FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
& THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, Rule 13]
A METHOD FOR SEPARATION OF 1-CHLORO-
2,2,2-TRIFLUOROETHYL DIFLUOROMETHYL
ETHER;
PIRAMAL HEALTHCARE LTD., A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1913, WHOSE ADDRESS IS PIRAMAL TOWER, GANPATRAO KADAM MARG, LOWER PAREL, MUMBAI 400 013, MAHARASHTRA, INDIA
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 continuous process for purification of 1-chloro-2,2,2-trifluoroethyl difluoromethyl ether (Isoflurane) from crude Isoflurane.
BACKGROUND OF THE INVENTION:
Isoflurane is chemically known as 1 -chloro-2,2,2-trifluoroethyl difluoromethyl ether and represented by the formula CF3CHCIOCHF2 (compound of formula I). It is normally a clear, colourless and non-flammable liquid with mildly pungent, musty, ethereal odor. Isoflurane is used as a potent inhalation anesthetic and hence, should be free of impurities.
The process for preparation of Isoflurane is disclosed in the prior arts references. Generally, the process involves chlorination of 2,2,2-trifluoroethyl difluoromethyl ether, CF3CH2OCHF2 (the compound of formula II). The Isoflurane obtained using said processes generally comprises impurities, which are present in various amounts based on the process parameters selected for chlorination of the compound of formula II. The Isoflurane obtained using such processes is hereinafter referred to as, 'crude Isoflurane'. The crude Isoflurane may contain following impurities which may be collectively referred to as halogenated ether impurities:
(l-Chloro-2,2,2-trifluoroethyl chloro difluoromethyl ether), (l,l-Dichloro-2,2,2-trifluoroethyl difluoromethyl ether) and (2,2,2-trifluoroethyl chloro difluoromethyl ether)
US Patent No. 3,535,388 and US Patent No. 3,535,425 describes the process for preparation of Isoflurane of formula I involving chlorination of 2,2,2-trifluoroethyl difluoromethyl ether, the compound of formula II to obtain Isoflurane in admixture with other halogenated ether impurities. Some of the halogenated ether impurities have boiling points sufficiently far from that of Isoflurane, so that the latter can be separated by very careful fractional distillation. However, the impurity, l-chloro-2,2,2-trifluoroethyl difluorochloromethyl ether

(CF3CHCIOCF2CI), co-distills with Isoflurane at about 2 percent concentration, so the separation of Isoflurane in high purity by distillation cannot be accomplished. Another means for separating Isoflurane from the other ether impurities is by vapor/liquid chromatography, but this type of operation is slow, expensive and not readily adaptable for preparing Isoflurane in commercially desirable quantities.
Conventionally, crude Isoflurane is purified by using methyl acetate as an entrainer. In this process, methyl acetate is mixed in the crude Isoflurane, which forms a high boiling azeotrope with isoflurane and then azeotropic distillation is carried out to purify crude Isoflurane. The crude Isoflurane purification using methyl acetate involves separation for Isoflurane from methyl acetate by hydrolysis of methyl acetate. The obtained Isoflurane, free of methyl acetate is then purified further to obtain pure Isoflurane of desired quality, as per US Pharmacopeia. The conventional process is not only expensive but also increases load on the effluent, as the pure Isoflurane is separated from methyl acetate generating salt of methyl acetate along with methanol.
US Patent. No. 3,720,587 discloses a method wherein acetone, methyl ethyl ketone or tetrahydrofuran is added to crude Isoflurane (containing impurities) so as to form a maximum boiling azeotrope with Isoflurane. The impurities are distilled out from the obtained azeotrope. The azeotrope is then broken by the addition of large volumes of water, allowing the distillation of Isoflurane as a water azeotrope, which on drying yields essentially pure Isoflurane. This separation process is a conventional process, which is normally followed in the industry. The distillation process requires lot of thermal energy to separate acetone from water as well as from Isoflurane. Further, the water left behind after the removal of Isoflurane contains residual organic materials together with azeotropic solvent, acetone and it requires effluent treatment before disposal. Furthermore, recovery of acetone with moisture contain below 0.5% is a difficult task.

OBJECTS OF THE INVENTION:
An object of the present invention is to provide a continuous process for purification of crude Isoflurane to yield pure Isoflurane.
Another object of the present invention is to provide a continuous process for purification of crude Isoflurane, wherein the entrainer used for the removal of impurities from crude Isoflurane is recycled in a continuous process.
Another object of the present invention is to provide a continuous process for purification of crude Isoflurane, wherein the water used for the separation of Isoflurane from entrainer is recycled in a continuous process.
Still another object of the present invention is to provide a continuous process for purification of crude Isoflurane, which is a green process.
Yet another object of the present invention is to provide a continuous process for purification of crude Isoflurane, which is cost-efficient, commercially viable and environment friendly.
SUMMARY OF THE INVENTION:
In accordance with an aspect of the present invention, there is provided a continuous process for purification of crude Isoflurane to yield pure Isoflurane comprising the steps of:
a. carrying out first liquid-liquid extraction of a water miscible solvent-
water mixture with crude Isoflurane extracting the said water miscible
solvent from the mixture to obtain a mixture of crude Isoflurane and
water miscible solvent and separating water from the said mixture,
b. distillating the mixture of crude Isoflurane and water miscible solvent
obtained in step (a) forming an azeotrope of Isoflurane with water
miscible solvent and distilling off the impurities to obtain a mixture of
Isoflurane and water miscible solvent,

c. carrying out second liquid-liquid extraction of the mixture of Isoflurane
and water miscible solvent obtained in step (b) with water separated in
step (a), extracting water miscible solvent into water to obtain the
Isoflurane and a mixture of water miscible solvent-water,
d. using the water miscible solvent-water mixture obtained in step (c) for
first liquid-liquid extraction of crude Isoflurane in step (a), thereby
recycling said water miscible solvent-water mixture,
e. distillating the Isoflurane obtained in step (c) to obtain pure Isoflurane;
wherein all the steps (a) to (d) are carried out as a continuous process to
yield pure Isoflurane.
In accordance with another aspect of the present invention, a continuous process for purification of crude Isoflurane involves first liquid-liquid extraction of mixture of water miscible solvent-water with crude Isoflurane to separate water from the mixture, which is then used for second liquid-liquid extraction to extract water miscible solvent from Isoflurane separating a mixture of water miscible solvent-water, thereby recycling the water separated in first liquid-liquid extraction in a continuous process for purification of Isoflurane. Moreover, the mixture of water miscible solvent-water separated in second liquid-liquid extraction is used for first liquid-liquid extraction of crude Isoflurane, making the process for purification of crude Isoflurane as a continuous process.
In accordance with another aspect of the present invention, the process for purification of crude Isoflurane involves reuse of solvents used in the process. Particularly, the entrainer, water miscible solvent used for the purification of crude Isoflurane is recycled, without any further treatment for purification of water miscible solvent. Also, the water used in the process is reused in a continuous process without any further treatment for purification of water, thereby making the process cost-effective. Thus, the process of the present invention for purification of crude Isoflurane involving recycle of solvents, water miscible solvent and water, making the process viable for large scale preparation.

In accordance with another aspect of the present invention, the process for purification of crude Isoflurane avoids generation of hazardous effluents, thereby making the process environment friendly.
BRIEF DESCRIPTION OF DRAWINGS:
The accompanying drawing, which is included to provide a further understanding of the invention and is incorporated in and constitute a part of this application, illustrate embodiment(s) of the invention and together with the description serve to explain the principle of the invention.
In the drawing, the Figure 1 shows a flow chart of a continuous process for purification of crude Isoflurane to yield pure Isoflurane according to the preferred embodiment of the present invention.
DESCRIPTION OF THE INVENTION:
The present invention relates to a continuous process for purification of crude Isoflurane to yield pure Isoflurane comprising the steps of:
a. carrying out first liquid-liquid extraction of a water miscible solvent-
water mixture with crude Isoflurane extracting the said water miscible
solvent from the mixture to obtain a mixture of crude Isoflurane and
water miscible solvent and separating water from the said mixture,
b. distillating the mixture of crude Isoflurane and water miscible solvent
obtained in step (a) forming an azeotrope of Isoflurane with water
miscible solvent and distilling off the impurities to obtain a mixture of
Isoflurane and water miscible solvent,
c. carrying out second liquid-liquid extraction of the mixture of Isoflurane
and water miscible solvent obtained in step (b) with water separated in
step (a), extracting water miscible solvent into water to obtain the
Isoflurane and a mixture of water miscible solvent-water,
d. using the water miscible solvent-water mixture obtained in step (c) for
first liquid-liquid extraction of crude Isoflurane in step (a), thereby
recycling said water miscible solvent-water mixture,

e. distillating the Isoflurane obtained in step (c) to obtain pure Isoflurane; wherein all the steps (a) to (d) are carried out as a continuous process to yield pure Isoflurane.
In an embodiment of the present invention, the crude Isoflurane containing impurities is purified using an entrainer such as, water miscible solvent to yield pure Isoflurane. The process is a continuous process for purification of crude Isoflurane involving continuous reuse of solvents used for the purification, such as water miscible solvent and water, without any additional step of purification of solvents or effluent treatment.
As used herein the term "entrainer" in used herein in its usual organic-chemistry sense to identify a substance having a high affinity for one component of a mixture and capable of forming an azeotrope therewith to induce a transfer of water from, say, one organic phase to a second phase which is at least in part an aqueous phase produced by the presence of the entrained water. The entrainer can chemically react with the water or may retain the water by physical entrapment, or otherwise may hold the water molecules by bonding which is weaker than chemical bonding. In the context of the present invention the "entrainer" used is water miscible solvent capable of forming azeotrope with Isoflurane.
In accordance with an embodiment of the present invention, as shown in figure 1, in the step (a), the first liquid-liquid extraction of a crude Isoflurane is carried out with a water miscible solvent-water mixture, wherein the crude Isoflurane extracts water miscible solvent from the mixture of water miscible solvent-water and separating water from the mixture. The first liquid-liquid extraction results in a mixture of crude Isoflurane and water miscible solvent.
In accordance with an embodiment of the present invention, in the step (a) the first liquid-liquid extraction is carried out with the feed ratio of crude Isoflurane to the mixture of water miscible solvent-water ranging from 1:1 to l:10(kg/hr).

In accordance with an embodiment of the present invention, in the step (b), as shown in the figure 1, the mixture of crude Isoflurane and water miscible solvent obtained in step.(a) is distilled, wherein the Isoflurane forms a high boiling azeotrope with water miscible solvent and distilling off the impurities from the mixture crude Isoflurane and water miscible solvent. The distillation yields a mixture of Isoflurane and water miscible solvent.
In accordance with an embodiment of the present invention, the impurities distilled off in step (b) contain traces of water miscible solvent. The water miscible solvent from impurity-water miscible solvent mixture is extracted with water and separated as water miscible solvent-water mixture discarding impurities. The separated water miscible solvent-water mixture is mixed with the water miscible solvent-water mixture obtained in second liquid-liquid extraction.
In accordance with an embodiment of the present invention, in the step (c), as shown in the figure 1, the second liquid-liquid extraction is carried out to the mixture of Isoflurane and water miscible solvent with water, which was separated in step (b). In the second liquid-liquid extraction water extracts water miscible solvent from the mixture of Isoflurane and water miscible solvent obtaining Isoflurane and a mixture of water miscible sol vent-water.
In accordance with an embodiment of the present invention, in the step (c) the second liquid-liquid extraction is carried out with the feed ratio of a mixture Isoflurane and water miscible solvent to water ranging from 1:1 to 1:10 (kg/hr).
In accordance with an embodiment of the present invention, in the step (c) the second liquid-liquid extraction is carried out till the water miscible solvent content in Isoflurane is < 20% w/w.
In accordance with an embodiment of the present invention, in the step (c) the second liquid-liquid extraction is carried out till the water miscible solvent content in Isoflurane is preferably < 10%w/w.

In accordance with an embodiment of the present invention, in the step (c) the second liquid-liquid extraction is carried out till the water miscible solvent content in Isoflurane is more preferably < 5% w/w.
In accordance with an embodiment of the present invention, in the step (d), as shown in the figure 1, the mixture of water miscible solvent-water obtained in step (c) is reused for first liquid-liquid extraction of the crude Isoflurane in step (a).
In accordance with an embodiment of the present invention, in the step (e) the Isoflurane obtained in step (c) contains < 20% of water miscible solvent. The obtained Isoflurane is dried using conventional processes followed by distillation of water miscible solvent to yield pure Isoflurane.
In accordance with an embodiment of the present invention, the water separated in step (a) and the water miscible solvent-water mixture obtained in step (c) is continuously recycled in the process for purification of crude Isoflurane. The process does not generate any effluent such as, water miscible solvent or water. Thus, the process for purification is cost-effective for the large scale purification of crude Isoflurane.
In accordance with an embodiment of the present invention, the water miscible solvent used in the continuous process for purification of is capable of forming an azeotrope with Isoflurane, as a result the impurities are separated from crude Isoflurane obtaining pure Isoflurane.
In accordance with an embodiment of the present invention, the water miscible solvent is selected from methyl ethyl ketone, tetrahydrofuran or acetone or mixture thereof.
In accordance with an embodiment of the present invention, the water miscible solvent is acetone.

In accordance with an embodiment of the present invention the first liquid-liquid extraction and second liquid-liquid extraction is carried out at a temperature range of 0°C to 50°C, preferably the first liquid-liquid extraction and second liquid-liquid extraction is carried out at a temperature range of 20°C to 40°C
According to the present invention, the crude Isoflurane extracted with water miscible solvent-water mixture in first liquid-liquid extraction, wherein the crude Isoflurane extracts water miscible solvent from the mixture of water miscible solvent-water, obtaining a mixture of crude Isoflurane and water miscible solvent and separating water from the mixture. The obtained mixture is then distilled, wherein the Isoflurane forms a high boiling azeotrope with water miscible solvent and the impurities are distilled off obtaining a mixture* of Isoflurane and water miscible solvent. The obtained mixture of Isoflurane and water miscible solvent then subjected to second liquid-liquid extraction to isolate Isoflurane from water miscible solvent. In the second liquid-liquid extraction the mixture of Isoflurane and water miscible solvent is extracted with water obtained in the first liquid-liquid extraction, in which water extracts water miscible solvent from the mixture obtaining Isoflurane and a mixture of water miscible solvent-water. The extracted water miscible solvent-water mixture is then reused for first liquid-liquid extraction of crude Isoflurane, wherein again the crude Isoflurane extracts water miscible solvent from the mixture of water miscible solvent-water and separating water. In this way, the water and mixture of water miscible solvent-water obtained in first liquid-liquid extraction and second liquid-liquid extraction respectively is reused continuously for the process of purification of crude Isoflurane.
The Isoflurane obtained according to this process contains < 20% w/w of water miscible solvent. The obtained Isoflurane is then dried using conventional processes and distilled to remove traces of water miscible solvent yielding pure Isoflurane of desired purity.
The following examples which fully illustrate the practice of the preferred embodiments of the present invention are intended to be for illustrative

purpose only and should not be considered in anyway to limit the scope of the present invention.
Example 1
The second liquid-liquid extraction is carried out at a temperature of 20°C to 40°C. The feed contains 34% acetone and 66% Isoflurane.

Extraction of Acetone from Org. layer by using water
Sr.
No. Feed (Kg/Hr) Flow Rate Ratio RPM Acetone Content In Isoflurane (After correction w/w%)

Org layer Water

1 8 16 01:02 1100 2.50
3 8 24 01:03 1000 1.63
3 8 24 01:03 1000 1.37
4 7 28 01:04 777 1.18
The acetone-water mixture extracted in the above extraction process is then used for treatment of crude Isoflurane.
To study the first liquid-liquid extraction, the inventors of the present invention has carried out extraction of 14% (w/w) acetone-water mixture with crude Isoflurane. The results are as follows:

Extraction of Acetone from Water by using Isoflurane
Sr.
No. Feed (Kg/Hr) Flow Rate Ratio RPM Acetone Content In
Isoflurane
(After correction
w/w%)

Isoflurane Water-Acetone

1 7 28 01:04 900 21.0
3 6 37 01:06 900 20.6
3 5 24 01:05 900 21.2
4 4 24 01:06 900 21.5

WE CLAIM:
1. A continuous process for purification of crude Isoflurane to yield pure
Isoflurane comprising the steps of:
a. carrying out first liquid-liquid extraction of a water miscible solvent-
water mixture with crude Isoflurane extracting the said water miscible
solvent from the mixture to obtain a mixture of crude Isoflurane and
water miscible solvent and separating water from the said mixture,
b. distillating the mixture of crude Isoflurane and water miscible solvent
obtained in step (a) forming an azeotrope of Isoflurane with water
miscible solvent and distilling off the impurities to obtain a mixture of
Isoflurane and water miscible solvent,
c. carrying out second liquid-liquid extraction of the mixture of Isoflurane
and water miscible solvent obtained in step (b) with water separated in
step (a), extracting water miscible solvent into water to obtain the
Isoflurane and a mixture of water miscible solvent-water,
d. using the water miscible solvent-water mixture obtained in step (c) for
first liquid-liquid extraction of crude Isoflurane in step (a), thereby
recycling said water miscible solvent-water mixture,
e. distillating the Isoflurane obtained in step (c) to obtain pure Isoflurane;
wherein all the steps (a) to (d) are carried out as a continuous process to
yield pure Isoflurane.
2. The continuous process as claimed in claim 1, wherein said water miscible solvent is capable of forming azeotrope with Isoflurane.
3. The continuous process as claimed in claim 2, wherein said water miscible solvent is selected from methyl ethyl ketone, tetrahydrofuran or acetone or mixture thereof.
4. The continuous process as claimed in claim 3, wherein said water miscible solvent is acetone.

5. The continuous process as claimed in claim 1, wherein in the step (c) said second liquid-liquid extraction is carried out till the water miscible solvent content in Isoflurane is < 20% w/w.
6. The continuous process as claimed in claim 5, wherein in the step (c) said second liquid-liquid extraction is carried out till the water miscible solvent content in Isoflurane is < 5% w/w.
7. The continuous process as claimed in claim 1, wherein in the step (a) involving first liquid-liquid extraction the feed ratio of crude Isoflurane to a mixture of water miscible solvent-water ranges from 1:1 to 1:10 (kg/hr).
8. The continuous process as claimed in claim 1, wherein in the step (c) involving second liquid-liquid extraction the feed ratio of a mixture crude Isoflurane and water miscible solvent to water ranges from 1:1 to 1:10 (kg/hr).
9. The continuous process as claimed in claim 1, wherein the first liquid-liquid extraction in the step (a) and the second liquid-liquid extraction in the step (c) are carried out at a temperature range of 0°C to 50°C.
10. The continuous process as claimed in claim 9, wherein the first liquid-liquid extraction in the step (a) and the second liquid-liquid extraction in the step (c) is carried out at a temperature of 20°C to 40°C.