spray, cream, emulsion, solid, liquid, dispersion, foam, oil, gel, hydrogel, lotion, mousse, ointment, powder, patch, pomade, solution, pump spray, stick, towelette, or soap. In some embodiments, the composition is in any form commonly employed in the art of cosmetic and skin care formulation. The topical compositions can be in an emulsion form. Topical administration of the compositions of the present disclosure is especially useful when the desired treatment involves areas or organs readily accessible by topical application. In some embodiments, the topical composition comprises a combination of any one of the compounds and therapeutic agents disclosed herein, and one or more additional ingredients, carriers, excipients, or diluents including, but not limited to, absorbents, anti-irritants, anti-acne agents, preservatives, antioxidants, coloring agents / pigments, emollients (moisturizers), emulsifiers, film-forming / holding agents, fragrances, leave-on exfoliants, prescription drugs, preservatives, scrub agents, silicones, skin-identical / repairing agents, slip agents, sunscreen actives, surfactants / detergent cleansing agents, penetration enhancers, and thickeners.

[0034] In some embodiments, the topical composition is an ophthalmic composition, e.g., for intraocular administration. Suitable examples of ophthalmic compositions include eye drops, saline drops, suspensions, ointments, emulsions, nanoemulsions, oil, gel, hydrogel, solutions, . Any one of these ophthalmic compositions can be administered directly to the cornea, pupil, retina, choroid, sclera, and / or iris of the eye, using, for example, a plastic or latex applicator (e.g., a single-use applicator), an eye dropper, a glass pipette, or a rubber bulb. These formulations may contain, for example, a partially fluorinated alkane liquid vehicle, as described above. In addition, the ophthalmic composition may contain water, saline, a dextrose solution, a cellulose or its derivative, such as hydroxypropylmethylcellulose, a surfactant such as polysorbate 20, a chelating agent, or a cyclodextrin.

[0035] In some embodiments, the disclosure provides a composition comprising a compound of Formula (I):and substantially free of a compound of Formula (V):wherein m = 0 to 12 and R1is a linear or branched C1-20 alkyl group; and wherein the composition is made by a process comprising the steps: (i) reacting a compound of Formula (II), wherein W is P(Ph3)+,with a compound of Formula (III)in the presence of a base and a solvent to produce an alkene of Formula (IV)(ii) hydrogenating the alkene to yield the composition comprising the compound of Formula (I).

[0036] In some embodiments, the process further comprises (iii) purifying the compound of Formula (I) by fractional distillation.

[0037] In some embodiments, the compound of Formula (II) is a Wittig reagent wherein W is P(Ph3)+. In some embodiments, W is P(Ar3)+, wherein Ar is an substituted or unsubstituted C6 aryl group. In some embodiments, the compound of Formula (II) is a Horner-Wadsworth-Emmons reagent wherein W is P(O)(OEt)2.

[0038] In some embodiments, the compound of Formula (I) is CF3(CF2)m(CH2)2R1. In some embodiments, wherein m is 0 to 15. In some embodiments, wherein m is 2 to 10. In some embodiments, wherein m is 4 to 8. In some embodiments, wherein m is 4to 6. In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some embodiments, m is 5.

[0039] In some embodiments, R1is a C1-20 linear or branched alkyl group. In some embodiments, R1is a C2-15 linear or branched alkyl group. In some embodiments, R1is a C3-12 linear or branched alkyl group. In some embodiments, R1is a C4-8 linear or branched alkyl group. In some embodiments, R1is a C2 linear or branched alkyl group. In some embodiments, R1is a C3 linear or branched alkyl group. In some embodiments, R1is a C4 linear or branched alkyl group. In some embodiments, R1is a C5 linear or branched alkyl group. In some embodiments, R1is a C6 linear or branched alkyl group. In some embodiments, R1is a C7 linear or branched alkyl group. In some embodiments, R1is a C8 linear or branched alkyl group. In some embodiments, R1is a C9 linear or branched alkyl group. In some embodiments, R1is a C10 linear or branched alkyl group. In some embodiments, R1is a C11 linear or branched alkyl group. In some embodiments, R1is a C12 linear or branched alkyl group. In some embodiments, R1is a C13 linear or branched alkyl group. In some embodiments, R1is a C14 linear or branched alkyl group. In some embodiments, R1is a C15 linear or branched alkyl group. In some embodiments, R1is a C16 linear or branched alkyl group. In some embodiments, R1is a C17 linear or branched alkyl group. In some embodiments, R1is a C18 linear or branched alkyl group. In some embodiments, R1is a C19 linear or branched alkyl group. In some embodiments, R1is a C20 linear or branched alkyl group. In some embodiments, R1is selected from ethyl, n-propyl, iso- propyl, sec-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, sec- pentyl, tert-pentyl, and neo-pentyl. In some embodiments, R1is n-pentyl.

[0040] In some embodiments, the compound of Formula (I) is CF3(CH2)2CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)(CH2)2CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)2(CH2)2CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)3(CH2)2CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)4(CH2)2CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)5(CH2)2CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)6(CH2)2CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)7(CH2)2CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)8(CH2)2CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)9(CH2)2CH3. In someembodiments, the compound of Formula (I) is CF3(CF2)10(CH2)2CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)11(CH2)2CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)12(CH2)2CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)13(CH2)2CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)14(CH2)2CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)15(CH2)2CH3.

[0041] In some embodiments, the compound of Formula (I) is CF3(CH2)3CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)(CH2)3CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)2(CH2)3CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)3(CH2)3CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)4(CH2)3CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)5(CH2)3CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)6(CH2)3CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)7(CH2)3CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)8(CH2)3CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)9(CH2)3CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)10(CH2)3CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)11(CH2)3CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)12(CH2)3CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)13(CH2)3CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)14(CH2)3CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)15(CH2)3CH3.

[0042] In some embodiments, the compound of Formula (I) is CF3(CH2)7CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)(CH2)4CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)2(CH2)4CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)3(CH2)4CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)4(CH2)4CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)5(CH2)4CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)6(CH2)4CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)7(CH2)4CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)8(CH2)4CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)9(CH2)4CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)10(CH2)4CH3. In someembodiments, the compound of Formula (I) is CF3(CF2)11(CH2)4CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)12(CH2)4CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)13(CH2)4CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)14(CH2)4CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)15(CH2)4CH3.

[0043] In some embodiments, the compound of Formula (I) is CF3(CH2)5CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)(CH2)5CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)2(CH2)5CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)3(CH2)5CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)4(CH2)5CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)5(CH2)5CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)6(CH2)5CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)7(CH2)5CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)8(CH2)5CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)9(CH2)5CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)10(CH2)5CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)11(CH2)5CH3.In some embodiments, the compound of Formula (I) is CF3(CF2)12(CH2)5CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)13(CH2)5CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)14(CH2)5CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)15(CH2)5CH3.

[0044] In some embodiments, the compound of Formula (I) is CF3(CH2)6CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)(CH2)6CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)2(CH2)6CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)3(CH2)6CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)4(CH2)6CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)5(CH2)6CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)6(CH2)6CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)7(CH2)6CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)8(CH2)6CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)9(CH2)6CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)10(CH2)6CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)11(CH2)6CH3. In someembodiments, the compound of Formula (I) is CF3(CF2)12(CH2)6CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)13(CH2)6CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)14(CH2)6CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)15(CH2)6CH3.

[0045] In some embodiments, the compound of Formula (I) is CF3(CH2)7CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)(CH2)7CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)2(CH2)7CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)3(CH2)7CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)4(CH2)7CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)5(CH2)7CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)6(CH2)7CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)7(CH2)7CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)8(CH2)7CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)9(CH2)7CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)10(CH2)7CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)11(CH2)7CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)12(CH2)7CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)13(CH2)7CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)4(CH2)7CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)15(CH2)7CH3.

[0046] In some embodiments, the compound of Formula (I) is CF3(CH2)8CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)(CH2)8CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)2(CH2)8CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)3(CH2)8CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)4(CH2)8CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)5(CH2)8CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)6(CH2)8CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)7(CH2)8CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)8(CH2)8CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)9(CH2)8CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)10(CH2)8CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)11(CH2)8CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)12(CH2)8CH3. In someembodiments, the compound of Formula (I) is CF3(CF2)13(CH2)8CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)14(CH2)8CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)15(CH2)8CH3.

[0047] In some embodiments, the compound of Formula (I) is CF3(CH2)9CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)(CH2)9CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)2(CH2)9CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)3(CH2)9CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)4(CH2)9CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)5(CH2)9CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)6(CH2)9CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)7(CH2)9CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)8(CH2)9CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)9(CH2)9CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)10(CH2)9CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)11(CH2)9CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)12(CH2)9CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)13(CH2)9CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)14(CH2)9CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)15(CH2)9CH3.

[0048] In some embodiments, the compound of Formula (I) is CF3(CH2)10CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)(CH2)10CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)2(CH2)10CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)3(CH2)10CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)4(CH2)10CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)5(CH2)10CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)6(CH2)10CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)7(CH2)10CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)8(CH2)10CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)9(CH2)10CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)10(CH2)10CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)11(CH2)10CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)12(CH2)10CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)13(CH2)10CH3. In someembodiments, the compound of Formula (I) is CF3(CF2)14(CH2)10CH3. In some embodiments, the compound of Formula (I) is CF3(CF2)15(CH2)10CH3.

[0049] In some embodiments, the compound of Formula (I) has a purity of about 60% or more, such as 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In some embodiments, the compound of Formula (I) has a purity of about 60% to 70%. In some embodiments, the compound of Formula (I) has a purity of about 70% to 80%. In some embodiments, the compound of Formula (I) has a purity of about 80% to 90%. In some embodiments, the compound of Formula (I) has a purity of about 90% to 100%. In some embodiments, the compound of Formula (I) has a purity of about 90% or more. In some embodiments, the compound of Formula (I) has a purity of about 95% or more. In some embodiments, the compound of Formula (I) has a purity of about 98% or more. In some embodiments, the compound of Formula (I) has a purity of about 99% or more.

[0050] In some embodiments, the compound of Formula (I) retains most or all of the fluorine atoms from the compound of Formula (IV); in other words, there is minimal or no loss of fluorine atoms in the product of the hydrogenation step from hydrodefluorination (e.g the replacement in a substrate of a carbon–fluorine bond by a carbon–hydrogen bond.) In some embodiments, the compound of Formula (I) retains more than 60% of the fluorine atoms from the compound of Formula (IV). In some embodiments, the compound of Formula (I) retains 60% or more of the fluorine atoms from the compound of Formula (IV), such as 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%. In some embodiments, the compound of Formula (I) retains more than 90 % of the fluorine atoms from the compound of Formula (IV). In some embodiments, the compound of Formula (I) retains more than 95 % of the fluorine atoms from the compound of Formula (IV). In some embodiments, the compound of Formula (I) retains more than 98 % of the fluorine atoms from the compound of Formula (IV). In some embodiments, the compound of Formula (I) retains more than 99 % of the fluorine atoms from the compound of Formula (IV). Insome embodiments, the compound of Formula (I) retains 100% of the fluorine atoms from the compound of Formula (IV).

[0051] In some embodiments, the base of the reacting step is an alkali metal base. In some embodiments, the base of the reacting step is an alkali metal carbonate. In some embodiments, the base of the reacting step is selected from cesium carbonate, lithium carbonate, sodium carbonate, and potassium carbonate.

[0052] In some embodiments, the base is an organolithium base. In some embodiments, the base is selected from MeLi, n-BuLi, t-BuLi, and sec-BuLi. In some embodiments, the base is selected from lithium bis(trimethylsilyl)amide (LiHMDS).

[0053] In some embodiments, the solvent of the reacting step comprises a polar protic solvent, a di-C1-6 alkyl ether, a 4-10 membered heterocycloalkyl ether, or a mixture thereof. In some embodiments, the solvent of the reacting step comprises water and 1,4-dioxane.

[0054] In some embodiments, the reacting step is carried out at a temperature from about 15°C to about 150 °C. In some embodiments, the reacting step is carried out at a temperature from about 50°C to about 105 °C. In some embodiments, the reacting step is carried out at a temperature from about 80°C to about 105 °C. In some embodiments, the reacting step is carried out at a temperature of about 95°C.

[0055] In some embodiments, the hydrogenation step is carried in the presence of a hydrogenating reagent. In some embodiments, the hydrogenating agent comprises hydrogen gas and Palladium (Pd) on carbon.

[0056] In some embodiments, the hydrogenating step is carried out at a temperature from about 5°C to about 50 °C. In some embodiments, the hydrogenating step is carried out at a temperature from about 15°C to about 40 °C. In some embodiments, the hydrogenating step is carried out at a temperature from about 20°C to about 30 °C. In some embodiments, the hydrogenating step is carried out at a temperature of about 25°C.

[0057] In some embodiments, the solvent of the hydrogenating step comprises a polar aprotic solvent. In some embodiments, the polar aprotic solvent is ethyl acetate.

[0058] In some embodiments, the composition is in the form of a liquid solution. In some embodiments, the composition is a liquid solution having a refractive index of about 1.30 to about 1.35 at 25° C., as determined by refractometer. In someembodiments, the composition has a dynamic viscosity of less than 10 mPa-s, as determined at 25° and 1 atmosphere pressure.

[0059] In some embodiments, the composition comprises from about 1 wt % to about 50 wt % of the compound of Formula (I), based on the total weight of the composition, such as about 1 wt % to about 5 wt %, about 5 wt % to about 10 wt %, about 10 wt % to about 15 wt %, about 15 wt % to about 20 wt %, about 20 wt % to about 25 wt %, about 25 wt % to about 30 wt %, about 30 wt % to about 35 wt %, about 35 wt % to about 40 wt %, about 40 wt % to about 45 wt %, about 45 wt % to about 50 wt %. In some embodiments, the composition comprises from about 1 wt % to about 25 wt % of the compound of Formula (I), based on the total weight of the composition. In some embodiments, the composition comprises from about 5 wt % to about 15 wt % of the compound of Formula (I), based on the total weight of the composition.

[0060] In some embodiments, the composition is an ophthalmic composition.

[0061] In some embodiments, the composition is substantially free of water.

[0062] In some embodiments, the composition is substantially free of a preservative.

[0063] In some embodiments, the composition further comprises a pharmacologically active ingredient.

[0064] In some embodiments, the pharmacologically active ingredient is selected from atropine, pirenzepine, aclidinium bromide, benztropine, cyclopentolate, diphenhydramine, doxylamine, dimenhydrinate, dicyclomine, darifenacin, flavoxate, hydroxyzine, ipratropium, mebeverine, oxybutynin, procyclidine, scopolamine, solifenacin, tropicamide, tiotropium, trihexyphenidyl, and tolterodine, or pharmaceutically acceptable salt thereof, or combinations thereof. In some embodiments, the pharmacologically active ingredient is selected from atropine, or pharmaceutically acceptable salt thereof.

[0065] In some embodiments, the composition comprises from about 0.0001 wt % to about 1.0 wt % of the pharmacologically active ingredient, based on the total weight of the composition. In some embodiments, the composition comprises from about 0.001 wt % to about 0.1 wt % of the pharmacologically active ingredient, based on the total weight of the composition. In some embodiments, the composition comprises from about 0.01 wt % to about 0.1 wt % of the pharmacologically active ingredient, based on the total weight of the composition.

[0066] In some embodiments, an effective amount (e.g., in the systemic formulation) of the pharmacologically active ingredient can range, for example, from about 0.001 mg / kg to about 500 mg / kg (e.g., from about 0.001 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 150 mg / kg; from about 0.01 mg / kg to about 100 mg / kg; from about 0.01 mg / kg to about 50 mg / kg; from about 0.01 mg / kg to about 10 mg / kg; from about 0.01 mg / kg to about 5 mg / kg; from about 0.01 mg / kg to about 1 mg / kg; from about 0.01 mg / kg to about 0.5 mg / kg; from about 0.01 mg / kg to about 0.1 mg / kg; from about 0.1 mg / kg to about 200 mg / kg; from about 0.1 mg / kg to about 150 mg / kg; from about 0.1 mg / kg to about 100 mg / kg; from about 0.1 mg / kg to about 50 mg / kg; from about 0.1 mg / kg to about 10 mg / kg; from about 0.1 mg / kg to about 5 mg / kg; from about 0.1 mg / kg to about 2 mg / kg; from about 0.1 mg / kg to about 1 mg / kg; or from about 0.1 mg / kg to about 0.5 mg / kg). In some embodiments, an effective amount of a pharmacologically active ingredient is about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, or about 5 mg / kg. The foregoing dosages can be administered on a daily basis (e.g, as a single dose or as two or more divided doses, e.g, once daily, two times daily, three times daily, or four times daily) or non-daily basis (e.g, every other day, every two days, every three days, once weekly, twice weekly, once every two weeks, once a month).

[0067] In some embodiments, the composition further comprises one or more pharmacologically acceptable excipients or additives.

[0068] In some embodiments, the disclosure provides a method for preparing a compound of Formula (I):wherein: m = 0 to 15; R1is a linear or branched C1-20 alkyl group; and comprising the steps of: (i) reacting an F-alkyl phosphonium salt of Formula (II), wherein W is P(Ph3)+,with an aldehyde of Formula (III) (III) in the presence of a base and a solvent to produce an alkene of Formula (IV)(ii) hydrogenating the alkene to yield the compound of Formula (I).

[0069] In some embodiments, X, wherein m is 0 to 15. In some embodiments, X, wherein m is 2 to 10. In some embodiments, X, wherein m is 4 to 8. In some embodiments, X, wherein m is 4 to 6. In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some embodiments, m is 5.

[0070] In some embodiments, R1is a C2-15 linear or branched C1-20 alkyl group. In some embodiments, R1is a C2-15 linear or branched alkyl group. In some embodiments, R1is a C3-12 linear or branched alkyl group. In some embodiments, R1is a C4-8 linear or branched alkyl group. In some embodiments, R1is a C2 linear or branched alkyl group. In some embodiments, R1is a C3 linear or branched alkyl group. In some embodiments, R1is a C4 linear or branched alkyl group. In some embodiments, R1is a C5 linear or branched alkyl group. In some embodiments, R1is a C6 linear or branched alkyl group. In some embodiments, R1is a C7 linear or branched alkyl group. In some embodiments, R1is a C8 linear or branched alkyl group. In some embodiments, R1is a C9 linear or branched alkyl group. In some embodiments, R1is a C10 linear or branched alkyl group. In some embodiments, R1is a C11 linear or branched alkyl group. In some embodiments, R1is a C12 linear or branched alkyl group. In some embodiments, R1is a C13 linear or branched alkyl group. In some embodiments, R1is a C14 linear or branched alkyl group. In some embodiments, R1is a C15 linear or branched alkyl group. In some embodiments, R1is a C16 linear or branched alkyl group. In some embodiments, R1is a C17 linear or branched alkylgroup. In some embodiments, R1is a C18 linear or branched alkyl group. In some embodiments, R1is a C19 linear or branched alkyl group. In some embodiments, R1is a C20 linear or branched alkyl group. In some embodiments, R1is selected from ethyl, n-propyl, iso-propyl, sec-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso- pentyl, sec-pentyl, tert-pentyl, and neo-pentyl. In some embodiments, R1is n-pentyl.

[0071] In some embodiments, the base is an alkali metal base. In some embodiments, the base is an alkali metal carbonate. In some embodiments, the base is selected from cesium carbonate, lithium carbonate, sodium carbonate, and potassium carbonate.

[0072] In some embodiments, the base is an organolithium base. In some embodiments, the base is selected from MeLi, n-BuLi, t-BuLi, and sec-BuLi. In some embodiments, the base is selected from lithium bis(trimethylsilyl)amide (LiHMDS).

[0073] In some embodiments, the solvent comprises a polar protic solvent, a di- C1-6 alkyl ether, a 4-10 membered heterocycloalkyl ether, or a mixture thereof. In some embodiments, the solvent comprises water and 1,4-dioxane.

[0074] In some embodiments, the reacting step is carried out at a temperature from about 15°C to about 150 °C. In some embodiments, the reacting step is carried out at a temperature from about 50°C to about 105 °C. In some embodiments, the reacting step is carried out at a temperature from about 80°C to about 105 °C. In some embodiments, the reacting step is carried out at a temperature of about 95°C.

[0075] In some embodiments, the yield of the reacting step is above 50%, such as 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, or 99%. In some embodiments, the yield is in a range of about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100%.

[0076] In some embodiments, the hydrogenation step is carried in the presence of a hydrogenating reagent. In some embodiments, the hydrogenating agent comprises hydrogen gas and Palladium (Pd) on carbon.

[0077] In some embodiments, the hydrogenating step is carried out at a temperature from about 5°C to about 50 °C. In some embodiments, the hydrogenating step is carried out at a temperature from about 15°C to about 40 °C. In some embodiments, the hydrogenating step is carried out at a temperature from about 20°C to about 30 °C. In some embodiments, the hydrogenating step is carried out at atemperature of about 25°C. In some embodiments, the hydrogenating step is carried out at a temperature of about 22°C.

[0078] In some embodiments, wherein the solvent comprises a polar aprotic solvent. In some embodiments, the polar aprotic solvent is ethyl acetate.

[0079] In some embodiments, the method provides the compound of Formula (I) substantially free of a compound of Formula (V):

[0080] In some embodiments, the method further comprises a step (ia) reacting a compound of Formula (VI), wherein X is a halogen,with triphenylphosphine to yield the compound of Formula (II).

[0081] In some embodiments, X is selected from I and Br.

[0082] In some embodiments, the method further comprises a step (ib) isolating the compound of Formula (II).

[0083] In some embodiments, the compound of Formula (II) of step (ia) is used in step (ii) without purification.

[0084] In some embodiments, the method further comprises a step (iii) purifying the compound of Formula (I) by fractional distillation.

[0085] In some embodiments, the method provides the compound of Formula (I) with a purity of about 60% or more, such as 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In some embodiments, the method provides the compound of Formula (I) with a purity of about 60% to 70%. In some embodiments, the method provides the compound of Formula (I) with a purity of about 70% to 80%. In some embodiments, the method provides the compound of Formula (I) with a purity of about 80% to 90%. In some embodiments, the method provides the compound of Formula (I) with a purity of about 90% to 100%. In some embodiments, the methodprovides the compound of Formula (I) with a purity of about 90% or more. In some embodiments, the method provides the compound of Formula (I) in a purity of about 95% or more. In some embodiments, the method provides the compound of Formula (I) has a purity of about 98% or more. In some embodiments, the method provides the compound of Formula (I) has a purity of about 99% or more.

[0086] In some embodiments, the yield of the hydrogenating step is above 50%, such as 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, or 99%. In some embodiments, the yield is in a range of about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100%.

[0087] In some embodiments, the method allows for the compound of Formula (I) to retain most or all of the fluorine atoms from the compound of Formula (IV); in other words, there is minimal or no loss of fluorine atoms in the product of the hydrogenation step from hydrodefluorination (e.g the replacement in a substrate of a carbon–fluorine bond by a carbon–hydrogen bond.) In some embodiments, the method provides the compound of Formula (I) with more than 60% of the fluorine atoms retained from the compound of Formula (IV). Without being bound by the following theory, the hydrogenation step of the method is mild and leads to minimal or no loss of fluorine atoms in the product of the hydrogenation step, i.e. the compound of Formula (I) from hydrodefluorination (e.g the replacement in a substrate of a carbon–fluorine bond by a carbon–hydrogen bond.) In some embodiments, the method provides the compound of Formula (I) with 60% or more of the fluorine atoms retained from the compound of Formula (IV), such as 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In some embodiments, the method provides the compound of Formula (I) with more than 90 % of the fluorine atoms retained from the compound of Formula (IV). In some embodiments, the method provides the compound of Formula (I) with more than 95 % of the fluorine atoms retained from the compound of Formula (IV). In some embodiments, the method provides the compound of Formula (I) with more than 98 % of the fluorine atoms retained from the compound of Formula (IV). In some embodiments, the methodprovides the compound of Formula (I) with more than 99 % of the fluorine atoms retained from the compound of Formula (IV).

[0088] In some embodiments, the disclosure provides a method for treating an ophthalmological disorder or condition comprising administering an effective amount of a composition described herein to an eye of a subject in need thereof.

[0089] In some embodiments, the disorder or condition is selected from dry eye disease, meibomian gland dysfunction, keratoconjunctivitis sicca, corneal damage, myopia, presbyopia, glaucoma filtration surgery, glaucoma surgery failure, minimally invasive glaucoma surgery failure, neovascular glaucoma, cornea transplant surgery with graft rejection, neovascularization, meibomian gland dysfunction, dry eye diseases, Sjogren’s syndrome, alkali burns, ulceration, graft versus host disease, atopic conjunctivitis, ocular rosacea, ocular pemphigoid, cicatricial pemphigoid, stem cell deficiency, Lyell’s syndrome, Steven Johnson syndrome, viral infection, bacterial infection, fungal infection, parasitic infection, hyperemia, pterygium, pinguecula, corneal damage, cornea transplant infection, cornea parasitic infection, and contact lens induced neovascularization.

[0090] In

[0091] some embodiments, composition is administered topically to the eye of the subject. In some embodiments, the composition is administered by injection into the eye of the subject. In some embodiments, administration of the composition is administered by intravitreal injection. NUMBERED EMBODIMENTS

[0092] Embodiment 1: A method for preparing a compound of Formula (I):wherein: m = 0 to 15; R1is an linear or branched C1-20 alkyl group; and comprising the steps of: (iii) reacting an F-alkyl phosphonium salt of Formula (II), wherein W is P(Ph3)+,with an aldehyde of Formula (III)in the presence of a base and a solvent to produce an alkene of Formula (IV)(iv) hydrogenating the alkene to yield the compound of Formula (I).

[0093] Embodiment 2: The method of embodiment 1, wherein the base is an alkali metal base or an organolithium base.

[0094] Embodiment 3: The method of embodiment 1 or 2, wherein the base is an alkali metal carbonate.

[0095] Embodiment 4: The method of any one of embodiments 1-3, wherein the base is selected from cesium carbonate, lithium carbonate, sodium carbonate, and potassium carbonate.

[0096] Embodiment 5: The method of any one of embodiments 1-4, wherein the solvent comprises a polar protic solvent, a di-C1-6 alkyl ether, a 4-10 membered heterocycloalkyl ether, or a mixture thereof.

[0097] Embodiment 6: The method of any one of embodiments 1-5, wherein the solvent comprises water and 1,4-dioxane.

[0098] Embodiment 7: The method of any one of embodiments 1-6, wherein the reacting step is carried out at a temperature from about 15°C to about 150 °C.

[0099] Embodiment 8: The method of any one of embodiments 1-7, wherein the reacting step is carried out at a temperature from about 50°C to about 105 °C.

[0100] Embodiment 9: The method of any one of embodiments 1-8, wherein the reacting step is carried out at a temperature from about 80°C to about 105 °C.

[0101] Embodiment 10: The method of any one of embodiments 1-9, wherein the reacting step is carried out at a temperature of about 95°C.

[0102] Embodiment 11: The method of any one of embodiments 1-10, wherein the hydrogenation step is carried in the presence of a hydrogenating reagent.

[0103] Embodiment 12: The method of any one of embodiments 1-11, wherein the hydrogenating agent comprises hydrogen gas and Palladium (Pd) on carbon.

[0104] Embodiment 13: The method of any one of embodiments 1-12, wherein the hydrogenating step is carried out at a temperature from about 5°C to about 50 °C.

[0105] Embodiment 14: The method of any one of embodiments 1-13, wherein the hydrogenating step is carried out at a temperature from about 15°C to about 40 °C.

[0106] Embodiment 15: The method of any one of embodiments 1-14, wherein the hydrogenating step is carried out at a temperature from about 20°C to about 30 °C.

[0107] Embodiment 16: The method of any one of embodiments 1-15, wherein the hydrogenating step is carried out at a temperature of about 25°C.

[0108] Embodiment 17: The method of any one of embodiments 1-15, wherein the hydrogenating step is carried out at a temperature of about 22°C.

[0109] Embodiment 18: The method of any one of embodiments 1-17, wherein the solvent comprises a polar aprotic solvent.

[0110] Embodiment 19: The method of any one of embodiments 1-18, wherein the polar aprotic solvent is ethyl acetate.

[0111] Embodiment 20: The method of any one of embodiments 1-19, wherein the compound of Formula (I) is substantially free of a compound of Formula (V):

[0112] Embodiment 21: The method of any one of embodiments 1-20, further comprising a step (ia) reacting a compound of Formula (VI), wherein X is a halogen,with triphenylphosphine to yield the compound of Formula (II).

[0113] Embodiment 22: The method of any one of embodiments 1-21, further comprising a step (ib) isolating the compound of Formula (II).

[0114] Embodiment 23: The method of embodiment 21 or 22, wherein the compound of Formula (II) of step (ia) is used in step (ii) without purification.

[0115] Embodiment 24: The method of any one of embodiments 21-23, wherein X is selected from I and Br.

[0116] Embodiment 25: The method of any one of embodiments 1-24, further comprising a step (iii) purifying the compound of Formula (I) by fractional distillation.

[0117] Embodiment 26: The method of any one of embodiments 1-25, wherein the compound of Formula (I) has a purity of about 90% or more.

[0118] Embodiment 27: The method of any one of embodiments 1-26, wherein the compound of Formula (I) has a purity of about 95% or more.

[0119] Embodiment 28: The method of any one of embodiments 1-27, wherein the compound of Formula (I) has a purity of about 98% or more.

[0120] Embodiment 29: The method of any one of embodiments 1-28, wherein the compound of Formula (I) has a purity of about 99% or more.

[0121] Embodiment 30: The method of any one of embodiments 1-29, wherein the compound of Formula (I) retains more than 90% of the fluorine atoms from the compound of Formula (IV).

[0122] Embodiment 31: The method of any one of embodiments 1-30, wherein the compound of Formula (I) retains more than 95% of the fluorine atoms from the compound of Formula (IV).

[0123] Embodiment 32: The method of any one of embodiments 1-31, wherein the compound of Formula (I) retains more than 98% of the fluorine atoms from the compound of Formula (IV).

[0124] Embodiment 33: The method of any one of embodiments 1-32, wherein the compound of Formula (I) retains more than 99% of the fluorine atoms from the compound of Formula (IV).

[0125] Embodiment 34: The method of any one of embodiments 1-33, wherein m is 2 to 10.

[0126] Embodiment 35: The method of any one of embodiments 1-34, wherein m is 4 to 8.

[0127] Embodiment 36: The method of any one of embodiments 1-35, wherein m is 4 to 6.

[0128] Embodiment 37: The method of any one of embodiments 1-36, wherein m is 5.

[0129] Embodiment 38: The method of any one of embodiments 1-37, wherein R1is a C2-15 linear or branched alkyl group.

[0130] Embodiment 39: The method of any one of embodiments 1-38, wherein R1is a C3-12 linear or branched alkyl group.

[0131] Embodiment 40: The method of any one of embodiments 1-39, wherein R1is a C4-8 linear or branched alkyl group.

[0132] Embodiment 41: The method of any one of embodiments 1-40, wherein R1is a C5 linear or branched alkyl group.

[0133] Embodiment 42: The method of any one of embodiments 1-41, wherein R1is a n-pentyl.

[0134] Embodiment 43: A composition comprising a compound of Formula (I):and substantially free of a compound of Formula (V):wherein m = 0 to 12 and R1is a linear or branched C1-20 alkyl group; and wherein the composition is made by a process comprising the steps: (i) reacting a compound of Formula (II), wherein W is P(Ph3)+,with a compound of Formula (III)in the presence of a base and a solvent to produce an alkene of Formula (IV);(ii) hydrogenating the alkene to yield the compound of Formula (I); and (iii) optionally formulating the compound of Formula (I) to form the composition.

[0135] Embodiment 44: The composition of embodiment 43, further comprising (iia) purifying the compound of Formula (I) by fractional distillation.

[0136] Embodiment 45: The composition of embodiment 43 or 44, wherein the compound of Formula (I) has a purity of about 90% or more.

[0137] Embodiment 46: The composition of any one of embodiments 43-45, wherein the compound of Formula (I) has a purity of about 95% or more.

[0138] Embodiment 47: The composition of any one of embodiments 43-46, wherein the compound of Formula (I) has a purity of about 98% or more.

[0139] Embodiment 48: The composition of any one of embodiments 43-47, wherein the compound of Formula (I) has a purity of about 99% or more.

[0140] Embodiment 49: The composition of any one of embodiments 43-48, wherein the compound of Formula (I) retains more than 92% of the fluorine atoms from the compound of Formula (IV).

[0141] Embodiment 50: The composition of any one of embodiments 43-49, wherein the compound of Formula (I) retains more than 95% of the fluorine atoms from the compound of Formula (IV).

[0142] Embodiment 51: The composition of any one of embodiments 43-50, wherein the compound of Formula (I) retains more than 98% of the fluorine atoms from the compound of Formula (IV).

[0143] Embodiment 52: The composition of any one of embodiments 43-51, wherein the compound of Formula (I) retains more than 99% of the fluorine atoms from the compound of Formula (IV).

[0144] Embodiment 53: The composition of any one of embodiments 43-52, wherein m is 2 to 10.

[0145] Embodiment 54: The composition of any one of embodiments 43-53, wherein m is 4 to 8.

[0146] Embodiment 55: The composition of any one of embodiments 43-54, wherein m is 4 to 6.

[0147] Embodiment 56: The composition of any one of embodiments 43-55, wherein m is 5.

[0148] Embodiment 57: The composition of any one of embodiments 43-56, wherein R1is a C2-15 linear or branched alkyl group.

[0149] Embodiment 58: The composition of any one of embodiments 43-57, wherein R1is a C3-12 linear or branched alkyl group.

[0150] Embodiment 59: The composition of any one of embodiments 43-58, wherein R1is a C4-8 linear or branched alkyl group.

[0151] Embodiment 60: The composition of any one of embodiments 43-59, wherein R1is a C5 linear or branched alkyl group.

[0152] Embodiment 61: The composition of any one of embodiments 43-60, wherein R1is a n-pentyl.

[0153] Embodiment 62: The composition of any one of embodiments 43-61, wherein the base is an alkali metal base or an organolithium base.

[0154] Embodiment 63: The composition of any one of embodiments 43-62, wherein the base is an alkali metal carbonate.

[0155] Embodiment 64: The composition of any one of embodiments 43-63, wherein the base is selected from cesium carbonate, lithium carbonate, sodium carbonate, and potassium carbonate.

[0156] Embodiment 65: The composition of any one of embodiments 43-64, wherein the solvent comprises a polar protic solvent, a di-C1-6 alkyl ether, a 4-10 membered heterocycloalkyl ether, or a mixture thereof.

[0157] Embodiment 66: The composition of any one of embodiments 43-65, wherein the solvent comprises water and 1,4-dioxane.

[0158] Embodiment 67: The composition of any one of embodiments 43-66, wherein the reacting step is carried out at a temperature from about 15°C to about 150 °C.

[0159] Embodiment 68: The composition of any one of embodiments 43-67, wherein the reacting step is carried out at a temperature from about 50°C to about 105 °C.

[0160] Embodiment 69: The composition of any one of embodiments 43-68, wherein the reacting step is carried out at a temperature from about 80°C to about 105 °C.

[0161] Embodiment 70: The composition of any one of embodiments 43-69, wherein the reacting step is carried out at a temperature of about 95°C.

[0162] Embodiment 71: The composition of any one of embodiments 43-70, wherein the hydrogenation step is carried in the presence of a hydrogenating reagent.

[0163] Embodiment 72: The composition of any one of embodiments 43-71, wherein the hydrogenating agent comprises hydrogen gas and Palladium (Pd) on carbon.

[0164] Embodiment 73: The composition of any one of embodiments 43-72, wherein the hydrogenating step is carried out at a temperature from about 5°C to about 50 °C.

[0165] Embodiment 74: The composition of any one of embodiments 43-73, wherein the hydrogenating step is carried out at a temperature from about 15°C to about 40 °C.

[0166] Embodiment 75: The composition of any one of embodiments 43-74, wherein the hydrogenating step is carried out at a temperature from about 20°C to about 30 °C.

[0167] Embodiment 76: The composition of any one of embodiments 43-75, wherein the hydrogenating step is carried out at a temperature of about 25°C.

[0168] Embodiment 77: The composition of any one of embodiments 43-76, wherein the solvent comprises a polar aprotic solvent.

[0169] Embodiment 78: The composition of any one of embodiments 43-77, wherein the polar aprotic solvent is ethyl acetate.

[0170] Embodiment 79: The composition of any one of embodiments 43-78, wherein the composition is in the form of a liquid solution.

[0171] Embodiment 80: The composition of any one of embodiments 43-79, wherein the composition is a liquid solution having a refractive index of about 1.30 to about 1.35 at 25° C, as determined by refractometer.

[0172] Embodiment 81: The composition of any one of embodiments 43-80, wherein the composition has a dynamic viscosity of less than 10 mPa-s, as determined at 25° and 1 atmosphere pressure.

[0173] Embodiment 82: The composition of any one of embodiments 43-81, wherein the composition comprises from about 1 wt % to about 25 wt % of the compound of Formula (I), based on the total weight of the composition.

[0174] Embodiment 83: The composition of any one of embodiments 43-82, wherein the composition comprises from about 5 wt % to about 15 wt % of the compound of Formula (I), based on the total weight of the composition.

[0175] Embodiment 84: The composition of any one of embodiments 43-83, wherein the composition is substantially free of water.

[0176] Embodiment 85: The composition of any one of embodiments 43-84, wherein the composition is substantially free of a preservative.

[0177] Embodiment 86: The composition of any one of embodiments 43-85, wherein the compound of Formula (I) is CF3(CF2)5(CH2)7CH3.

[0178] Embodiment 87: The composition of any one of embodiments 43-86, wherein the composition further comprises a pharmacologically active ingredient.

[0179] Embodiment 88: The composition of any one of embodiments 43-87, wherein the composition is an ophthalmic composition.

[0180] Embodiment 89: The composition of embodiment 87, wherein the pharmacologically active ingredient is selected from atropine, pirenzepine, aclidinium bromide, benztropine, cyclopentolate, diphenhydramine, doxylamine, dimenhydrinate, dicyclomine, darifenacin, flavoxate, hydroxyzine, ipratropium, mebeverine, oxybutynin, procyclidine, scopolamine, solifenacin, tropicamide, tiotropium, trihexyphenidyl, and tolterodine, or pharmaceutically acceptable salt thereof, or combinations thereof.

[0181] Embodiment 90: The composition of embodiment 88 or 89, wherein the pharmacologically active ingredient is selected from atropine, or pharmaceutically acceptable salt thereof.

[0182] Embodiment 91: The composition of any one of embodiments 87-90, wherein the composition comprises from about 0.0001 wt % to about 1.0 wt % of the pharmacologically active ingredient, based on the total weight of the composition.

[0183] Embodiment 92: The composition of any one of embodiments 87-91, wherein the composition comprises from about 0.001 wt % to about 0.1 wt % of the pharmacologically active ingredient, based on the total weight of the composition.

[0184] Embodiment 93: The composition of any one of embodiments 87-92, wherein the composition comprises from about 0.01 wt % to about 0.1 wt % of the pharmacologically active ingredient, based on the total weight of the composition.

[0185] Embodiment 94: The composition of any one of embodiments 87-93, wherein the composition further comprises one or more pharmacologically acceptable carriers, excipients, or additives.

[0186] Embodiment 95: A method for treating an ophthalmological disorder or condition comprising administering an effective amount of the composition of any one of embodiments 43-94 to an eye of a subject in need thereof.

[0187] Embodiment 96: The method of embodiment 95, wherein the disorder or condition is selected from dry eye disease, meibomian gland dysfunction, keratoconjunctivitis sicca, corneal damage, myopia, presbyopia, glaucoma filtration surgery, glaucoma surgery failure, minimally invasive glaucoma surgery failure, neovascular glaucoma, cornea transplant surgery with graft rejection, neovascularization, meibomian gland dysfunction, dry eye diseases, Sjogren’s syndrome, alkali burns, ulceration, graft versus host disease, atopic conjunctivitis, ocular rosacea, ocular pemphigoid, cicatricial pemphigoid, stem cell deficiency, Lyell’s syndrome, Steven Johnson syndrome, viral infection, bacterial infection, fungal infection, parasitic infection, hyperemia, pterygium, pinguecula, corneal damage, cornea transplant infection, cornea parasitic infection, and contact lens induced neovascularization.

[0188] Embodiment 97: The method of embodiments 95 or 96, wherein the composition is administered topically to the eye of the subject.

[0189] Embodiment 98: The method of any one of embodiments 95-97, wherein the composition is administered by injection into the eye of the subject.

[0190] Embodiment 99: The method of embodiment 98, wherein administration of the composition is administered by intravitreal injection. EXAMPLES

[0191] Representative syntheses of compounds of the present disclosure are described in schemes below, and the particular examples that follow. The following examples are merely illustrative, and not intended to limit this disclosure in any way. It is to be understood that individual steps described herein may be combined. It is also to be understood that separate batches of a compound may be combined and carried forth in the next synthetic step.

[0192] Scheme 1 shows a general synthesis of the compounds of the embodiments. The methodology is compatible with a wide variety of functionalities.

[0194] To a solution of 1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluoro-8-iodooctane 1 (20 g, 42 mmol, 1.0 eq) in DMF (40 mL) was added Ph3P (11.6 g, 44 mmol, 1.05 eq). The mixture was stirred at 105 °C for 16 h. HNMR showed the reaction was completed. Dilute the mixture with petroleum ether (200 mL) and precipitate the crude product. Filter the mixture and washed the filter cake with petroleum ether. Afford triphenyl(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)- phosphanium iodide 2 (28 g, 90% yield) as a white solid.

[0195] Step B: Preparation of (6E)-9,9,10,10,11,11,12,12,13,13,14,14,14- tridecafluorotetradec-6-ene 5

[0196] To a solution of triphenyl(3,3,4,4,5,5,6,6,7,7,8,8,8- tridecafluorooctyl)phosphanium iodide 2 (28 g, 38.1mmol, 1.0 eq) in dioxane (200 mL) and distilled water (0.6 mL)was added K2CO3 (6.28 g, 45.4 mmol, 1.2 eq), hexanal 3 (3.79 g, 38.1 mmol, 1.0 eq). The mixture was Stirred at 95 °C for 16 h. LCMS showed the reaction was completed. Cool the mixture to room temperature and concentrated. Add CH2Cl2 (200 mL) and water (200 mL) to the reaction mixture. Separate the organic phase. Dry the organic phase over Na2SO4.Then the mixture was purified by silica gel column (petroleum ether, chromogenic agent: KMnO4) to afford (6E)-9,9,10,10,11,11,12,12,13,13,14,14,14-tridecafluorotetradec-6-ene 4 (14 g, 86 % yield） as a colorless oil.

[0197] Step C: Preparation of 1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluorotetradecane:

[0198] To a solution of (6E)-9,9,10,10,11,11,12,12,13,13,14,14,14- tridecafluorotetradec-6-ene 4 (14 g, 32.5 mmol) in EA (300 mL) was added Pd / C (1.7 g, 10wt%, 1.62 mmol, 0.05 equiv). The mixture was stirred at hydrogen atmosphere with a hydrogen balloon at 25oC for 16 h. The mixture was filtered and filtrate was concentrated to afford 1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluorotetradecane (CAS: 133331-77-8) (14 g, 99 % yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 2.11-1.98 (m, 2H), 1.63-1.56 (m, 2H), 1.41-1.21 (m, 10H), 0.89 (t, J = 6.8 Hz, 3H). Example 2: Preparation of 1,1,1,2,2,3,3,4,4-nonafluorononane (CAS: 1190430- 21-7)

[0199] Step A: Preparation of (3,3,4,4,5,5,6,6,6- nonafluorohexyl)triphenylphosphonium iodide

[0200] To a solution of 1,1,1,2,2,3,3,4,4-nonafluoro-6-iodohexane 5 (30.0 g, 80.2 mmol) in DMF (30 mL) was added PPh3 (22 g, 84 mmol) at 95oC. The mixture was stirred at 95oC for 16 h. Filter the mixture and washed the filter cake with petroleum ether and THF. Afford (3,3,4,4,5,5,6,6,6-nonafluorohexyl)triphenylphosphonium iodide 6 (50 g, 98% yield) as a white solid. LCMS (ESI) calcd for C24H19F9IP+[M + H]+m / z 509.1, found 509.1.

[0201] Step B: Preparation of (E)-6,6,7,7,8,8,9,9,9-nonafluoronon-3-ene 8

[0202] To a solution of (3,3,4,4,5,5,6,6,6-nonafluorohexyl)triphenylphosphonium iodide 6 (20.0 g, 31.4 mmol) in THF (40 mL) was dropped n-BuLi (12 mL, 29.8 mmol, 2.5 M in THF) at -78oC under nitrogen protection. The reaction mixture was stirred at -78oC for 1 h under nitrogen protection. Then propionaldehyde 7 (1.8 g, 31.4mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at 25oC for 16 h under nitrogen protection. LCMS showed the reaction worked well. The mixture was filtered, and the filter cake rinsed with hexane. The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The mixture was distilled at 100oC to remove hexane and continued to distill at 100oC under vacuum to afford (E)-6,6,7,7,8,8,9,9,9-nonafluoronon-3-ene 8 (3.5 g, 39%) as a colorless oil.

[0203] 1H NMR(400 MHz, CDCl3) δ 5.69 (dd, J = 16.7, 8.9 Hz, 1H), 5.31(dd, J = 17.6, 7.7 Hz, 1H), 2.84-2,73 (m, 2H), 2.10-1.96 (m, 2H), 0.93 (t, J = 7.5Hz, 3H).

[0204] Step C: Preparation of 1,1,1,2,2,3,3,4,4-nonafluorononane:

[0205] To a solution of (E)-6,6,7,7,8,8,9,9,9-nonafluoronon-3-ene 8 (40 g, 138.8 mmol) in hexane (30 mL) was added Pd / C (7.24 g, 10wt%, 6.9 mmol). The mixture was stirred at hydrogen atmosphere with a hydrogen balloon at 25oC for 16 h. The mixture was filtered and filtrate was concentrated to afford 1,1,1,2,2,3,3,4,4- nonafluorononane (CAS: 1190430-21-7) (40 g, 98%) as a colorless oil.

[0206] 1HNMR (400 MHz, CDCl3) δ 2.12-1.96 (m, 2H), 1.65-1.56 (m, 2H), 1.40-1.32 (m, 4H), 0.96-0.89 (m, 3H). Example 3. GC Analysis

[0207] The samples were analyzed using a Agilent 8890 GC method with an HP-5 30m*0.32mm*0.5um GC column (150 mm X 2.1 mm FD.). The GC protocols and parameters are listed below: Gas Flow rate: 2ml / min Injection Volume：0.5ul（Direct injection） Column Temp：70ºC Inject Temp：280ºC Detector Temp (FID): 300ºC Gradient: 70ºC ( hold 2min ) → 12ºC / min → 280ºC ( hold 7min ) Gas Ratio: 30:1 N2: 25ml / min H2: 30ml / min Air: 300ml / min.

[0208] The chromatogram of Figure 1 has a peak that corresponds to 1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluorotetradecane (labelled on the chromatogram as “F6H8”) synthesized by the method of Example 1. The retention time of the peak is 28.814 minutes.

[0209] 1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluorotetradecane was prepared by a standard commercial process and the gas chromatogram in Figure 2 shows the peak for F6H8 and an undesirable methyl isomer (retention time of 27.329 minutes).OTHER EMBODIMENTS

[0210] It is to be understood that while the present disclosure has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the present application, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method for preparing a compound of Formula (I):wherein: m = 0 to 15; R1is a linear or branched C1-20 alkyl group; and comprising the steps of: (i) reacting an F-alkyl phosphonium salt of Formula (II), wherein W is P(Ph3)+,with an aldehyde of Formula (III)in the presence of a base and a solvent to produce an alkene of Formula (IV)(ii) hydrogenating the alkene to yield the compound of Formula (I).

2. The method of claim 1, wherein the base is an alkali metal base or an organolithium base.

3. The method of claim 1 or 2, wherein the hydrogenation step is carried in the presence of a hydrogenating reagent.

4. The method of any one of claims 1-3, wherein the compound of Formula (I) is substantially free of a compound of Formula (V):

5. The method of any one of claims 1-4, further comprising a step (ia) reacting a compound of Formula (VI), wherein X is a halogen,with triphenylphosphine to yield the compound of Formula (II).

6. The method of claim 5, wherein X is selected from I and Br.

7. The method of any one of claims 1-6, wherein the compound of Formula (I) has a purity of about 98% or more.

8. The method of any one of claims 1-7, wherein m is 2 to 10.

9. The method of any one of claims 1-8, wherein R1is a C2-15 linear or branched alkyl group.

10. A composition comprising a compound of Formula (I):and substantially free of a compound of Formula (V):wherein m = 0 to 12 and R1is a linear or branched C1-20 alkyl group; andwherein the composition is made by a process comprising the steps: (i) reacting a compound of Formula (II), wherein W is P(Ph3)+,with a compound of Formula (III) (III) in the presence of a base and a solvent to produce an alkene of Formula (IV);(ii) hydrogenating the alkene to yield the compound of Formula (I); and (iii) optionally formulating the compound of Formula (I) to form the composition.

11. The composition of claim 10, wherein the compound of Formula (I) has a purity of about 98% or more.

12. The composition of claim 10 or 11, wherein the compound of Formula (I) retains more than 98% of the fluorine atoms from the compound of Formula (IV).

13. The composition of any one of claims 10-12, wherein m is 2 to 10.

14. The composition of any one of claims 10-13, wherein the composition is in the form of a liquid solution.

15. The composition of any one of claims 10-14, wherein the composition is a liquid solution having a refractive index of about 1.30 to about 1.35 at 25° C, as determined by refractometer.

16. The composition of any one of claims 10-15, wherein the composition has a dynamic viscosity of less than 10 mPa-s, as determined at 25° and 1 atmosphere pressure.

17. The composition of any one of claims 10-16, wherein the composition comprises from about 1 wt % to about 25 wt % of the compound of Formula (I), based on the total weight of the composition.

18. The composition of any one of claims 10-17, wherein the composition is substantially free of water or a preservative.

19. The composition of any one of claims 10-18, wherein the compound of Formula (I) is CF3(CF2)5(CH2)7CH3.

20. The composition of any one of claims 10-19, wherein the composition further comprises a pharmacologically active ingredient.

21. The composition of any one of claims 10-20, wherein the composition is an ophthalmic composition.

22. The composition of claim 20 or 21, wherein the pharmacologically active ingredient is selected from atropine, pirenzepine, aclidinium bromide, benztropine, cyclopentolate, diphenhydramine, doxylamine, dimenhydrinate, dicyclomine, darifenacin, flavoxate, hydroxyzine, ipratropium, mebeverine, oxybutynin, procyclidine, scopolamine, solifenacin, tropicamide, tiotropium, trihexyphenidyl, and tolterodine, or pharmaceutically acceptable salt thereof, or combinations thereof.

23. The composition of any one of claims 20-22, wherein the composition comprises from about 0.0001 wt % to about 1.0 wt % of the pharmacologically active ingredient, based on the total weight of the composition.

24. The composition of any one of claims 20-23, wherein the composition further comprises one or more pharmacologically acceptable carriers, excipients, or additives.

25. A method for treating an ophthalmological disorder or condition comprising administering an effective amount of the composition of any one of claims 10-24 to an eye of a subject in need thereof.

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