Claims:1) A process for the preparation of Guaifenesin of Formula (I)

(I)
comprising the steps of:
a. reacting the Epichlorohydrin in the presence of Phosphoric acid in a suitable solvent at temperature ranges between 60-150oC to obtain a Monochlorohydrin compound of formula IV;
(IV)
b. reacting the compound of monochlorohydrin compound of Formula (IV) with Guaiacol in the presence of base to obtain crude Guaifenesin as an oil;
c. subjecting crude Guaifenesin oil to high vacuum distillations carried using Heat transfer fluids to obtain pure Guaifenesin oil;
d. Crystallising pure Guaifenesin oil in an organic solvent system.

2) A process for the preparation of Guaifenesin (I) according to claim 1, where in step a) solvents are selected from ester solvents as ethyl acetate, isopropyl acetate, butyl acetate or halogenated solvents as methylene chloride, ethylene dichloride, chloroform, chlorobenzene or nitrile solvents as acetonitrile or ketones as acetone, methyl ethyl ketone, methyl isobutyl ketone or halogenated solvents as methylene chloride, ethylene dichloride, chloroform, chlorobenzene or ether solvents as diethyl ether, diisopropyl ether, tetrahydrofuran or hydrocarbon solvents as methyl cyclohexane, cyclohexane, n-hexane, n-heptane or water and mixtures thereof.

3) A process for the preparation of Guaifenesin (I) according to claim 1, where in base is selected from inorganic base as sodium hydroxide, sodium carbonate, ammonia, ammonium hydroxide and calcium carbonate or organic base as triethyl amine, isopropyl ethyl amine, tertiary butyl ethyl amine, isopropyl ethyl amine, diisopropyl ethyl amine.

4) A process for the preparation of Guaifenesin (I) according to claim 1, wherein Heat transfer fluids comprises paraffin oils, silicone oils, white oils, chemical aromatic or synthetic organic fluids having boiling point higher than 150°C.

5) A process for the preparation of Guaifenesin (I) according to claim 4, wherein silicone oils selected form polydimethylsiloxane (PDMS).

6) A process for the preparation of Guaifenesin (I) according to claim 1, step d) Crystallising pure Guaifenesin in a solvent selected from water or alcohol solvents as methanol, ethanol, propanol, isopropyl alcohol, butanol, or halogenated solvents as methylene chloride, ethylene dichloride, chloroform or ketones as acetone, methyl ethyl ketone, methyl isobutyl ketone or ester solvents as ethyl acetate, isopropyl acetate, butyl acetate or ether solvents as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxan, dimethylsulfoxide (DMSO), N,N-dimethyl formamide (DMF), non-polar solvents as hexane, toluene and the like or mixture thereof .

7) A process for the preparation of Guaifenesin (I) according to claim 1

(I)
comprising the steps of:
a. reacting the Epichlorohydrin in the presence of Phosphoric acid in a suitable water at temperature ranges between 60-150oC to obtain a monochlorohydrin compound of formula IV;
(IV)
b. reacting the compound of Monochlorohydrin compound Formula (IV) with Guaiacol in the presence of sodium hydroxide to obtain crude Guaifenesin as an oil;
c. Subjecting crude Guaifenesin oil to high vacuum distillations carried using silicone oils to obtain pure Guaifenesin oil;
d. Crystallising pure Guaifenesin oil in an organic solvent system to obtain crystalline Guaifenesin (I).

8) A process for the preparation of Guaifenesin (I) according to claim 1, wherein Guaifenesin (I) having HPLC purity atleast 95%.

9) A process for the preparation of Guaifenesin (I) according to claim 1, wherein Guaifenesin (I) yield obtained = 60%.
, Description:FIELD OF THE INVENTION
The present invention relates to an improved and industrially applicable process for the preparation Guaifenesin of Formula (I).
(I)
Said Guaifenesin (I), is used to control cough.

BACKGROUND OF THE INVENTION
Guaifenesin is a well-known commercially available compound. It is frequently referred to as guaiphenesin or glyceryl guiacolate or guaiacol glyceryl ether. Guaifenesin of formula I, is used to treat cough and is chemically known as 3-(2-methoxyphenoxy)propane-1,2-diol.

(I)

Guaifenesin finds its principal use as an expectorant for promoting or facilitating the removal of secretions from the respiratory tract in a warm-blooded animal, principally a human being. It helps to loosen phlegm (mucus) and thin bronchial secretions to rid the bronchial passageways of bothersome mucus, drain bronchial tubes and makes coughs more productive. It is typically administered to human beings in need of such medication in the form of tablets and/or suspensions.
T. Kametani, et.al discloses in the journal Yakugaku Zasshi 87(8), 967 (1967), guaifenesin is prepared by reaction of guaiacol with epichlorohydrin in the presence of molar amounts of sodium hydroxide in water. This reaction, however, requires relatively long reaction times at a temperature of around 85-90°C and only results in small yields (32%) of guaifenesin.
According to William Bradley et.al in GB628497, guaifenesin can be obtained by employing 2,3-epoxypropanol, i.e. glycidol, in reaction with phenols, among others, p-methoxyphenol, in presence of tertiary amine or quaternary ammonium salts as catalysts.
According to Polish patent No. 48485 (1964), reaction of epichlorohydrin will give glycerine-a-monochlorohydrin by addition of a suitable aqueous acid (e.g. 0.2% H2SO4). It is also necessary in the reaction with glycerine-a-monochlorohydrin to use molar amounts of an alkaline catalyst such as sodium hydroxide to obtain crude guaifenesin oil by repeated distillation of crude guaifenesin oil will give pure guaifenesin oil. This process is not economical for the industrial use.
Most of the above said references it is very clear that is to develop an alternative and improved process suitable synthetic route for industrial scale up. The process of present invention overcome disadvantages of prior art by avoiding use of conventional repeated distillation methods and also involving easy isolation of guaifenesin by using less amount of the solvent. Thus, present invention fulfills the need of the art and provides an improved and industrially applicable process for preparation of guaifenesin, which provides guaifenesin for its synthesis in high overall yield and purity.

SUMMARY OF INVENTION
Particular aspects of the present invention relates to a process for the preparation of guaifenesin (I). Guaifenesin (I) obtained by the process of the present invention is found to substantially pure and with high yields.

(I)
In one aspect of the present invention, relates to process for the preparation of guaifenesin (I) comprising the steps of:
a. reacting the Epichlorohydrin in the presence of Phosphoric acid in a suitable solvent at temperature ranges between 60-100 oC to obtain a monochlorohydrin compound of formula IV;
(IV)
b. reacting the compound of monochlorohydrin compound Formula (IV) with Guaiacol in the presence of base to obtain crude Guaifenesin as an oil;
c. subjecting crude Guaifenesin oil to high vacuum distillations using Heat transfer fluids to obtain pure Guaifenesin oil;
d. Crystallising pure Guaifenesin oil in an organic solvent system.

In another aspect of the present application relates to a process for the preparation
of Guaifenesin (I) comprising the steps of:
a. reacting the Epichlorohydrin in the presence of Phosphoric acid in a suitable water at temperature ranges between 60-100 oC to obtain a monochlorohydrin compound of formula IV;
(IV)
b. reacting the compound of monochlorohydrin compound Formula (IV) with Guaiacol in the presence of sodium hydroxide to obtain crude Guaifenesin as an oil;
c. subjecting crude Guaifenesin oil to high vacuum distillations using silicone oils to obtain pure Guaifenesin oil;
d. crystallizing pure Guaifenesin oil in an organic solvent system to obtain crystalline Guaifenesin.
Further particular aspects of the invention are detailed in the description part of the specification, wherever appropriate.

DETAILED DESCRIPTION
As set forth herein, embodiments of the present invention provide an efficient process for the preparation of Guaifenesin (I). Guaifenesin (I) obtained by the process of the present invention is found to be substantially pure.
In another embodiment according to present application, it provides a process for the preparation of Guaifenesin (I), comprising the steps of:
a. reacting the Epichlorohydrin in the presence of Phosphoric acid in a suitable solvent at temperature ranges between 60-150 oC to obtain a Monochlorohydrin compound of formula IV;
(IV)
b. reacting the compound of monochlorohydrin compound Formula (IV) with Guaiacol in the presence of base to obtain crude Guaifenesin as an oil;
c. subjecting crude Guaifenesin oil to high vacuum distillations carried using Heat transfer fluids to obtain pure Guaifenesin oil;
d. Crystallising pure Guaifenesin oil in an organic solvent system.
Individual steps of the embodiments are detailed herein below.
In process step (a), Epichlorohydrin was dissolved in a suitable solvent and the reaction was performed using catalytical amount of Phosphoric acid to obtain monochorohydrin (IV) at temperature ranges between 60-150oC for a period of 30 minutes to 2 hours.
In one of the embodiment according to present invention, suitable solvents useful in the step (a) were selected from ester solvents as ethyl acetate, isopropyl acetate, butyl acetate or halogenated solvents as methylene chloride, ethylene dichloride, chloroform, chlorobenzene or nitrile solvents as acetonitrile or ketones as acetone, methyl ethyl ketone, methyl isobutyl ketone or halogenated solvents as methylene chloride, ethylene dichloride, chloroform, chlorobenzene or ether solvents as diethyl ether, diisopropyl ether, tetrahydrofuran or hydrocarbon solvents as methyl cyclohexane, cyclohexane, n-hexane, n-heptane or water and mixtures thereof.
In another particular embodiment according to present invention, substituted solvent is water.
In the process step (b) of the present invention, guaiacol was added to the monochlorohydrin (IV) formed in the step (a) in the presence of a base selected from the group consisting inorganic base as sodium hydroxide, sodium carbonate, ammonia, ammonium hydroxide and calcium carbonate or organic base as triethylamine, isopropyl ethyl amine, tertiary butyl ethyl amine, isopropyl ethyl amine, diisopropyl ethylamine and the reaction was performed for a period of 1-5 hours at temperature 60-150oC.
In one of the particular embodiment according to present application, base in the process step (b) was sodium hydroxide.
In one of the particular embodiment according to present application, step (b) performed for a period of 2 hours.
In one of the particular embodiment according to present application, step (b) performed at temperature 102oC.
In the process step (c) of the present invention, subjecting the crude Guaifenesin oil to high vacuum distillations carried using Heat transfer fluids to obtain pure Guaifenesin oil. In this process step, Heat transfer fluids selected from paraffin oils, silicone oils, white oils chemical aromatic or synthetic organic fluids chemical aromatic or synthetic organic fluids having boiling point higher than 150°C. Heat transfer fluids were added to the crude Guaifenesin oil obtained according to step (b).
According to the present invention, this step (c) was crucial step as the prior-art process was using the conventional distillation methods. According Inventors of the present invention, conventional distillation methods were giving very low yield of 50 – 60 % of Guaifenesin (I). Whereas, according to the present invention distillations carried using Heat transfer fluids would lead to minimizing impurities like unreacted Guaiacol, process related impurities such as ß-isomer, dimer, etc. In addition, impurities obtained by the oxidative degradation, thermal disintegration / cracking of the starting organic compounds when directly contact with high temperatures as in the conventional distillation methods. There by decreasing all these types of impurities by maintaining the distillation temperature uniformly in the reactor by carrying out the distillations using Heat transfer fluids leading to increase in the final yield of the compound Guaifenesin (I). After completion of the reaction, Heat transfer fluids were recovered and used in processes.
In one of the particular embodiment according to present application, Heat transfer fluid in step (c) was Silicone oil.
In another particular embodiment according to present application, Silicone oils used in step (c) were Linear polydimethylsiloxanes (PDMS). Linear polydimethylsiloxanes (PDMS) were polymeric organosilicon substances commonly referred to as “silicones”. They are particular suitable for the distillation reactions because of their typical physical and chemical properties. They are clear, colourless, odourless and viscous fluids and found to be with no vapour pressure. They exhibit remarkable stability to chemical and oxidative degradation, essentially insoluble in water. PDMS was reportedly used for the treatment of urological and opthalmological problems. Safety of PDMS has been recognised by its widespread use in wide range of applications for nearly 50 years. PDMSs were widely used in industrial, consumer, food and medicinal or pharmaceutical application. They break down to dimethyl silanediol, inorganic silicate, carbon dioxide and water. Acute and repeated dose toxicity studies do not show any significant adverse effects. Long-term chronic/carconogenicity and reproductive toxicity studies were also without adverse effects. PDMS was not mutagenic in vitro and no effect on immune system. Further, they were eco-friendly and does not harm to human kind. Some of the major applications of PDMS were used in the preparation of adhesives, antifoam, damping fluid, electrical, hydraulic, transformer, lubricant, mould release agent, sealents, textile softening, softener, water repellent, Cosmetic, domestic rinse agent , personal care products, polish, sunscreens, Antifoam in food processing, eg beer, jam, etc. Antifoam in frying fat and vegetable oil, Anti-gas/anti-flatulent, Head Lice etc
Physico-Chemical Properties of PDMS
Chemical Structure:

(V)
• E 900 which is used for PDMS with a viscosity of 200 to 1050 cSt approved as a food additive
• Solubility in organic solvents like Hexane, Toluene, Chloroform, Diethyl ether.
• Freezing point : -50 - 35oC
• Relative Density at 25oC: 0.93-0.97
• Refractive Index: 1.399-1.404
• Vapour Pressure: Not measurable
• Solubility in water: <1 ng/L
• Explosion/flammability: Not applicable
• Auto-flammability, ignition temperature: 450oC

In one of the embodiment according to present application, 0.1-20% of Heat transfer fluids were added to crude Guaifenesin oil.
In one of the particular embodiment according to present application, 0.1-10% of Heat transfer fluids were added to crude Guaifenesin oil.
In one of the particular embodiment according to present application, the temperature of the distillation was carried at 100-250oC after the addition of Heat transfer fluids to the crude Guaifenesin oil.
In another particular embodiment according to present application, the temperature of the distillation was carried at 170oC after the addition of Heat transfer fluids to the crude Guaifenesin oil.
In the process step (d) of the present application, crystallizing the pure Guaifenesin (I) by dissolving the pure Guaifenesin oil in a suitable organic solvents selected from the group comprising of ester solvents as ethyl acetate, isopropyl acetate, butyl acetate or halogenated solvents as methylene chloride, ethylene dichloride, chloroform, chlorobenzene or nitrile solvents as acetonitrile or alcoholic solvents as methanol, ethanol, isopropanol, n-butanol, ketones as acetone, methyl ethyl ketone, methyl isobutyl ketone or halogenated solvents as methylene chloride, ethylene dichloride, chloroform, chlorobenzene or ether solvents as diethyl ether, diisopropylether, tetrahydrofuran or hydrocarbon solvents as methyl cyclohexane, cyclohexane, n-hexane, n-heptane or water and mixtures thereof.
In one of the particular embodiment according to present application, solvent used in the process step (d) was mixture of toluene and isopropyl alcohol.
In another embodiment of the present application provides pure Guaifenesin oil having HPLC purity of atleast 95%.
In another embodiment crystalline Guaifenesin (I) obtained according to the process of the present invention results in the final API purity by HPLC of more than 99% and preferably greater than 99.5%. The purity of the Guaifenesin samples was measured using chromatography. Chromatography was performed with Waters Alliance HPLC system (MILD, USA) that consists of quaternary pump equipped with a 2695 separation module with inbuilt auto injector and 2996 photodiode array detector. The output signal was monitored and processed using chromelean software version 6.8.
In another embodiment of the present invention provides pure crystalline Guaifenesin (I) can be obtained with yield = 60%.
The invention was further defined by reference to the following examples describing in detail by the preparation of the compounds of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
EXAMPLES
Example 1:
Charge water (240ml), phosphoric acid (2.5gm) and Epichlorohydrin (93gm) maintain temp at 95°C for 45 min. Charge sodium hydroxide (45gm) and guaiacol (120gm) maintain at 102°C for 2hrs. Separate the Aqueous layer & organic layer and distill the solvent. Apply vaccum and raise the temperature at 120°C for 30 minutes, collect the 1st fraction. Raise the vapour temperature to below 170oC and collect the 2nd fraction (pure oil) 140 g HPLC Purity 96.5 %. Charge 350ml of Toluene and Isopropyl alcohol into 2nd fraction. Cool the mass to 15-25°C. Filter the product.
Yield: 105-108g

Example 2:
Charge water (240ml), phosphoric acid (2.5gm) and Epichlorohydrin ( 93gm) maintain temp at 95°C for 45 min. Charge sodium hydroxide (45gm) and guaiacol (120gm) maintain at 102°C for 2hrs. Separate the Aqueous layer organic layer and distill the solvent. Charge white oil (10gm) to organic layer. Apply vaccum and raise the temperature at 120°C for 15 minutes, collect the 1st fraction. Raise the vapour temperature to below 170oC and collect the 2nd fraction (pure oil) 159 g HPLC Purity 97.17%. Charge 350ml of Toluene and Isopropyl alcohol into 2nd fraction. Cool the mass to 15-25°C. Filter the product.
Yield: 115-123 g

Example 3:
Charge water (240ml), phosphoric acid (2.5gm) and Epichlorohydrin (93gm) maintain temp at 95°C for 45 min. Charge sodium hydroxide (45gm) and guaiacol (120gm) maintain at 102°C for 2hrs. Separate the aqueous layer organic layer and distill the solvent. Charge silicon oil (10gm) to organic layer. Apply vaccum and raise the temperature at 120°C for 15 min,, collect the 1st fraction. Raise the vapour temperature to below 170oC and collect the 2nd fraction (pure oil) 157 g, HPLC Purity 98.0%. Charge 350ml of Toluene and Isopropyl alcohol into 2nd fraction. Cool the mass to 15-25°C. Filter the product.
Yield 115-120 gm

Example 4:
Charge water (240ml), phosphoric acid (2.5gm) and Epichlorohydrin (93gm) maintain temp at 95°C for 45 min. Charge sodium hydroxide (45gm) and guaiacol (120gm) maintain at 102°C for 2hrs. Separate the Aqueous layer organic layer and distill the solvent. Charge recovered silicon oil (10gm) to organic layer. Apply vaccum and raise the temperature at 120c for 15 min, collect the 1st fraction. Raise the vapour temperature to below 170oC and collect the 2nd fraction (pure oil) 158 g, HPLC Purity 95.89%. Charge 350ml of Toluene and Isopropyl alcohol into 2nd fraction. Cool the mass to 15-25°C. Filter the product.
Yield: 115-120 g

Example 5:
Charge water (240ml), phosphoric acid (2.5gm) and Epichlorohydrin (93gm) maintain temp at 95°C for 45 min. Charge sodium hydroxide (45gm) and guaiacol (120gm) maintain at 102°C for 2hrs. Separate the Aqueous layer organic layer and distill the solvent. Charge recovered silicon oil (5 gm) to organic layer. Apply vaccum and raise the temperature at 120°C for 15 min, collect the 1st fraction. Raise the vapour temperature to below 170°C and collect the 2nd fraction (pure oil) 153 g, HPLC Purity 96.92%. Charge 350ml of Toluene and Isopropyl alcohol into 2nd fraction. Cool the mass to 15-25°C. Filter the product.
Yield: 110-113 g.

Purity of Guaifenesin obtained using/without using silicon oils is tabulated in Table I.
Table I:
Examples High vacuum distillation (HVD) Qty (g) Guaifenesin Purity
(by HPLC) Weight (g)
Example 1 Without Silicon oil 0 96.50 105-108
Example 2 With White oil 14.4 97.17 115-123
Example 3 With Silicon oil 10.0 98.00 115-120
Example 4 With recovered silicon oil 10.0 95.89 115-120
Example 5 With reduced silicon oil 5.0 96.92 110-113

While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are illustrative only of the core of the invention and non-limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.