DESC:The following specification particularly describes the invention and the manner in which it is to be performed.
PROCESS FOR PREPARATION OF N-METHYLHEX-5-EN-1-AMINE AND ITS SALTS

INTRODUCTION
The invention relates to improved processes for the preparation of N-methylhex-5-en-1-amine and its salts. The said compound is an intermediate in HCV compounds like Simeprevir.

BACKGROUND
The drug compound having the adopted name “Simeprevir” having the chemical name (2R,3aR,10Z,11aS,12aR,14aR)-N-(cyclopropylsulfonyl)-2[[2-(4-isopropyl-1,3-thiazol-2-yl)-7-methoxy-8-methyl-4-quinolinyl]oxy]-5-methyl-4,14 dioxo2,3,3a, 4,5,6,7,8,9, 11a,12,13,14,14atetradecahydrocyclopenta [c] cyclopropa [g] [1,6] diazacyclotetradecine-12a(1H)-carboxamide and Formula I has been developed by Janssen and Medivir for the treatment of HCV infection in adults.


Formula I

Compound of formula II or its salts is a key intermediate in the preparation of Simeprevir.

Formula II
US patents viz., US8148399, US8212043, US8927722, US20130005976A1 and US20140228574A1 reported processes for preparation of Simeprevir or its intermediates.
US8148399 and Bioorganic & Medicinal Chemistry, 15(22), 7184-7202; 2007 reported methods for preparation of compound of Formula II.
The methods reported in prior art suffer from various drawbacks like the use of sodium hydride, use of protecting groups, longer reaction times, need of vacuum distillation for purification, inferior quality products etc. Ease of operation, high quality and yield are the pre-requisites for any preferred process in the pharmaceutical industry. Thus there remains a need for commercially viable process for preparation of compound of Formula II or its salts while overcoming the drawbacks presented by the processes described in the art.
We herein disclose an improved process for the preparation of compound of Formula II and its salts, specifically p-tosylate salt of Formula II. The processes of the present invention are advantageous in that they are suitable for large scale production, avoid the use of protecting groups and alleviate the requirement for strong bases. Further, cumbersome purification steps, in particular by chromatography, are avoided.
The quality of starting material plays an important role in the preparation of active pharmaceutical ingredient. Therefore, the use of p-tosylate salt of compound of Formula II prepared according to the present invention for preparation of a compound of Formula I is highly advantageous as it results in high yield and better purity, of compound of Formula I.

SUMMARY
In the first embodiment, the present application provides a process for preparing a compound of Formula II or a compound of Formula IIa, comprising
a) reacting a compound of Formula IV with a sulfonating agent of Formula V to afford a compound of Formula III,

Formula IV Formula V Formula III

R1= leaving group;
R2 = C1-C6 alkyl, C3-C7 cycloalkyl, or phenyl substituted with R4; where R4 = -H, -Cl, -Br, -F, -NO2, alkyl, cycloalkyl, or -OR5; and where R5= C1-C6 alkyl or C3-C7 cycloalkyl.
b) reacting the compound of Formula III with methyl amine to afford a compound of Formula II,


Formula II
c) converting the compound of Formula II into a salt of Formula IIa.

Formula IIa
d) optionally, generating the compound of Formula II by basification of the compound of Formula IIa.
e) isolating the compound of Formula II or the compound of Formula IIa.

In the second embodiment, the present application provides a process for preparing a compound of Formula II or a salt thereof, comprising;
a) reacting a compound of Formula VI with methyl amine to afford a compound of Formula II,


Formula VI Formula II

Where X is halogen
b) converting the compound of Formula II into a salt of Formula IIa.

Formula IIa
c) optionally, generating the compound of Formula II by basification of the compound of Formula IIa.
d) isolating the compound of Formula II or the compound of Formula IIa.
In the third embodiment, the present application provides a process for the preparation of Simeprevir of Formula I from a compound of Formula II or a compound of Formula IIa.

Formula II Formula IIa

DETAILED DESCRIPTION
In the first embodiment, the present application provides a process for preparing a compound of Formula II or a compound of Formula IIa, comprising
a) reacting a compound of Formula IV with a sulfonating agent of Formula V to afford a compound of Formula III,

Formula IV Formula V Formula III

R1= leaving group such as -Cl, -Br, or -F;
R2 = C1-C6 alkyl, C3-C7 cycloalkyl, or phenyl substituted with R4; where R4 = -H, -Cl, -Br, -F, -NO2, alkyl, cycloalkyl, or -OR5; and where R5= C1-C6 alkyl or C3-C7 cycloalkyl.
Step a) is materialized in presence of a suitable base and a suitable solvent.
Suitable solvents that can be used comprise esters such as ethyl acetate, isopropyl acetate, ketones such as acetone, methyl ethyl ketone (MEK), methyl iso-butyl ketone (MIBK), halogenated hydrocarbons such as dichloromethane (DCM) or chloroform, ethers such as methyl tert-butyl ether (MTBE), tetrahydrofuran (THF) or 2-methyltetrahydrofuran (MeTHF), hydrocarbon solvents such as toluene or xylene, dipolar aprotic solvents such as DMF, DMA, acetonitrile, pyridine or mixtures thereof. Preferred solvents are MTBE, toluene, acetone, acetonitrile, ethyl acetate or mixtures thereof.
Suitable bases that can be employed in step a) include but are not limited to: tertiary organic bases such as triethylamine, ethyl di-isopropylamine, N-methyl Morpholine, DABCO (1,4-diazabicyclo[2.2.2]octane), pyridine, N-methylimidazole and the like; and inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like. In a preferred embodiment, an organic base such as triethylamine is employed.
The reaction may also be conducted in the presence of a base catalyst, e.g. 4-dimethylaminopyridine (DMAP).
Suitable temperatures for conducting the reaction range from about 0°C to 40oC.
b) reacting the compound of Formula III with methyl amine to afford a compound of Formula II,


Formula II
The said step involves treatment of compound of the Formula III with a solution of methyl amine in an appropriate solvent (e.g. ethanol or methanol), or directly with gaseous methylamine in a pressure vessel. The said step can be materialized either by providing an isolated compound of Formula III in a suitable solvent followed by treatment with methyl amine or alternatively mixture may be obtained by a previous step of reaction between compound of Formula IV with compound of Formula V.
Suitable solvents that can be employed in step b) will generally be inert to the reaction conditions. In a preferred embodiment, MTBE is employed.
Optionally, the steps (a) and (b) can be carried out in one pot.
c) converting the compound of Formula II into a salt of Formula IIa.

Formula IIa

This step can be materialized by addition of a suitable acid to the mixture of step b). The free acid can be directly added as solid/liquid or its mixture in a solvent. Alternatively, acid can be R2 moiety and can optionally come from previous step b) itself, which involved removal of leaving group from compound of Formula III by reaction with methyl amine. Suitable inert solvents can be selected from the list mentioned for step a). In a preferred embodiment, MEK is employed.
A suitable acid that can be employed in step c) is a mineral or organic acid. Suitable mineral acids for salt formation include hydrochloric, hydrobromic, hydroiodic, nitric, and sulphuric acid. Suitable organic acids include organic achiral acids such as para-toluenesulfonic acid, acetic, trifluoroacetic, oxalic, succinic acid and formic acid. Preferably, organic acid is employed and more preferably, para-toluene sulfonic acid is employed.
Non-dissolved particles from a mixture of step c) can be removed suitably by filtration, centrifugation, decantation, or other techniques, such as passing the solution through paper, glass fiber, a particulate bed, or a membrane material.
The acids are employed in salt preparation-depending on whether a mono- or polybasic acid is concerned and depending on which salt is desired in an equimolar quantitative ratio or one differing therefrom.
The reaction can be efficiently completed at room temperature or ambient temperature or if required reaction mass can be heated to elevated temperatures or up to about the reflux temperatures, and maintained for a time from about 10 minutes to about 5 hours or longer. Suitable temperatures for crystallization are from about 0°C to about 50°C, from about 10 to about 30°C, or any other suitable temperatures may be used. Suitable times for crystallization will vary, and can be from about 10 minutes to about 10 hours, or longer.
In one variant of the first embodiment, the steps (a) to (c) can be carried out in one pot.
d) optionally, generating the compound of Formula II by basification of the compound of Formula IIa.
The said step involves basification of compound of Formula IIa to generate free base of Formula II. Suitable bases that can be employed in this step include but not limited to inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like; and organic bases such as triethylamine, ethyl di-isopropylamine, N-methyl Morpholine, DABCO (1,4-diazabicyclo[2.2.2]octane), pyridine, N-methylimidazole and the like. In a preferred embodiment, an inorganic base such as sodium hydroxide is employed.
e) isolating the compound of Formula II or the compound of Formula IIa.
The isolation of compound in step e) is done by conventional techniques known in the art. For example, useful techniques include, but are not limited to, decantation, filtration, concentrating, rotational drying, spray drying, thin-film drying, freeze-drying, and the like. The isolation may be optionally carried out at atmospheric pressure or under a reduced pressure. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher than desired percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor. Evaporation as used herein refers to distilling a solvent completely, or almost completely, at atmospheric pressure or under a reduced pressure. Flash evaporation as used herein refers to distilling of solvent using techniques including, but not limited to, tray drying, spray drying, fluidized bed drying, or thin-film drying, under atmospheric or a reduced pressure.
Isolated product can be optionally further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, Büchi® Rotavapor®, air oven, fluidized bed dryer, spin flash dryer, flash dryer, cone dryer, agitated nutsche filter cum dryer, nauta dryer or the like or any other suitable dryer. The drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 150°C, less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, or any other suitable temperatures. The drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.
The dried product can be optionally milled to get desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller, hammer mills and jet mills.
In an aspect of the first embodiment comprises a process for preparation of the compound of Formula II or IIa wherein one or more intermediate compounds may not be isolated and used in organic solution itself for the next step. For example, a compound of Formula IV can be reacted with a compound of Formula V to give a compound of Formula III which optionally without isolation on reaction with methyl amine would afford a compound of Formula II which optionally without isolation on subsequent reaction with a suitable acid results in a compound of Formula IIa. In a preferred embodiment, the compound of Formula IIa obtained by such process is N-methylhex-5-en-1-amine-p- toluenesulfonate salt.
In another aspect of the first embodiment, the compound of Formula IIa is obtained in a single step by reaction of the compound of Formula III with methyl amine.
Optionally one or more steps of the first embodiment can be carried out in one pot.
In the second embodiment, the present application provides a process for preparing a compound of Formula II or a salt thereof, comprising;
a) reacting a compound of Formula VI with methyl amine to afford a compound of Formula II,


Formula VI Formula II

Where X is halogen selected from chloro, bromo, fluoro, iodo.
The said step can be carried out under the conditions described above.
b) converting the compound of Formula II into a salt of Formula IIa.

Formula IIa
A suitable acid that can be used in step b) is a mineral or organic acid and can be selected from the list described in aforementioned aspect of present application. In a preferred embodiment, para-toluene sulfonic acid is employed. In one variant of the first embodiment, the steps (a) and (b) can be carried out in one pot.
c) optionally, generating compound of Formula II by basification of Formula IIa.
The said step involves basification of the compound of Formula IIa to generate the free base of Formula II. Suitable bases that can be employed in this step can be selected from the list described in aforementioned aspect of present application.
d) isolating the compound of Formula II or the compound of Formula IIa.
Compound of Formula II or Formula IIa, can be isolated by conventional methods provided in the application like by evaporation of solvent, by addition of suitable anti-solvent or by combination of both etc.
In the third embodiment, the present application provides a process for the preparation of Simeprevir of Formula I from a compound of Formula II or Formula IIa.

Formula IIa Formula II

For example compound of Formula II can be converted to Simeprevir of Formula I by the methods known in the art. Methods known in US8148399, US8212043, US8927722, and US20130005976A1 are incorporated herein by reference in their entirety.
The chemical transformations described throughout the specification may be carried out using substantially stoichiometric amounts of reactants, though certain reactions may benefit from using an excess of one or more of the reactants. Additionally, many of the reactions disclosed throughout the specification, may be carried out at room temperature, but particular reactions may require the use of higher or lower temperatures, depending on reaction kinetics, yields, and the like.
Room temperature as used herein refers to ‘the temperatures of the thing close to or same as that of the space, e.g., the room or fume hood, in which the thing is located’. Typically, room temperature can be from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.
The reactions of the processes described herein can be carried out in air or under an inert atmosphere. Typically, reactions containing reagents or products that are substantially reactive with air can be carried out using air-sensitive synthetic techniques that are well known to the person skilled in art.
Some of the stages may benefit from being conducted in pressurized, sealed vessels to prevent loss of gaseous reagents. Furthermore, many of the chemical transformations may employ one or more compatible solvents, which may influence the reaction rates and yields. Depending on the nature of the reactants, one or more solvents may be polar protic solvents, polar aprotic solvents, non-polar solvents, or any of their combinations.
The compounds obtained by the chemical transformations of the present application can be used for subsequent steps without further purification, or can be effectively separated and purified by employing a conventional method well known to those skilled in the art, such as recrystallization, column chromatography, by transforming them into a salt, or by washing with an organic solvent or with an aqueous solution, and eventually adjusting pH. Compounds at various stages of the process may be purified by precipitation or slurrying in suitable solvents, or by commonly known recrystallization techniques. The suitable recrystallization techniques include, but are not limited to, steps of concentrating, cooling, stirring, or shaking a solution containing the compound, combination of a solution containing a compound with an anti-solvent, seeding, partial removal of the solvent, or combinations thereof, evaporation, flash evaporation, or the like. An anti-solvent as used herein refers to a liquid in which a compound is poorly soluble. Compounds can be subjected to any of the purification techniques more than one time, until the desired purity is attained.
Compounds may also be purified by slurrying in suitable solvents, for example, by providing a compound in a suitable solvent, if required heating the resulting mixture to higher temperatures, subsequent cooling, and recovery of a compound having a high purity. Optionally, precipitation or crystallization at any of the above steps can be initiated by seeding of the reaction mixture with a small quantity of the desired product. Suitable solvents that can be employed for recrystallization or slurrying include, but are not limited to: alcohols, such as, for example, methanol, ethanol, and 2-propanol; ethers, such as, for example, diisopropyl ether, methyl tert-butyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran (THF), and methyl THF; esters, such as, for example, ethyl acetate, isopropyl acetate, and t-butyl acetate; ketones, such as acetone and methyl isobutyl ketone; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, and the like; hydrocarbons, such as toluene, xylene, and cyclohexane; nitriles, such as acetonitrile and the like; water; and any mixtures of two or more thereof.
Compound of Formula II or compound of IIa manufactured by the present invention is substantially free from impurities. Typically, the level of impurities may be less than about 2%, 1% or 0.5%, by weight, as determined by using high performance liquid chromatography (HPLC).
DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise. Terms such as "about," "generally," "substantially," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify, as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error, or instrument error for a given technique used to measure a value.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, the terms “comprising” and “comprises” mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
The term “optional” or “optionally” is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.
The term “halogen”, include chlorine, bromine, fluorine and iodine.
Unless specified otherwise, the word "pure" as used herein means that the material is at least about 99% pure. In general, this refers to purity with regard to unwanted residual solvents, reaction by-products, impurities, and unreacted starting materials. "Substantially pure" as used herein means at least about 98% pure and, likewise, "essentially pure" as used herein means at least about 95% pure.
"Substantially free of one or more of its corresponding impurities" as used herein, unless otherwise defined refers to the compound that contains less than about 2%, or less than about 1 %, or less than about 0.5%, or less than about 0.3%, or less than about 0.2%, or less than about 0.1 %, or less than about 0.05%, or less than about 0.03%, or less than about 0.01 %, by weight, of each individual.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner.

EXAMPLES
EXAMPLE 1: PREPARATION OF HEX-5-EN-1-YL METHANESULFONATE (FORMULA III)
A flask is charged with hexenol (100g), methyl tert-butyl ether (400 mL) and stirred for clear solution. Then methanesulfonyl chloride (79 mL) is added and the mixture is cooled to about 7oC. Then triethylamine (155 mL) is slowly added to this mixture over a period of 45 minutes, maintaining the temperature of the reaction mixture below 30oC. The reaction mixture is stirred for further 30 minutes and then quenched with water (200 mL). The layers are separated and the aqueous layer is extracted with MTBE (200 mL). The organic layers are combined and washed with water (200 mL) and brine solution (100 mL) to afford the title compound as a solution in MTBE which is used for the next step.

EXAMPLE 2: PREPARATION OF N-METHYLHEX-5-EN-1-AMINE-p-TOSYLATE (FORMULA IIa)
A flask is charged with a solution of methylamine in ethanol (750 mL, 33%wt). This solution is added to the MTBE solution of hex-5-en-1-yl methanesulfonate obtained under Example 1. The resulting mixture is heated to reflux at about 60oC and maintained at this temperature for 18 hours. After completion of the reaction as monitored by TLC or GC, the mixture is cooled to ambient temperature and subjected to complete distillation under vacuum. The resulting mass is suspended in MTBE (800 mL) and washed with 2M sodium hydroxide solution (2x500 mL) to give a clear mixture followed by addition of p-toluenesulfonic acid monohydrate (190.2 g) to afford a biphasic mixture. The mixture was concentrated under vacuum and resulting residue is treated with methyl ethyl ketone (300 mL) and again subjected to complete distillation. This operation is repeated additionally for 3 times. Then resulting residue is suspended in MEK (600 mL) and stirred overnight at 21oC. The slurry is then cooled in an ice-bath and stirred for 1 hour followed by isolation of solid by filtration, washing of solid with cold MEK (~50 mL) and then drying of solid under vacuum at 40oC for 24 hours to afford the title compound as a pale yellow solid in 48% overall yield (starting from hexenol).

EXAMPLE 3: PREPARATION OF HEX-5-EN-1-YL p-TOLUENESULFONATE (FORMULA III)
A flask is charged with hexenol (20g), methyl tert-butyl ether (200 mL) and p-toluenesulfonyl chloride (40 g) and the mixture is stirred until a clear solution is obtained. The mixture is cooled to about 7oC, and then triethylamine (30 mL) is added followed by 4-dimethylaminopyridine (70 mg). The mixture is warmed to ambient temperature (21°C) and stirred for approximately 72 hours. Additional triethylamine (10 ml) is added and then the mixture is warmed to 40°C. After 45 min, additional p-toluenesulfonyl chloride (1 g) and MTBE (50 ml) are added, and after 15 min a further portion of p-toluenesulfonyl chloride (1 g) is added. After a further 45 min, more 4-dimethylaminopyridine (50 mg) is added and the reaction is left for a further 1h. Water (200 ml) is added and after stirring for 10 minutes the phases are separated to give a solution of the product in MTBE that is used directly in the next stage.

EXAMPLE 4: PREPARATION OF N-METHYLHEX-5-EN-1-AMINE-p- TOLUENESULFONATE (FORMULA IIa)
The solution of hex-5-en-1-yl p-toluenesulfonate in MTBE prepared in example 3 is charged to a suitable flask and warmed to 50°C. A solution of methylamine in ethanol (200 mL, 33%wt) is added and the resulting mixture is heated to reflux at about 60oC and maintained at this temperature for 18 hours. After completion of the reaction as monitored by TLC or GC, the mixture is cooled to ambient temperature to give a thick slurry. The precipitated solid (methylamine p-toluenesulfonate salt) is removed by filtration and discarded. The filtrate is concentrated to remove volatile solvents (pressure 100 mbar, temperature 45°C) and then MEK (200 mL) and p-toluenesulfonic acid monohydrate (20 g) are added to afford a clear yellow solution. The mixture was concentrated under vacuum and resulting residue is treated with methyl ethyl ketone (200 mL) to give thick slurry. This slurry was stirred at 21°C for 18 hours followed by isolation of solid by filtration, washing of solid with cold MEK (~50 mL) and then drying of solid under vacuum at 40oC for 24 hours to afford the title compound as a pale yellow solid.

EXAMPLE 5: PREPARATION OF N-METHYLHEX-5-EN-1-AMINE-p- TOLUENESULFONATE (FORMULA IIa)
A flask is charged with a solution of 1-bromohex-5-ene (2 g; 12.3 mmol) in MTBE (30 mL) and to it a solution of methylamine in ethanol (33 wt%, 20 mL; 160 mmol) is added and the resulting mixture is heated to a gentle reflux (internal temperature ~55°C) under nitrogen. The mixture is maintained at the same temperature for 5 hours and then cooled to 40°C and further maintained for 72 hours. The mixture is then cooled to ambient temperature, and is washed with water (2 x 30 mL). The layers are separated and the aqueous layer is back extracted with MTBE (30 mL). The combined MTBE layers are washed with water (10 mL), filtered through a pad of MgSO4 and concentrated under vacuum at 40°C to give a pale yellow liquid. Then p-toluenesulfonic acid monohydrate (2.5 g) is added and the mixture is concentrated to dryness. Then, acetone (10 mL) is added and the mixture is again concentrated to dryness. The residue obtained is dissolved in acetone (10 mL) and left at 21°C for 18 hours, during which time a solid precipitated. The slurry is stirred in an ice-bath (~5°C) for 2 hours and then the solid is isolated by filtration, washed with minimal cold acetone (~10 mL) and MTBE (~10 mL). The solid is then dried on the filter under suction to give the desired product (940 mg) as a pale yellow solid.
,CLAIMS:We Claim

Claim 1: A process for preparing compound of Formula II or a compound of Formula IIa, comprising;

Formula II Formula IIa

a) reacting a compound of Formula IV with a sulfonating agent of Formula V to afford a compound of Formula III,

Formula IV Formula V Formula III

R1= leaving group;
R2 = C1-C6 alkyl, C3-C7 cycloalkyl, or phenyl substituted with R4; where R4 = -H, -Cl, -Br, -F, -NO2, alkyl, cycloalkyl, or -OR5; and where R5= C1-C6 alkyl or C3-C7 cycloalkyl.
b) reacting the compound of Formula III with methyl amine to afford a compound of Formula II,

Formula II
c) converting the compound of Formula II into a compound of Formula IIa,

Formula IIa
d) optionally, generating the compound of Formula II by basification of compound of Formula IIa,
e) isolating the compound of Formula II or Formula IIa.

Claim 2: The process of claim 1, wherein R2 in step a) is selected from methanesulfonyl, p-toluenesulfonyl and p-bromobenzenesulfonyl.

Claim 3: The process of claim 1, wherein R1 in step a) is selected from chloro, bromo and iodo.

Claim 4: The process of claim 1, wherein suitable solvent in step a) comprises ethers, hydrocarbons, halogenated hydrocarbons, ketones, esters or mixtures thereof.

Claim 5: The process of claim 1, wherein steps a) to c) are carried out in one pot.

Claim 6: The process of claim 1, wherein HX in Formula IIa is p-toluenesulfonic acid.

Claim 7: A process for preparing a compound of Formula II or a compound of Formula IIa, comprising;

Formula II
a) reacting a compound of Formula VI with methyl amine to afford a compound of Formula II,


Formula VI Formula II

Where X is halogen
b) converting the compound of Formula II into a compound of Formula IIa.

Formula IIa
c) optionally, generating the compound of Formula II by basification of the compound of Formula IIa.
d) isolating the compound of Formula II or Formula IIa.

Claim 8: The process of claim 7, wherein X in Formula VI is bromo.

Claim 9: The process of claim 8, wherein suitable solvent in step a) comprises ethers, hydrocarbons, halogenated hydrocarbons, ketones, esters or mixtures thereof.

Claim 10: A process for preparation of Simeprevir of Formula I, from a compound of Formula II or a compound of Formula IIa prepared according to any of the claims 1-9.

Formula I