Description:TECHNICAL FIELD
[0001] The present disclosure relates to technical field of organic synthesis. In particular, the present disclosure relates to a process for preparation of substituted phenyl glyceryl ether compounds having therapeutic utility.

BACKGROUND
[0002] Background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is a prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is a prior art.
[0003] Substituted phenyl glyceryl ether compounds have valuable therapeutic properties, like muscle-relaxant, anti-convulsive, antifungal, sedative, analgesic, biocidal or neurotoxic. Examples of such compounds are 3-(4-chlorophenoxy)-1,2-propanediol (Chlorphenesin), 3-(2-methylphenoxy)-1,2-propanediol (Mephenesin), 3-(2-methoxyphenoxy)-1,2-propanediol (Guaifenesin), etc. Guaifenesin is well known drug molecule which is principally used for the treatment of cold and cough. Chlorphenesin carbamate and mephenesin are active CNS muscle relaxant. Chlorphenesin carbamate is also used as biocidal and antifungal agent.
[0004] Chinese patent CN109293483 discloses a process for the preparation of chlorphenesin by using the micro-channel continuous flow reactor. A methanol mixed solution of chlorophenol, 3-chloro-1,2-propanediol and a liquid sodium methoxide solution is used in the micro-channel continuous flow reactor.
[0005] Chinese patent CN105016989 relates to a synthetic method for preparing chlorobenzene glyceryl ether by using 3-chloro-1,2-propanediol, p-chlorophenol, phase transfer catalyst tetrabutylammonium bromide and 18% NaOH solution at 105? temperature.
[0006] German patent DE219325 discloses a process for the preparation of glyceryl mono o- and p-chlorophenyl ethers by reacting with glycerylmonochlorohydrin on the alkali salts of the o- or p-chlorophenol or on a mixture of the corresponding chlorophenol and alkali lye.
[0007] Chinese patent CN111056928 relates to a method for synthesizing Chlorphenesin, which comprises adding p-chlorophenol, 3-chloro-1, 2-propylene glycol and a proper amount of ethanol into a reactor, stirring, heating, and adding drop wise a 20-60% aqueous alkali solution. Reaction temperature is 60-90°C and the reaction lasts for 2-10 hours.
[0008] Chinese patent CN101445436 relates to a method for synthesizing Chlorphenesin, which comprises reaction of epichlorohydrin and dilute sulfuric acid, at 100-105? for 1 hour and after cooling to 80?, further addition of p-chlorophenol, and 37% sodium hydroxide aqueous solution. Reaction temperature is 105-115? and after workup, product is obtained.
[0009] Chinese patent CN113979841 relates to a method for synthesizing Chlorphenesin, which comprises reaction of p-chlorophenol and 3-chloro-1,2-propanediol in presence of 10% sodium hydroxide solution at a reaction temperature of 70°-90°C.
[00010] Chinese patent CN113149818 discloses a process for the preparation of Chlorphenesin, by using 3-chloro-1,2-propanediol and p-chlorophenol in presence of potassium hydroxide solution, solvent and catalyst. Then heat the reaction liquid to 50°C and react for 2 hours to get the target compound after workup.
[00011] Chinese patent CN113185384 discloses a process for the preparation of Chlorphenesin, by reaction of p-chlorophenol and glycidol in the presence of water, sodium hydroxide and benzyltriethylammonium chloride at 50-60°C.
[00012] Journal of Medicinal Chemistry, 56(12), 5071–5078 describes synthesis of mephenesin and guaifenesin by reaction the of 3-chloro-1,2-propanediol and corresponding phenol in the presence of sodium hydroxide, N,N-dimethylformamide under microwave at 210°C.
[00013] However, the existing methods for preparing substituted phenyl glyceryl ether compounds have numerous drawbacks, including: the need of large amount of phenols, impurities formation, tedious procedure for the preparation of catalyst system, large amount of catalyst loadings, prolonged reaction times, the use of moisture sensitive reagents, and the need of special reaction setup, e.g. cyclic continuous-flow reactor for the reaction.
[00014] Apart from the above-mentioned disadvantages, the known processes use water as a reaction medium, which leads to the generation of a large amount of aqueous effluents containing high levels of phenolic compounds. These effluents cannot be economically recycled and limiting the concentrations of phenolic compounds in such aqueous effluents within an acceptable range is difficult. Further, since water has become a scarce resource nowadays, its use has to be minimized as much as possible.
[00015] There is thus a need in the art to provide a new, improved and ecofriendly process for the preparation of substituted phenyl glyceryl ether compounds, that overcomes the afore-mentioned disadvantages of the prior-art processes and provides overall satisfactory results. The present disclosure satisfies these needs and provides further related advantages.

OBJECTS
[00016] It is an object of the present disclosure to provide a new and improved process for preparation of substituted phenyl glyceryl ethers, which overcomes one or more disadvantages of the prior art specified above.
[00017] It is another object of the present disclosure to provide a process for preparation of substituted phenyl glyceryl ethers that does not use water as a solvent at the reaction stage.
[00018] It is another object of the present disclosure to provide an economical, efficient and eco-friendly process for preparation of substituted phenyl glyceryl ethers.
[00019] It is another object of the present disclosure to provide an improved process that provides substituted phenyl glyceryl ether compounds in good yield, while minimizing the formation of impurities.
[00020] It is yet another object of the present disclosure to provide an ecofriendly process for preparing substituted phenyl glyceryl ethers, which is simple to operate on a commercial scale, with minimum production of effluent.
[00021] Other and further objects of this invention will be apparent from the following detailed description and appended claims which form a part of this specification.

SUMMARY
[00022] The foregoing and other objects are attained by the present disclosure, which in one aspect provides a process for preparation of substituted phenyl glyceryl ethers of formula (I), which comprises reacting an alkali metal salt of formula (II) with a dihydroxy compound of formula (III), as shown in the following Reaction Scheme 1.
Reaction Scheme 1

wherein,
M is an alkali metal;
R and R1 represent, independently of one another, hydrogen, chloro, methoxy or methyl; and
R3 is chloro or bromo.
[00023] In formula (II), M is an alkali metal. Alkali metal M is preferably sodium or potassium. Thus, the alkali metal salt can be a sodium salt or potassium salt. The alkali metal salt of formula (II) can be prepared by reaction of a hydroxide, carbonate, bicarbonate, hydride or alkoxide of an alkali metal with a phenol compound of formula (IV). It is preferred that the reaction is carried out in a suitable solvent. During the reaction of the alkali metal compound with the phenol compound of formula (IV), water or alcohol may be formed as a by-product and it can be removed readily from the reaction mixture by known procedures, such as distillation or azeotropic distillation.

wherein R and R1 are as defined above.
[00024] In one embodiment, the processes disclosed herein further comprise providing a compound of formula (1A) by converting the compound of formula (I) to the compound of formula (IA) under a suitable condition.

wherein R and R1 are as defined above for the compound of formula (I).
[00025] Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments.

DETAILED DESCRIPTION
[00026] The following is a detailed description of embodiments of the present disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
[00027] In one aspect, the present disclosure provides a process for preparation of substituted phenyl glyceryl ethers of formula (I), which comprises reacting an alkali metal salt of formula (II) with a dihydroxy compound of formula (III), as shown in the following Reaction Scheme 1.
Reaction Scheme 1

wherein,
M is an alkali metal;
R and R1 represent, independently of one another, hydrogen, chloro, methoxy or methyl; and
R3 is chloro or bromo.
[00028] In formula (II), M is an alkali metal. Alkali metal M is preferably sodium or potassium. Thus, the alkali metal salt can be a sodium salt or potassium salt. Alkali metal salt of formula (II) can be prepared by reaction of a hydroxide, carbonate, bicarbonate, hydride or alkoxide of an alkali metal with a phenol compound of formula (IV). It is preferred that the reaction is carried out in a suitable solvent, such as a hydrocarbon, a chlorinated hydrocarbon, an aromatic hydrocarbon, or an ether. During the reaction of the alkali metal compound with the phenol compound of formula (IV), water or alcohol may be formed as a by-product and it can be removed readily from the reaction mixture by known procedures, such as by distillation or azeotropic distillation.

wherein R and R1 are as defined above.
[00029] In an embodiment, the phenol compound of formula (IV) is 4-chlorophenol, 2-methylphenol, 2-methoxyphenol, 2,4-dichlorophenol, 2-methyl-4-chlorophenol, or 2,4,6-trichlorophenol.
[00030] In some embodiments, compound of formula (II) is prepared by reacting the phenol compound of formula (IV) with sodium hydroxide or potassium hydroxide.
[00031] In some embodiments, the conversion of the compound of formula (IV) to obtain the alkali metal salt of formula (II) is carried out in a solvent, which is selected from the group consisting of ethylene dichloride, carbon tetrachloride, xylenes, chloroform, o-dichlorobenzene, chlorobenzene, toluene, tetrahydrofuran, methyl-t-butylether, hexane, heptane, 1,2-dimethoxyethane, 1,4-dioxane, and a mixture thereof.
[00032] In some embodiments, the compound of formula (III) can be prepared by ring-opening of an epoxide of formula (V)

in which R3 is as defined above for formula (III).
Ring opening of compound of formula (V) can be carried out under standard conditions. In some embodiments, the compound of formula (III) can be synthesized by reacting the epoxide of formula (V) and water using sulfuric acid as a catalyst. In some embodiments, the epoxide of formula (V) can be converted to the compound of formula (III) using ultrasonic irradiation.
[00033] In some embodiments, the compound of formula (V) is epichlorohydrin.
[00034] In various embodiments, reacting the alkali metal salt of formula (II) with the dihydroxy compound of formula (III) comprises providing a reaction mixture comprising the alkali metal salt of formula (II) and the dihydroxy compound of formula (III), wherein the reaction mixture is devoid of water; and mixing the reaction mixture at a temperature ranging from 50°C to 150° C for a period of time sufficient to form the compound of formula (I). An important feature of the reaction process is that the reaction mixture is devoid of water. Accordingly, the reaction is considered a “non-aqueous” reaction due to the absence of water. In various embodiments, the reaction may be performed either in neat condition or in an organic solvent. Suitable organic solvents include ethylene dichloride, carbon tetrachloride, xylenes, chloroform, o-dichlorobenzene, chlorobenzene, toluene, methyl-t-butylether, hexane, heptane, 1,2-dimethoxyethane, and a mixture thereof. The completion of the reaction can be monitored by any suitable analytical technique. After completion of the reaction, the compound of formula (I) may be isolated from the reaction mixture by any known methods which may include, filtration of precipitated solid, cooling crystallization, anti-solvent addition, removal of solvent by evaporation, distillation, or any combinations of these methods. In some embodiments, the compound of formula (I) is isolated by filtration. The isolated product may optionally be purified to achieve desired purity by techniques known in the art like recrystallization, slurrying, column chromatography, fractional distillation or acid base treatment. In some embodiments, the isolated product is purified by recrystallization.
[00035] In one embodiment, the dihydroxy compound of formula (III) is 3-chloro-1,2-propanediol or 3-bromo-1,2-propanediol.
[00036] In one embodiment, the molar ratio of the compound of formula (II) to the dihydroxy compound of formula (III) ranges from 1: 1-1.2, preferably 1:1.
[00037] Some embodiments herein describe a process for preparing the compound of Formula (I)

wherein R and R1 represent, independently of one another, hydrogen, chloro, methoxy or methyl;
comprising:
a) reacting a phenol compound of formula (IV)
wherein R and R1 are as defined above;
with a hydroxide, carbonate, bicarbonate, hydride or alkoxide of an alkali metal to form a compound of formula (II)

wherein M is an alkali metal; and R and R1 are as defined above;
b) converting an epoxide of formula (V)

wherein R3 is chloro or bromo;
to a compound of formula (III)

wherein R3 is as defined above; and
c) reacting the compound of formula (II) with the compound of formula (III) to form the compound of formula (I).
[00038] In some embodiments, the process further comprises converting the compound of formula (I) from step c) to the compound of formula (IA) under a suitable condition.

wherein R and R1 are as defined above for the compound of formula (I).
[00039] In various embodiments, the compound of formula (IA) as described above can be chlorphenesin carbamate, mephenesin carbamate or guaifenesin carbamate.
[00040] In various embodiments, the compound of formula (I) produced in accordance with the process disclosed herein has a purity of greater than 97% as determined by HPLC.
[00041] The process according to the present disclosure has a number of advantages over the known processes for the preparation of substituted phenyl glyceryl ethers. It enables to obtain substituted phenyl glyceryl ether compounds of high purity. The process is amenable to scale up. The raw materials and reagents are readily available and economically viable. The process of the present invention is thus convenient to operate on a commercial scale.
[00042] While the foregoing description discloses various embodiments of the invention, other and further embodiments of the invention may be devised without departing from the basic scope of the invention. The invention is not limited to the described embodiments, versions or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art.
EXAMPLES
[00043] The present invention is further explained in the form of following examples. However, it is to be understood that the foregoing examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention.
Example 1: Preparation of Chlorphenesin
[00044] Add 32.5g of p-chlorophenol, 75g of toluene and 10.2g sodium hydroxide flakes, into a 250ml three-necked flask, heat and stir to raise the temperature to remove water azeotropically. After water removal, cool and add 28.2g of 3-chloro-1,2-propanediol. After addition, heat to 105°C and maintain. Monitor the reaction on HPLC and after completion of the reaction, cool down and filter to remove the generated salt with product. To the solid, add dilute hydrochloric acid to adjust the pH to 6, cool and stir. Filter the solid at pump, and dry at 50°C to obtain the crude product. Followed by purification using toluene, filter the product and dry under vacuum at 50°C. HPLC purity >98%; Yield: 45.3g (89.7%).
Example 2: Preparation of Chlorphenesin
[00045] Add 65.6g of p-chlorophenol, 150g of ethylene dichloride and 20.4g sodium hydroxide flakes, into a 500ml three-necked flask, heat and stir to raise the temperature to remove water azeotropically. After water removal, cool and add 56.4g of 3-chloro-1,2-propanediol dropwise. After addition, heat to 80°C and maintain the reaction for 4 hours. Monitor the reaction on HPLC and after completion of the reaction, distill off the solvent under vacuum. Charge 100g of toluene, cool and filter to remove the generated salt with product. To the solid, add dilute hydrochloric acid to adjust the pH to 6, charge water, cool and stir. Filter the solid at pump, and dry at 50°C to obtain the crude product. Followed by purification using toluene, filter the product and dry under vacuum at 50°C. HPLC purity >98%; Yield: 91g (90%).
Example 3: Preparation of Chlorphenesin carbamate
[00046] Transfer the product of Example 2 in a three-necked flask and add 450g of toluene. Stir the mass and add 45g phosgene over a period of 1 hour maintaining temperature 30°C until solid dissolution. Then add 45g of 25% ammonia solution slowly dropwise. Cool the mass to 5°C, extracted with 600ml cold water to remove ammonium chloride from the mass. The toluene fraction containing 3-(4-chlorophenoxy)-1,2-propanediol carbamate is crystallized to get pure title product. HPLC purity >98%; Yield: 91.42 g (82.5%).
Example 4: Preparation of Mephenesin
[00047] Add 54.1g of 2-methylphenol, 150g of toluene and 20.4g sodium hydroxide flakes, into a 500ml three-necked flask, heat and stir to raise the temperature to remove water azeotropically. After water removal, cool and add 56.4g of 3-chloro-1, 2-propanediol dropwise. After addition, heat to 100°C and maintain the reaction for 4 hours. Monitor the reaction on HPLC and after completion of the reaction, cool down and filter to remove the generated salt with product. To the solid, add dilute hydrochloric acid to adjust the pH to 6, put it in water, cool and stir. Filter the white solid at pump, and dry at 50°C to obtain the crude product. Followed by purification using isopropyl alcohol, filter the product and dry under vacuum at 50°C. HPLC purity >98%; Yield: 80.45 g (88.3%).
Example 5: Preparation of Guaifenesin
[00048] Add 62.1g of 2-methoxyphenol, 150g of ethylene dichloride and 20.4g sodium hydroxide flakes, into a 500ml three-necked flask, heat and stir to raise the temperature to remove water azeotropically. After water removal, cool to 60°C add 56.4g of 3-chloro-1, 2-propanediol. After addition, heat to 80°C and maintain the reaction for 4 hours. Monitor the reaction on HPLC and after completion of the reaction, cool down. Charge water and stir vigorously. Adjust pH to 7 using dilute hydrochloric acid. Filter the separated product at pump. Dry at 50°C to obtain the crude product. Followed by purification using acetonitrile, filter the product and dry under vacuum at 50°C. HPLC purity >98%; Yield: 88.2 g (89%).
Example 6: Preparation of Chlorphenesin
[00049] Take 65.6g of p-chlorophenol, 150g of toluene and 27.6g sodium methoxide powder into a 500ml three-necked flask, heat and stir to raise the temperature to remove methanol, after azeotropic removal of methanol, cool to 60°C. Add 56.4g of 3-chloro-1,2-propanediol dropwise to above reaction mass. After addition, heat the mass to 80°C and maintain the reaction mass for 4 hours. After completion of the reaction, cool down the mass and filter with suction to remove the generated salt along with product. To the solid, add dilute hydrochloric acid to adjust the pH to 6, a white solid will precipitate out, filter the solid and dry at 50°C to obtain the crude product. Followed by purification using toluene, filter the mass and dry at 50°C to obtain the product, HPLC purity >98%; Yield: 90g (90%).
[00050] The process according to the present invention have various advantages, such as:
1. The present invention provides a process having characteristics of economic viability and environment friendly with less effluent waste.
2. No use of catalyst.
3. Minimum production of effluent.
4. Purity of the compounds: All the compounds give more than (>) 97% HPLC purity.
5. Wide applicability: The process has wide applicability in production of various phenyl glyceryl ether compounds.
6. The present invention process involves less expensive and readily available reagents and solvents.
7. Solvents used in present invention were less expensive and can be recovered and reused.
8. Product of present invention is directly isolated from the reaction mass without involving any laborious work-up processes. Therefore, the process of the present invention is suitable for commercial scale.
9. The present invention provides a new process for preparing substituted phenyl glyceryl ether compounds, which involves efficient process resulting in competitive yield of the product with optimum purity at commercial scale with respect to the conventional prior art procedures.
10. The present invention provides a process for preparing substituted phenyl glyceryl ether compounds that provides lower impurities in the final product, as mild reaction conditions restrict the formation of undesired impurities.
11. The present invention provides a process that is simple, safe, time saving and having convenient operational steps at commercial scale.
12. The present invention provides a process that saves utility at commercial scale because of simple work-up and product isolation procedure.
13. The present invention provides a process that improves productivity and equipment utilization at commercial scale.

, Claims:1. A process for preparing a compound of Formula (I)

wherein R and R1 represent, independently of one another, hydrogen, chloro, methoxy or methyl;
comprising: reacting a compound of formula (II)

wherein M is an alkali metal; and R and R1 are as defined above;
with a compound of formula (III)

wherein R3 is chloro or bromo;
to obtain the compound of formula (I).
2. The process as claimed in claim 1, wherein, in formula (II), M is sodium or potassium.
3. The process as claimed in claim 1, wherein the reaction is performed at a temperature ranging from 50°C to 150°C.
4. The process as claimed in claim 1, wherein the reaction is performed in absence of water.
5. The process as claimed in claim 1, wherein the reaction is carried out in a solvent selected from the group consisting of ethylene dichloride, carbon tetrachloride, xylene, chloroform, o-dichlorobenzene, chlorobenzene, toluene, methyl-t-butylether, hexane, heptane, 1,2-dimethoxyethane, and a mixture thereof.
6. The process as claimed in claim 1, further comprises a step of purifying the compound of formula (I) thus obtained.
7. The process as claimed in claim 1, further comprises a step of converting the compound of formula (I) thus obtained to a compound of formula (IA)

wherein R and R1 are as defined above.