FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Complete specification [See section 10 and rule 13]

1. Title of the invention
"Improved Processes for Manufacturing 4-Phenyl-l-Butanol"
2. Applicant (s)
1 Applicant Anlon Chemical Research Organization
Address 101/102-Silver Coin Complex, Opp. Crystal Mall, Kalawad Road, Rajkot 360005 (Gujarat), INDIA
3. Preamble to the Description:
The following specification particularly describes Invention and the manner in which it is to be performed
ABSTRACT:
The present invention relates to improved processes for the manufacture of 4-Phenyl-l-Butanol 1, a key starting material for drugs eg, Salmeterol, Pranlukast and their salts. The title compound is also used in flavours, perfumery and fragrances industry. The invention describes innovative use of a novel reducing agent eg, sodium borohydride in the presence of an acid eg, aluminum chloride, boron-trifluoride etherate, iodine or Cone. Sulfuric acid etc., for efficient conversion of carboxylic acids or esters to corresponding alcohols. The synthesis starts with readily available and inexpensive starting materials eg, benzene and ybutyro lactone, has less number of steps and is commercially viable. The . invention specifically defines the fingerprint of impurities of the title compound in GC, produced via these methods.

FIELD OF THE INVENTION
This invention relates to the field of Organic synthesis, bulk drugs and intermediates manufacturing and their use thereof. The invention describes improved processes for manufacturing of 4-Phenyl-l-Butanol.
Background of the Invention
Salmeterol 2 and Pranlukast 3 are the drugs currently being marketed for the treatment of asthma, chronic obstructive pulmonary disease (COPD) and for bronchospasm in asthma respectively. As the structure of 2 and 3 indicate, 4-phenyl-l-butanol 1 is the key starting material for both drugs. Literature refers the use of 1 for flavor, perfumery and fragrances etc. also.

The prior art searches for the synthesis of 4-phenyl-l-butanol provides various routes of synthesis (ROS). Some of the prominent and latest ROS are described in Scheme 1. ROS-1 describes the Friedel-Craft alkylation of 4-chlorobutanol 7 with benzene, in the presence of anhydrous aluminum chloride. (CN101450943, June 10, 2009) . However, it is a low yielding reaction, because the alcohol in 4-chlorobutanol may quench the reactivity of aluminum chloride. Similarly ROS-2 reports the Friedel
Craft Reaction of Y-butyrolactone 6. with benzene 5 and
subsequent reduction of carboxylic acid 8 to desired 4-phenyl-1-butanol 1. However, there is a possibility of formation of side products, a-tetralone, during Friedel-Craft step. The reduction of carboxylic acids to corresponding alcohols requires strong reducing agents eg, Lithium aluminum hydride, BH3:Et20 etc. For reduction with milder reducing agents eg, sodium borohydride, the reduction of ester 9 is reported in ROS-3 (Huadong Shifan Daxue Xuebao, 2003, 102-104 from East China Normal University, Shanghai). Alternatively, ROS-4 reports the Friedel-Craft reaction of benzene 5 with succinic anhydride to give keto-ester 11, which on exhaustive reduction gives 1^ (Guangzhou Huaxue 2005, 30, 31-34). One of the latest publication in JACS (ROS-5) reports chemo-selective reduction of amides L5 with samarium iodide in water, in the presence of amine (J. Am. Chem. Soc. 2014, 136, 2268-2271) for the preparation of 4-phenyl-l-butanol 1. Yet another catalytic chemo-selective, domino-hydroformylation and sequential reduction steps, using olefin 14 and carbon monoxide is reported in ROS-6 (Angew. Chem. International Ed. Engl. 2013, 52, 2949-2953) . The use of Grignard Reaction of benzyl Grignard 12 with trimethylene oxide 13 to get 1 is reported in ROS-7 (Science of Synthesis, 2004, 7 , 549-554 from Chiba University, Japan). Similarly hydrolysis of 4-phenyl-l-bromobutane 1() is reported in ROS-8 by Sumitomo (US 6,037,509). The synthesis of bromo-compound 1_0 itself involves multi-step synthesis of Friedel-Craft reaction with 4-bromobutyryl halides and subsequent chemo-selective hydrogenation with either palladium or platinum or ruthenium or Ni- Catalysts or their combination thereof.

As it is obvious from the prior art discussions, there is a need for improved processes, technologies for manufacture of 4-Phenyl-l-butanol 1. There are problems of low yield (ROS-1), multiple steps (ROS-1,3,4,5,8), need for anhydrous and costly reagents, raw materials (ROS-7), special organometallic catalysts under high pressure condition (ROS-6 & 8) or use of pyrophoric and highly moisture sensitive reagents eg, lithium aluminum hydride (ROS-3 & 4). The present invention reports an improved manufacturing process for 4-Phenyl-l-Butanol, which is scalable and commercially viable, just in two steps, from readily available raw materials eg. benzene 5 and Y-butyrolactone 6.
Summary of the Invention:
The present invention describes improved processes for the manufacture of 4-phenyl-l-butanol, a key starting material for drugs eg. Salmeterol and Pranlukast and as one of the additives in flavours, perfumery and fragrances. The invention also describes innovative use of sodium borohydride in the presence of a Lewis acid eg. A1C13, BF3:Et20 or cone. H2SO4, for efficient reduction of carboxylic acid/ esters to corresponding alcohol. A particularly preferred embodiment of present invention is the use of aluminium chloride with sodium borohydride, in the presence of 1,2-dimethoxy ethane, which accelerates the rate of reduction, thereby completing the reaction very fast, even on large scale. The invention specifically defines the impurity profile of title

compound in GC prepared via this method. The present invention is suitable for commercial production of 4-phenyl-1-butanol.
Description of the Invention:
The present invention encompasses improved processes for the manufacturing of 4-phenyl-l-butanol. The process comprises two step chemistry, starting from readily available starting materials, which are high yielding and scalable. The first step in the reaction involves Friedel Craft reaction between benzene 5 and Y-butyro lactone 6 in the presence of aluminium chloride (ROS 2, 3). In this step, benzene is used in large scale, which works as a reagent and as a solvent as well. The Lewis acid can be either anhydrous aluminium chloride or aluminium bromide. Preferably, aluminium chloride is used. The molar ratio of aluminium chloride to Y-butyro lactone can be 1.5:1 to 1.1:1. More specifically a ratio of 1.25:1 is used. The reaction is carried out with heating, for example between 30-85 °C and particularly between 50-70 °C. The reaction is completed between 10 min to 2 hours, more specifically between 30 minutes to 1 hour, depending on the molar ratio of aluminium chloride to ykutyro lactone, temperature and scale of reaction. The reaction mass is cooled and treated with large excess of methanol and thionyl chloride is slowly added to a warm 50-70 °C reaction mixture to get ester in the same reaction vessel in the same step.
After completion of the reaction, the reaction mass is treated with either large access of chilled water or water acidified with HC1, particularly at a temperature less then 40 °C and the mixture is stirred for 30 minutes. Slowly layer separation occurs. Alternatively, extraction of desired Methyl-4-phenyl butanoate 9a can be accomplished with ethyl acetate also. Addition of ethyl acetate accelerates layer separation. The methyl ester of 4-phenyl butanoic acid is extracted in organic layer and dried over anhydrous sodium sulfate. Removal of solvent and high vacuum distillation of crude mass gives Methyl-4-phenyl butanoate in high yield.
Alternatively, one can isolate carboxylic acid i.e 4-phenyl butanoic acid 8 separately and esterify with various alcohols eg, methanol, ethanol, isopropanol, benzyl alcohol etc to get the corresponding esters 9. The reduction of these esters 9; can as well give 4-phenyl-l-butanol 1 the title compound, as discussed in step-2.

The second step of the improved process involves novel reduction of methyl-4-phenyl butanoate to 4-phenyl butanol, by reaction with sodium borohydride in the presence of an acid' agent. The acid agent can be cone. H2S04, AlCl3 or AlBr3 or TiCl4. The reduction is also possible with other reducing agents eg, vitride and syn-hydride (CAS no. 22722-98-1) . The present invention more particularly reports the use of sodium borohydride with anhydrous aluminium chloride in presence of 1,2-dimethoxy ethane. To the chilled mixture prepared from 1,2-dimethoxy ethane and anhydrous aluminium chloride, sodium borohydride is added and to this, neat methyl-4-phenyl butanoate is added. The molar ratio of ester to sodium borohydride to anhydrous aluminium chloride is 1:0.4:0.1 to 1:1.5:1.5. Preferred ration is 1:0.5:0.2 to 1:1:0.7
The reaction is completed by heating between 40° to 60° C, more particularly between 50° to 55 °C. The duration of the reaction is dependent on the volume of 1,2-dimethoxy ethane, amount of anhydrous aluminium chloride, amount of sodium borohydride, speed of addition of methyl-4-phenyl butanoate, rate of heating and temperature of reaction mass. After completion of reaction, the work up is carried out by treating with either large excess of chilled water or cooled acidified water. The desired 4-phenyl-butan-1-ol is extracted in toluene and the organic layer is washed with dilute HC1. Subsequent washing of organic layer with water and/or brine and concentration leads to 85-95% pure 4-phenyl-l-butanol. The GC of this sample is attached in Annexure:l. (GC Column: Porapack Q, Length- 2 meter, I.D.- 6 mm, Injector Temperature: 250 °C, Detector Temperature: 250 °C, run time: 30 minutes). The RRT's (relative retention time) of impurities with this process are 0.69, 0.86, 1.01, 2.03, 2.16, where 4-phenyl butanol appears around 5.86 min. Subsequently, the crude 4-phenyl butanol was purified by distillation (at 120 °C under vacuum) to obtain >98% pure product (Annexure:2). (GC Column: BP-5, Length- 30 meter, I.D.-0.5mm, Film- 1 (im, Injector Temperature: 250 °C, Detector Temperature: 250 °C, run time: 30 minutes).
In the following, the present invention is illustrated by a number of examples, which are non-limiting, at provisional stage of application. These examples are non-optimized and only illustrative in nature and do not limit the scope and spirit of invention. It will be apparent for these skilled in the art that many obvious modifications, both to materials and methods, are possible, without departing from scope of the invention.

Experiment procedures for Methyl-4-phenyl-butanoate
Example 1:
In a 2 liter three neck flask equipped with rotary anchor agitation device are charged 500 ml of dry benzene and 233 g of anhydrous aluminium chloride (1.75 mol, 1.5 equiv) . The reaction mass is heated to 60-65 °C. To this heated solution, y-butyro lactone (100 g, 1.16 mol, 1 equiv) is added and the reaction mixture is further stirred at 60-65 °C for 30 minutes to 1 hour for completion of reaction. The progress of the reaction is monitored by TLC and consumption of ybutyro lactone is indicator of completion of reaction. The reaction mixture is cooled and 500 ml of methanol is added at room temperature. Slight exothermicity is observed. Subsequently, thionyl chloride (130 ml) is added to hot solution at around 60-65 °C till completion of reaction. The work up of reaction is carried out by quenching with acidic water (ice-cooled) and extraction of desired compound is done with ethyl acetate. The organic layer is separated, washed with dilute HC1 and dried over anhydrous sodium sulfate. Filteration, concentration and distillation of crude gives 170 gm of methyl-4-phenyl-butanoate (90% from GC) . (9a,, R=Me, Scheme-1) .
Example 2:
In a 2 liter three neck flask equipped with rotary anchor agitation device, under N2 atmosphere, is charged 500 ml of dry benzene and 185 g (1.39 mol, 1.2 equiv) of anhydrous aluminium chloride. The reaction mass is heated to 60-65 °C. To this heated solution, y_butyro lactone (100 g, 1.16 mol) is added and the reaction mixture is further stirred at 60-65 °C for 30 minutes to 1 hour for completion of the reaction. The reaction mixture is cooled and 300 ml of methanol is added at room temperature. Slight exothermicity is observed. Subsequently, thionyl chloride (130 ml) is added to dropwise and stirred at 60-65 °C. After completion of the reaction, quench the reaction mixture with acidic water (ice-cooled) and extract with ethyl acetate. The organic layer is separated, washed with water and dried over anhydrous sodium sulfate. Filtration, concentration and distillation of crude gives 161 gm of pure methyl-4-phenyl-butanoate. (S)a, R=Me, Scheme-1) .

Example 3:
In a 100 mL flask, charged with 50 ml of dry benzene, was added anhydrous AlBr3 (46.3 gm, 0.17 mol) under nitrogen atmosphere at room temperature. Heat the reaction mass to 50-55 °C and y-butyro lactone (10 g, 0.11 mol) was added dropwise over the period of 15-20 min. Continue stirring at 50-55 °C until completion of the reaction. Then reaction mixture is cooled to room temperature and added 50 ml of methanol. Subsequently, thionyl chloride (25 ml) is added and heated the reaction mixture to 60-65 °C. Upon completion, add dilute aqueous solution of hydrochloric acid to the reaction mixture and extract with ethyl acetate. The organic layer is separated, washed with water and dried over anhydrous sodium sulfate. Concentration under vacuum and distillation of crude gives 13 gm of pure methyl-4-phenyl-butanoate. (9a, R=Me, Scheme-1).
Example 4:
In a 100 mL flask containing 40 ml of dry benzene, was added anhydrous FeCl3 (19.6 gm, 0.12 mol) at room temperature. Heat the reaction mass to 50-55 °C and y-butyro lactone (10 g, 0.11 mol) was added dropwise over the period of 15-20 min. Heat the reaction mixture to 80-85 and continue stirring at the same temperature. Upon completion, cool the reaction mixture to room temperature and add 45 ml of methanol. Subsequently, thionyl chloride (25 ml) is added and heated the reaction mixture to 60-65 °C. After completion of the reaction pour the reaction mixture in IN HC1 and extract with ethyl acetate. The organic layer is separated, washed with water and dried over anhydrous sodium sulfate. Concentration under vacuum and distillation of crude gives 12.5 gm of pure methyl-4-phenyl-butanoate. (9a, R=Me, Scheme-1).
Example 5:
In a 1 liter three neck flask equipped with rotary anchor agitation device is charged 250 ml of dry benzene and 116 g of anhydrous aluminium chloride (0.87 mol). The reaction mass is heated to 60-65 °C. To this heated solution, yfrutyro lactone (50 g, 0.58 mol) is added and the reaction mixture is further stirred at 60-65 °C for 1 hour. After completion, the reaction mixture is cooled to room temperature, poured in acidic water and extracted with ethyl acetate. The organic layer is washed with water dried over sodium sulfate and evaporated under vacuum to get crude 4-phenyl butyric acid. Dissolve this 4-phenyl butyric acid in methanol (200 ml) at room

temperature and add thionyl chloride (60 ml) dropwise. Heat the reaction mixture around 60-65 °C till completion of reaction. Distil out volatile solvents under vacuum. Add water and extract with ethyl acetate. Wash organic layer with saturated NaHC03 solution. Removal of ethyl acetate under vacuum gives 88 gm of methyl-4-phenyl-butanoate.(9a, R=Me, Scheme-1).
Experimental procedures for 4-phenyl-l-butanol
Example 6:
Methyl-4-phenyl butanoate 9a{70 g, 0.39 mol, from example 1) is added to a chilled solution of 1,2-dimethoxy ethane (350 ml), anhydrous aluminium chloride (30 g, 0.22 mol) and sodium borohydride (18.5 g, 0.5 mol). The reaction mass is heated to 50-60 °C until completion. Cool the reaction mixture, add acidified water and extracted with toluene. The organic layer was washed with acidified water, water and brine. Concentration of toluene layer gives 90% GC pure 4-phenyl-l-butanol.
Example 7:
In a 250 ml flask containing Methyl-4-phenyl butanoate 9_a(20 g, 0.11 mol, from example 1) was added dropwise to a chilled solution of 1,2-dimethoxy ethane (80 ml), anhydrous aluminium chloride (4.87 gm, 0.036 mol) and sodium borohydride (4.07, 0.11 mol). Heat the reaction mass to 50-60 °C. After completion cool the reaction mixture to room temperature and IN HC1 was added. Extract the aqueous layer with toluene. The organic layer was washed with water and brine. Concentration of toluene layer gives 4-phenyl-l-butanol in 56% of yield.
Example 8:
Dissolve Methyl-4-phenyl butanoate 9a (50 g, 0.28 mol, from example 1) in methanol (200 ml) . Coo the reaction mixture to 5-10 °C. Add sodium borohydride (15.5 gm, 0.42 mol) in small portions over 30 min. Slowly warm the reaction mixture to room temperature and then 50-60 °C. Upon completion, pour the reaction mixture in acidic water and extract with ethyl acetate. The organic layer was washed with water and brine. Removal of toluene under vacuum gives 4-phenyl-l-butanol in 49% of yield.

Example 9:
A mixture of sodium borohydride (3.11 gm, 0.08 mol), cone. H2SO4 (0.54 gm, 0.0056 mol) and 1,2-dimethoxy ethane (50 ml) was added solution of Methyl-4-phenyl butanoate 9a (10 g, 0.056 mol, from example 1) in 1,2-dimethoxy ethane dropwise, at 0-5 °C, over 30 min. Heat the reaction mixture to 40-50 °C. After completion, pour the reaction mixture in water and extracted with toluene. The organic layer was washed with brine and dried over sodium sulphate. Removal of toluene under vacuum gives 34% of 4-phenyl-1-butanol.
Claims:
1. We claim a product 4-phenyl butanol, with specific impurity profile.
2. A product 4-phenyl butanol with GC impurities (GC Column: Porapack Q, Length- 2 meter, I.D.- 6 mm, Injector Temperature: 250 °C, Detector Temperature: 250 °C, Run Time: 30 minutes at 0.69, 0.86, 1.01, 2.03, 2.16 RRT's where 4-phenyl butanol appears at 5.86 minutes and/or within vicinity of 5-6 minutes.
3. A process for manufacturing 4-phenyl butanol from alkyl 4-phenyl butanoate.
4. A process for manufacturing 4-phenyl butanol from methyl-4-phenyl butanoate, by catalytic reduction.
5. A process as per claim 4, where the catalytic reduction comprises sodium borohydride in the presence of acids.
6. A process, as per claim 5, where acids are either Lewis acids or protic acids.
7. A process, as per claim 6, where Lewis acid is AICI3 and/or AlBr3 or BF3.OET2
8. A process, as per claim 6, where protic acid is cone. H2S04.
9. A process, as per claim 7, where molar ratio of methyl 4-phenyl butanoate to NaBH4 to A1C13 is 1:0.4:0.1 to 1:1.5:1.5.
10. A preferred process, as per claim 7, 1:0.5:0.2 to 1:1:0.7.
11. A process, as per claim 7, where 1,2-Dimethoxy ethane is an additive for catalytic reduction.
12. A process, as per claim 7, where temperature range is 40 to 60 °C.