DESC:
The following specification particularly describes the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION

The present invention relates to a process for preparation of 1-Perfluorohexyloctane and pharmaceutical composition containing the same.

BACKGROUND OF THE INVENTION

1-Perfluorohexyloctane is a class of semifluorinated alkane compounds and is chemically known as 1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluorotetradecane, and structurally be represented as Formula I.

Formula I

1-Perfluorohexyloctane is an ophthalmic solution marketed by Bausch & Lomb Americas Inc. under the trade name MIEBO™ in US for treatment of the signs and symptoms of dry eye disease. Perfluorohexyloctane, is also marketed under the name NovaTears® and EvoTears® as a medical device in Europe, New Zealand and Australia.

The synthesis of 1-Perfluorohexyloctane was described in WO2017154948A1, WO2018202835A1, WO2018228975A1 and CN115703693A.

1-Perfluorohexyloctane is an important approved ophthalmic solution available in the market for the treatment of signs and symptoms of dry eye disease. The above-mentioned documents collectively disclose processes for preparation of 1-Perfluorohexyloctane. Still there is an unmet need in the field for the provision of a simple and robust process for the preparation of 1-Perfluorohexyloctane, which is commercially feasible on large scale production with ease of operation and greater yield with higher purity.

SUMMARY OF THE INVENTION

The present invention encompasses a process for preparation of 1-Perfluorohexyloctane of Formula I.

In accordance with one embodiment, the present invention provides a process for preparation of 1-Perfluorohexyloctane of Formula I, comprising:

Formula I
a) reacting a compound of Formula II with a compound of Formula III in presence of a suitable initiator and in a suitable solvent or a mixture thereof to obtain a compound of Formula IV; wherein “X” is selected from chlorine, bromine or iodine, and

Formula II Formula III Formula IV
b) reacting the compound of Formula IV with a suitable metal catalyst, reducing agent and in a suitable solvent or a mixture thereof to obtain a compound of Formula I.

In accordance with another embodiment, the present invention provides a process for preparation of 1-Perfluorohexyloctane of Formula I, comprising:

Formula I
a) reacting a compound of Formula II with a compound of Formula III in presence of a suitable initiator and in a suitable solvent or a mixture thereof to obtain a compound of Formula IV; wherein “X” is selected from chlorine, bromine or iodine, and

Formula II Formula III Formula IV
b) reacting the compound of Formula IV with a suitable metal catalyst, reducing agent and in a suitable solvent or a mixture thereof to obtain a compound of Formula I.
wherein the suitable initiator is selected from the group comprising but not limited to Sodium dithionite, Sodium metabisulfite, Sodium thiosulfate, Sodium sulfide, Sodium sulphate and the like and mixture thereof;
wherein the metal catalyst is selected from the group comprising but not limited to NiCl2, NiBr2, CuCl2, FeCl3, CoCl2, CuCl2, RuCl3, CoBr2, CoSO4, PdCl2, Ni(OAc)2, CrCl3, FeCl2, AlCl3 and the like and mixture thereof; and
wherein the reducing agent is selected from the group comprising but not limited to NaBH4, LiAlH4, Tributyltin hydride, NaAlH4, CaH2 and the like and mixture thereof.

In accordance with another embodiment, the present invention provides a pharmaceutical composition, comprising 1-Perfluorohexyloctane of Formula I prepared by the processes of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for preparation of 1-Perfluorohexyloctane of Formula I.

In accordance with one embodiment, the present invention provides a process for preparation of 1-Perfluorohexyloctane of Formula I, comprising:

Formula I
a) reacting a compound of Formula II with a compound of Formula III in presence of a suitable initiator and in a suitable solvent or a mixture thereof to obtain a compound of Formula IV; wherein “X” is selected from chlorine, bromine or iodine, and

Formula II Formula III Formula IV
b) reacting the compound of Formula IV with a suitable metal catalyst, reducing agent and in a suitable solvent or a mixture thereof to obtain a compound of Formula I.

The compound of Formula II and Formula III, which is used herein as a starting materials are known in the art and can be prepared by any known methods.

The step a) of forgoing process involves reaction of a compound of Formula II; wherein “X” is selected from chlorine, bromine or iodine, with a compound of Formula III in presence of a suitable initiator and in a suitable solvent or a mixture thereof at a temperature of about 0°C to about reflux temperature to obtain a compound of Formula IV.

The suitable initiator used in reaction of a compound of Formula II; wherein “X” is selected from chlorine, bromine or iodine; preferably Iodine, with a compound of Formula III is selected from the group comprising but not limited to Sodium dithionite, Sodium metabisulfite, Sodium thiosulfate, Sodium sulfide, Sodium sulphate and the like and mixture thereof; preferably Sodium dithionite.

After completion of the reaction, the obtained compound of Formula IV is collected from the reaction mixture according to a method usually employed. For example, the compound of formula IV can be collected by removing inorganic substances as an aqueous layer and distilling off the solvent in the organic layer. The obtained compound of Formula IV can be further purified by distillation or chromatography according to need.

The step b) of forgoing process involves reaction of the compound of Formula IV with a suitable metal catalyst, reducing agent and in a suitable solvent or a mixture thereof at a temperature of about 0°C to about reflux temperature to obtain a compound of Formula I.

The suitable metal catalyst used herein is selected from the group comprising but not limited to NiCl2, NiBr2, CuCl2, FeCl3, CoCl2, CuCl2, RuCl3, CoBr2, CoSO4, PdCl2, Ni(OAc)2, CrCl3, FeCl2, AlCl3 and the like and mixture thereof; preferably NiCl2.

The reducing agent used herein is selected from the group comprising but not limited to NaBH4, LiAlH4, Tributyltin hydride, NaAlH4, CaH2 and the like and mixture thereof; preferably NaBH4.

The suitable solvent or a mixture thereof of the step a) and b) are is selected from the group comprising but not limited to amides, esters, ketones, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons, water and the like and mixtures thereof. The amides include, but are not limited to dimethylacetamide, dimethylformamide, N-methylpyrrolidone and the like and mixtures thereof; esters include, but are not limited to ethyl acetate, methyl acetate and the like and mixtures thereof; ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like and mixtures thereof; nitriles include, but are not limited to acetonitrile, propionitrile and the like and mixtures thereof; ethers include, but are not limited to tetrahydrofuran, methyl tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like and mixtures thereof; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like and mixtures thereof; aromatic hydrocarbons include, but are not limited to toluene, xylene and the like and mixture thereof; preferably suitable solvent for step a) is a mixture of dimethylformamide and water; and suitable solvent for step b) is dimethylformamide.

After completion of the reaction, the 1-Perfluorohexyloctane of Formula I is collected from the reaction mixture according to a method usually employed. For example, the compound of formula I can be collected by removing inorganic substances as an aqueous layer and distilling off the solvent in the organic layer. The obtained 1-Perfluorohexyloctane of Formula I can be further purified by distillation or chromatography according to need.

In another embodiment, the present invention provides process for purification of 1-Perfluorohexyloctane of Formula I by high vacuum distillation at a suitable temperature.

In another embodiment, the present invention provides process for purification of 1-Perfluorohexyloctane of Formula I by spinning band high vacuum distillation at a suitable temperature.

In another embodiment, the present invention provides a pharmaceutical composition, comprising 1-Perfluorohexyloctane of Formula I, prepared by the processes of the present invention.

In another embodiment, the present invention relates to a process for preparation of 1-Perfluorohexyloctane of Formula I, which is depicted as follows:

EXAMPLES

The following non limiting examples illustrate specific embodiments of the present invention. They are not intended to be limiting the scope of the present invention in any way.

EXAMPLE-1: Preparation of compound of Formula IV

Compound of Formula II (100 g), a mixture of dimethylformamide and water (400 mL, 1:1), compound of Formula III (30.2 g) and Sodium dithionite (29.3 g) were added sequentially in to a round bottom flask at below 25°C. Reaction mass was heated to 50-60°C and stir for 7-8 hr at same temperature. After completion of the reaction, reaction mass was cooled to 25-35°C and charged water (300 mL) at 25-35°C and allowed to stir for 15-20 min. The organic layer and aqueous layers were separated and the product containing organic layer washed with sodium chloride solution (30 g dissolved in 300 mL water). Then the product containing organic layer was separated and distil off under high vacuum at below 80°C and collected fraction containing pure compound of Formula IV. Yield; 90%. 1H-NMR: (CDCl3): 4.36 (m, 1H), 2.90 (m, 2H), 1.83 (m, 2H), 1.60-1.25 (m, 8H), 0.88 (t,3H, J 7 Hz), m/z: 431.2, IR: 2960 cm-1, 2860 cm-1, 1469 cm-1,1240 cm-1,1206 cm-1, 706 cm-1, 653 cm-1.

EXAMPLE-2: Preparation of compound of Formula I

Compound of Formula IV (100 g), dimethylformamide (500 mL), Nickel chloride (2.32 g) were added sequentially in to a round bottom flask at 25-35°C. Reaction mass was allowed to cool to 5-10°C and added sodium borohydride lot wise (20.3 g) at below 15°C and allowed to stir for 1 hr at same temperature. Maintain the reaction mass at 10-20°C for 1-2 hrs. After completion of the reaction, reaction mass was allowed to cool to 5-10°C and was added in to chilled water (1.2 lit) at below 25°C and allowed to stir for 1 hr at same temperature. To the reaction mass was added n-Heptane (300 mL) at 25-35°C. Filter the reaction mass on hy-flo bed and bed wash with n-Heptane (200 mL). Then the product containing organic layer was separated and distil off under vacuum at <70°C to obtain title compound. Yield; 90%. 1H-NMR: 0.89(t, j=7 Hz, 3H) 1.42 (m, 10H), 1.56-1.64 (m, 2H), 2.03-2.09 (m, 2H), 19F-NMR: -81.0 (m, 3F), -114.75 (m, 2F). -122.28 (m, 2F), -122.22 (m, 2F9,- 123.91 (m. 2F), - 126.48 (m, 2F), m/z 432.2, IR: 2930 cm-1, 2860 cm-1, 1469 cm-1,1240 cm-1,1206 cm-1, 706 cm-1 and 653 cm-1.

EXAMPLE-3: Purification of compound of Formula I by spinning band high vacuum distillation.

Compound of Formula I (100 g) was purified by spinning band distillation under high vacuum under at 180-190°C with vapor temperature between 120-140°C. The relevant pure fractions of compound of Formula I are collected and combined and allowed to cool to room temperature. Purity by GC: 99.6%.

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore, the above description should not be constructed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.
,CLAIMS:We claim:
1. A process for preparation of 1-Perfluorohexyloctane of Formula I,
comprising:
Formula I
a) reacting a compound of Formula II with a compound of Formula III in
presence of a suitable initiator and in a suitable solvent or a mixture thereof
to obtain a compound of Formula IV; wherein “X” is selected from chlorine,
bromine or iodine, and
Formula II Formula III Formula IV
b) reacting the compound of Formula IV with a suitable metal catalyst,
reducing agent and in a suitable solvent or a mixture thereof to obtain a
compound of Formula I.
2. The process as claimed in claim 1, wherein in the “X” is selected from
chlorine, bromine or iodine.
3. The process as claimed in claim 1, wherein in the suitable initiator in step
a) is selected from Sodium dithionite, Sodium metabisulfite, Sodium
thiosulfate, Sodium sulfide, Sodium sulphate and mixture thereof.
4. The process as claimed in claim 1, wherein in the suitable solvent in step a)
is selected from dimethylacetamide, dimethylformamide, Nmethylpyrrolidone,
ethyl acetate, methyl acetate, acetone, methyl isobutyl
ketone, methyl ethyl ketone, acetonitrile, propionitrile, tetrahydrofuran,
methyl tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary
butyl ether, 1,4-dioxane, methylene chloride, ethylene chloride, chloroform,
toluene, xylene, water and mixture thereof.
Docusign Envelope ID: 042B760F-44AA-439F-B511-FB9759B88F1F
Page 11 of 12
5. The process as claimed in claim 1, wherein in the suitable metal catalyst in step b) is selected from NiCl2, NiBr2, CuCl2, FeCl3, CoCl2, CuCl2, RuCl3, CoBr2, CoSO4, PdCl2, Ni(OAc)2, CrCl3, FeCl2, AlCl3 and mixture thereof.
6. The process as claimed in claim 1, wherein in the reducing agent in step b) is selected from NaBH4, LiAlH4, Tributyltin hydride, NaAlH4, CaH2 and mixture thereof.
7. The process as claimed in claim 1, wherein in the suitable solvent in step b) is selected from dimethylacetamide, dimethylformamide, N-methylpyrrolidone, ethyl acetate, methyl acetate, acetone, methyl isobutyl ketone, methyl ethyl ketone, acetonitrile, propionitrile, tetrahydrofuran, methyl tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane, methylene chloride, ethylene chloride, chloroform, toluene, xylene and mixture thereof.
8. The process as claimed in claim 1, wherein in the “X” is iodine; initiator in step a) is Sodium dithionite; solvent in step a) is a mixture of dimethylformamide and water; metal catalyst is NiCl2; reducing agent is NaBH4; and solvent in step b) is dimethylformamide.
9. A process for purification of 1-Perfluorohexyloctane of Formula I by spinning band high vacuum distillation at a suitable temperature.
10. The process as claimed in claim 9, wherein in the distillation is carries out at a temperature between 180-190°C.