Technical Field of the Invention:
The present invention relates to a novel process of making an antiretroviral drug, particularly, to a non-nucleoside reverse transcriptase inhibitor used for treating Acquired Immuno Deficiency Syndrome (AIDS) caused by Human Immunodeficiency Virus (HIV). More specifically, the present invention relates to a process for preparation of substituted ll-Cyclopropyl-5,ll-dihydro-4-methyl-6H-dipyrido[3, 2-b:2', 3'-e][l,4]diazepin-6-one and certain novel picoline derivatives thereof
Background of the Invention:
Acquired immunodeficiency syndrome (AIDS) is caused by Human immunodeficiency virus, and the most virulent strain of HIV is HIV-1.
HIV bemg a retrovirus and its genetic material being RNA, the RNA is converted to DNA in the host by the enzyme reverse transcriptase. Therefore inhibiting the enzyme reverse transcriptase is found to inhibit progress and replication of HIV-1.
Nevirapine is a very important non-nucleoside reverse inhibitor.
11 -Cyclopropyl-5,11 -dihydro-4-methyl-6H-dipyrido[3,2-b:2',3 '-e] [ 1,4]diazepin-6-one, commonly known as nevirapine was first disclosed in Hargrave, Karl D. et al., "Novel Non-Nucleoside Inhibitors of HIV- 1 Reverse Transcriptase. 1. Tricyclic Pyridobenzo-and Dipyridodiazepines", J. Med. Chem, 1991, 34, 2231-2241.
US 5,366,972 issued to Hargrave et al discloses 11-Cyclopropyl-5,11-dihydro-4-methy 1-6H-dipyrido[3,2-b:2',3'-e][l,4]diazepin-6-one and teaches a number of methods to make nevirapine.
In the method generally known from US 5,366,972,2-chloronicotinoyl chloride is formed
by treating 2-chloronicotinic acid with thionyl chloride which is later reacted with 2-
chloro-4-methyl-3-pyridinamine to produce 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-
3-pyridinecarboxamide. This is treated with cyclopropylamine to give N-(2-chloro-4-
methyl-3-pyridinyl)-2-(cyclopropylamino)-3-pyridinecarboxamide. The said N-(2-chloro-
4-methyl-3-pyridinyl)-2-(cyclopropylamino)-3-pyridinecarboxamide undergoes

cyclization to produce nevirapine, which occurs on treatment of the final intermediate with a strong base like sodium hydride.
The said process takes place at elevated temperatures and the reaction being an exothermic reaction results in a highly volatile reaction. Also, it is required to control the. reaction temperature to about 145o C, above which the reaction becomes unstable presenting the possibility of explosion. Maintaining an exothermic reaction at the desired temperature of 145o C is difficult and poses risk. The taught method also uses large amount of cyclopropylamine.
Kelly et al in US 5,532,358 teaches another method of making nevirapine. US 5, 532,358 overcomes the disadvantages of using large amount of expensive cyclopropylamine by using a neutralizing agent such as Zinc Oxide. But the major disadvantage of this prior art is the use of heavy metal bases like n-butyllithium (nBuLi) during reaction. Also, the initial reaction takes place at a temperature between about -78° C and -10° C which makes it all the more difficult.
Schneider et al in US 5,569,760 discloses an improved method for preparing nevirapine wherein the reaction of 2-chloro-N-(2-chloro-4-methyl-3"pyridyl)-3-pyridinecarboxamide with cyclopropylamine is carried out in the presence of an oxide or hydroxide of an element of the second group of the periodic table and diglyme as a reaction solvent which results in saving of cyclopropylamine. The solvent may be recovered by distillation and used for a new reaction sequence.
Further, N-(2"chloro-4-methyl-3-pyridyl)-2-(cyclopropylamino)-3-pyridinecarboxamide, thus formed is not isolated but is converted after removal of the inorganic base to nevirapine. The major drawback of the taught method is the likelihood of formation of impurities that may be difficult to remove.
Most of the methods known in the art result in lower yield, say around 25%.
Therefore, there is a dire need to develop a new process for the preparation of nevirapine that overcomes the disadvantages of the prior art.

Objects of the Invention:
It is an object of the invention to develop a novel method of preparing nevirapine.
It is another important object of the invention to develop an efficient process for making nevirapine.
It is yet another important object of the invention to develop a safe and simple process of making nevirapine.
It is yet another important object of the invention to develop novel picoline derivatives.
Summary of the Invention:
Accordingly, to meet the stated objectives and overcome the disadvantages of the prior art, a process of making a compound of the formula I,

to yield compound (b) of the formula

wherein, Rl is a linear, branched or cyclic hydrocarbon of one to eight carbon atoms optionally substituted with one or more electron stabilizing groups;
X1 is a halogen selected from the group consisting of fluorine, chlorine, bromine and iodine;
X is a halogen selected from the group consisting of fluorine, chlorine, bromine and iodine;
X2 is a halogen selected from the group consisting of fluorine, chlorine, bromine and iodine;
X3 is a halogen selected from the group consisting of fluorine, chlorine, bromine and , iodine is described herein.
Also, the invention provides certain novel picoline derivatives such as.


X1 is a halogen selected from a group consisting of fluorine, chlorine, bromine and* iodine, preferably chlorine or bromine, most preferably bromine;
Rl is a linear, branched or cyclic hydrocarbon of one to eight carbon atoms, preferably R1 is a linear hydrocarbon of from one to four carbon atoms, most preferably R1 is methyl or ethyl, optionally substituted with one or more electron stabilizing groups selected from a list comprising of C6-C10 aryl, C1-C8 carboalkoxy,C1-C10 acyl (derived from aromatic or alkyl carboxylic acids), C1-C8 alkoxy, C1-Cg8 alkyl, C6-C10 arylthio, arylsulfmyl, arylsulfonyl, carboxyamido, nitro, phosphoryl and cyano is described herein.
Also described is a compound of formula (e)

and their pharmaceutically acceptable salts wherein,
X2 is a halogen selected from a group consisting of fluorine, chlorine, bromine and iodine, preferably chlorine or bromine, most preferably bromine;
X3 is a halogen selected from a group consisting of fluorine, chlorine, bromine and iodine, preferably chlorine or bromine, most preferably chlorine
Rl is a linear, branched or cyclic hydrocarbon of one to eight carbon atoms, preferably R1 is a linear hydrocarbon of from one to four carbon atoms, most preferably R1 is methyl or ethyl, optionally substituted with one or more electron stabilizing groups selected from a list comprising of C6-C10 aryl, C1-Cg8 carboalkoxy,C1-C10 acyl (derived from aromatic or alkyl carboxylic acids), C1-Cg8 alkoxy, C1-Cg8 alkyl, C6-C10 arylthio, arylsulfmyl, arylsulfonyl, carboxyamido, nitro, phosphoryl and cyano.


Xi is a halogen selected from a group consisting of fluorine, chlorine, bromine and iodine, preferably chlorine or bromine, most preferably bromine;
X3 is a halogen selected from a group consisting of fluorine, chlorine, bromine and iodine, preferably chlorine or bromine, most preferably chlorine;
Rl is a linear, branched or cyclic hydrocarbon of one to eight carbon atoms, preferably R1 is a linear hydrocarbon of from one to four carbon atoms, most preferably R1 is methyl or ethyl, optionally substituted with one or more electron stabilizing groups selected from a list comprising of C6-C10 aryl, C1-C8 carboalkoxy,C1-C10 acyl (derived from aromatic or alkyl carboxylic acids), C1-C8 alkoxy, C1-C8 alkyl, C6-C10 arylthio, arylsulfmyl, arylsulfonyl, carboxyamido, nitro, phosphoryl and cyano is described herein.

X1 is a halogen selected from a group consisting of fluorine, chlorine, bromine and iodine, preferably chlorine or bromine, most preferably bromine;

X2 is a halogen selected from a group consisting of fluorine, chlorine, bromine and iodine, preferably chlorine or bromine, most preferably chlorine;
X3 is a halogen selected from a group consisting of fluorine, chlorine, bromine and
A
iodine, preferably chlorine or bromine, most preferably chlorine;
Rl is a linear, branched or cyclic hydrocarbon of one to eight carbon atoms, preferably R1 is a linear hydrocarbon of from one to four carbon atoms, most preferably R1 is methyl or ethyl, optionally substituted with one or more electron stabilizing groups selected from a list consisting of Ce-Cio aryl, C1-C8 carboalkoxy,Ci-Cio acyl (derived from aromatic or alkyl carboxylic acids), CpCg alkoxy, C1-C8 alkyl, Ce-Cio arylthio, arylsulfinyl, arylsulfonyl, carboxyamido, nitro, phosphoryl and cyano is described herein.

Xi is a halogen selected from a group consisting of fluorine, chlorine, bromine and iodine, preferably chlorine or bromine, most preferably bromine;
X3 is a halogen selected from a group consisting of fluorine, chlorine, bromine and iodine, preferably chlorine or bromine, most preferably chlorine;
Rl is a linear, branched or cyclic hydrocarbon of one to eight carbon atoms, preferably R1 is a linear hydrocarbon of from one to four carbon atoms, most preferably R1 is methyl 01 ethyl, optionally substituted with one or more electron stabilizing groups selected from a

list comprising of C6-C10 aryl, C1-C8 carboalkoxy,C1-C10 acyl (derived from aromatic or alkyl carboxylic acids), C1-C8 alkoxy, C1-C8 alkyl, C6-C10 arylthio, arylsulfmyl, arylsulfonyl, carboxyamido, nitro, phosphoryl and cyano.

Xi is a halogen selected from a group consisting of fluorine, chlorine, bromine and iodine, preferably chlorine or bromine, most preferably bromine;
Rlis a linear, branched or cyclic hydrocarbon of one to eight carbon atoms, preferably R1 is a linear hydrocarbon of from one to four carbon atoms, most preferably R1 is methyl or ethyl, optionally substituted with one or more electron stabilizing groups selected from a list comprising of C6-C10 aryl, C1-C8 carboalkoxy,C1-C10 acyl (derived from aromatic or alkyl carboxylic acids), C1-C8 alkoxy, C1-C8 alkyl, C6-C10 arylthio, arylsulfmyl, arylsulfonyl, carboxyamido, nitro, phosphoryl and cyano is described herein.
Detailed Description of the Invention:
This invention describes a novel process for preparation of 1 l-Cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][l,4]diazepin-6-one. The general process summary of the present invention is as follows: (a) halogenating 2-amino-4-picoline (a) to yield 5-haIo-2-amino-4-picoline(b) or
instead 2-amino-4-picoline may be first acylated, then halogenated and further
hydrolysed to yield 5-halo-2-amino-4-picoline;

(b) nitrating the 5-halo derivative produced in the preceding step to yield 5-halo-2-
amino-3-nitro-4-picoline(c);
(c) diazotization of 5-halo-2-amino-3-nitro-4-picoline to yield 5-haio-2-hydroxy-3-
nitro-4-picoline(d);
(d) halogenating the 5-halo-2-hydroxy-3-nitro-4-picoline to yield 2,5-dihalo-3-nitro-4-picoline(e);
(e) reducing 2,5-dihalo-3-nitro-4-picoline to yield 2,5-dihalo-3-amino-4-picoline(f);
(f) treating 2,5-dihaIo-3-amino-4-picoline with a compound of the formula (II),

(g) treating the compound of formula (g) with cyclopropylamme to yield N-(2,5-
dihalo-4-methyl-3-pyridinyl)-2-cyclopropylamino-3-pyridinecarboxamide(h);
(h) treating N-(255-dihalo-4-methyl-3-pyridinyl)-2-cyclopropylamino-3-
pyridinecarboxamide with a strong base such as, for example, NaH to yield 3-halo-nevirapine(i); and
(i) dehalogenating 3-halo-nevirapine to yield nevirapine(I).
The following schemes, scheme 1 and scheme 2 further describe the invention, a novel process for the preparation of nevirapine and certain novel picoline derivatives:

wherein, in both the schemes,
Rl is a linear, branched or cyclic hydrocarbon of one to eight carbon atoms, preferably R1 is a linear hydrocarbon of from one to four carbon atoms, most preferably R1 is methyl or ethyl, optionally substituted with one or more electron stabilizing groups selected from a list comprising of C6-C10 aryl, C1-C8 carboalkoxy,CrCio acyl (derived from aromatic or alkyl carboxylic acids), CpCg alkoxy, C1-C8 alkyl, C6-C10 arylthio, arylsulfmyl arylsulfonyl, carboxyamido, nitro, phosphoryl and cyano;
X1 is a halogen selected from a group consisting of fluorine, chlorine, bromine and . iodme, preferably chlorine or bromine, most preferably bromine;
X2 is a halogen selected from a group consisting of fluorine, chlorine, bromine and iodine, preferably chlorine or bromine, most preferably chlorine;
X3 is a halogen selected from a group consisting of fluorine, chlorine, bromine and iodine, preferably chlorine or bromine, most preferably chlorine;
X is a halogen selected from a group consisting of fluorine, chlorine, bromine and iodine, preferably chlorine or bromine, most preferably chlorine.
The invention is further described in the following steps. While each step of the reaction sequence can be carried out by first isolating the product of the preceding step, it is possible to carry out some of the reaction steps sequentially, in one reaction vessel, without isolation of the intermediate formed by the preceding step.
Step 1
Halogenation of 2-amino-4-picoline
2-amino-4-picoline (a) may be halogenated by any of the processes generally known in the art, including the process taught in US 5453512. 2-amino-4-picoline is taken in aqueous solution of alkaline buffer and then a halogenating agent, preferably bromine, is added to the reaction mixture in the temperature range of 0o C to 60o C, preferably, in the

range of 0°C to 20° C followed by stirring. The product 5-halo-2-amino-4-picoline (b) is then fihered and washed with water.
Halogenating agent, alkaline buffer solution and solvent systems generally known in the art may be used.
It is also known in the art to first acylate 2-amino-4-picoline, then halogenate and hydrolyse it to yield 5-halo-2-amino-4-picoline.
Step 1(a)
Acylation of 2-ainino 4-picoline
The compound 2-amino-4-picoline is first heated to boil with an acylating agent and the reaction mixture is held under this condition for one hour or until the acylation is complete. The reaction mixture is then cooled to room temperature and poured into water to obtain compound 2-acylamino-4-picoline by filtration, washing and drying.
Suitable acylating reagents includes acid halides and acid anhydrides (open or cyclic), preferably acetyl chloride in acetic acid or acetic anhydride.
Step 1(b)
Halogenation of 2-acylamino-4-picoline
2-acylamino-4-picoline may be haiogenated by any of the processes generally known in the art, including the process taught in US 5453512. 2-acylamino-4-picoline is taken in aqueous solution of alkaline buffer; a halogenating agent, preferably bromine, is added drop wise and stirred in the temperature range of 0° C to 60° C, preferably, in the range of 18°C to 20° C till the reaction is complete. 5-halo-2-acylamino-4-picoline is obtained by filtration, followed by washing and drying the product.
Halogenating agent, alkaline buffer solution and solvent systems generally known in the art can be used.

step 1(c)
Hydrolysis of 5-halo-2-acyIainiDo-4-picoline
5-halo-2-acylamino-4-picoline is hydrolyzed by any of the processes generally known in-the art, including the process taught in US 5453512. The compound 5-halo-2-acylamino-4-picoline is heated with an alkali or a mineral acid at around 100o C. The reaction mixture is held under this condition until the hydrolysis is complete. The reaction mixture is then cooled to room temperature to obtain the compound, 5-halo-2-amino-4-picoline (b) by filtration.
Step 2
Nitration of 5-halo-2-ainino-4-picoIine
5-halo-2-amino-4-picoline is then nitrated using processes generally known in the art including the process taught in US 5453512. 5-halo-2-amino-4-picoline is first taken in a mineral acid and a suitable nitrating agent is added to it drop wise in the temperature, range of 30° C to 35*^ C, preferably, in the range of 31*^0 to 33° C. The reaction mixture is then stirred at the same temperature for 4 hours and poured into ice cold water. The pH of the resultant suspension is then adjusted to 5 using an inorganic base. The product 5-halo-2-amino-3-nitro-4-picoline (c) is filtered and washed with water and dried.
Nitrating agent of the process includes ethyl nitrate, isoamylnitrite or tert-butylnitrate, and other nitrating agents generally known in the art.
Step 3
Diazotization of 5-halo-2-amino-3-nitro-4-picoline
The compound 5-halo-2-amino-3-nitro-4-picoline is taken in a solvent, preferably a , mixture of inorganic and organic acids, and water, a suitable diazotization agent is then added drop wise to the mixture at room temperature. The reaction mixture is stirred for an hour at room temperature and heated to about 70° C and held under this condition for two hours or until the reaction is complete. The reaction mixture is then cooled to room temperature and poured into cold water. The pH of the resultant suspension is adjusted between 4-5 using an inorganic base selected from a group comprising of bicarbonates, carbonates, hydroxides of alkali or alkaline earth metals or alkoxides of alkali metals,

preferably hydroxides of alkali metals. The precipitate is suction filtered, washed and dried to obtain 5-halo-2-hydroxy-3-nitro-4-picoline (d).
Suitable diazotization agent of the process includes nitrites of alkaline and alkali earth metals, preferably nitrites of alkali earth metals selected from sodium nitrite, potassium nitrite and lithium nitrite, preferably potassium nitrite or sodium nitrite.
The solvent used in the reaction includes inorganic acids such as hydrochloric acid, sulphuric acid or orthophosphoric acid and organic acids such as formic acid, oxalic acid or acetic acid, preferably a mixture of acetic acid and sulphuric acid.
Step 4
Halogenation of 5-halo-2-hydroxy-3-nitro-4-picoline
The compound obtained in the previous step, 5-halo-2-hydroxy-3-nitro-4-picoline, is first treated with a halogenating agent preferably a chlorinating agent, and then the reaction mixture is heated to reflux at about 100o C to 120° C, preferably around 115° C and held under these conditions for about 5 hours or until the completion of halogenation. The excess halogenating agent can be removed by distillation. The reaction mixture is then cooled to ambient temperature and poured into water. The contents are then stirred for an hour. The product 2,5-dihalo-3-nitro-4-picoline (e) is filtered off and washed with cold water and dried.
Suitable halogenating agent of the above process includes phosphorus pentachloride, phosphorus trichloride, thionyl chloride, phosphorus oxychloride, phosgene and oxalyl chloride, phosphorus pentabromide, phosphorus tribromide, phosphorus oxybromide and thionyl bromide.
Steps
Reduction of 2,5-dihalo-3-nitro-4-picoline
The compound 2,5-halo-3-nitro-4-picoline obtained in the previous step is heated with a suitable reducing agent in a suitable solvent at a temperature in the range between 40° C-70° C, preferably between 50° C-60° C and then a small amount of acid like hydrochloric acid is added to the mixture. The reaction mixture is held under these conditions for 4

hours or until the reduction is complete. Then the solvent is removed and water is added followed by neutralization using an aqueous base to obtain compound (f) 255-halo-3-amino-4-picoIine by filtration, washing and drying.
Suitable reducing agent used in the reaction includes, nickel, lithium, zinc, tin, aluminum or iron, preferably iron. Other known reduction methods with suitable reducing agents may also be used.
Suitable acid used in the process are organic or inorganic acids including acetic acid, sulphuric acid, hydrochloric acid, orthophosphoric acid, preferably hydrochloric acid.
Suitable solvent of the reaction include chlorinated solvents, alcohols, esters, aliphatic or aromatic hydrocarbon, preferably an alcohol selected from a group comprising methanol, ethanol, propanol, and butanol, most preferably methanol.
Suitable aqueous base to neutralize the reaction mixture includes hydroxides, carbonates or bicarbonates of alkali or alkaline earth metals, especially a hydroxide solution selected from a group comprising of sodium hydroxide, potassium hydroxide, lithium hydroxide or calcium hydroxide, preferably potassium hydroxide or sodium hydroxide.
Other reduction procedures known in the art can also be employed, like reduction using • sodium dithionite or hydrogenation in the presence of catalyst.
Step 6
Preparation of N-(2,5-dihalo-4-methyl-3-pyridinyI)-2-haIo-3-
pyridinecarboxamide (g)
The compound 2,5-halo-3-nitro-4-picoline obtained in previous step is reacted with a compound having formula (II)


where, X is a halogen, selected from a group consisting of fluorine, chlorine, bromine and iodine, preferably chlorine or bromine, most preferably chlorine, X2 is a halogen, selected from a group consisting of fluorine, chlorine, bromine and iodine, preferably chlorine or bromine, most preferably chlorine, in the presence of an inert solvent and a base at a temperature in the range of 0°C-40o C. The reactants are stirred in temperature range of 20o C to 30o C to yield compound of the formula(g)

Solvent used in the process includes chlorinated solvents, esters and hydrocarbons, preferably dichloromethane.
The said base of the reaction includes pyridine, alkyl amine or N,N-dimethylaniline, preferably pyridine.
Step7
Preparation of N-(2,5-dihaIo-4-methyl-3-pyridinyl)-2-cyclopropylamino-3-
pyridinecarboxamide (h)
The compound N-(2,5-dihalo-4-methyl-3-pyridinyl)-2-halo-3-pyridinecarboxamide obtained by the earlier step is heated to about 120oC to 130o C for 16 hours along with-* cyclopropylamine in the presence of a neutralizing agent, which is an oxide or hydroxide of an element of the second main or second sub group of the periodic table, preferably calcium oxide, and an organic solvent. The reaction mixture is then cooled to 0° C to 5oC and allowed to stand at the same temperature for one hour. The product N-(2,5-dihalo-4-methylpyridin-3-yl)-2-cyclopropylamino-3-pyridinecarboxamide (h) is filtered off and dried in vacuum.
Organic solvent of the reaction includes aromatic and aliphatic hydrocarbons, preferably benzene, toluene or xylene, most preferably toluene.

steps
Preparation of 3-haIonevirapine (i)
The compound N-(2,5-dihalo-4-methyl-3-pyridinyl)-2-cyclopropylamino-3-
pyridinecarboxamide obtained by the earlier step is dissolved with an inert solvent diglyme, and treated with a base such as sodium hydride (NaH) or sodium hexamethyldisilazane (NaHMDS) in the temperature range of 130o C to 150o C. The mixture is stirred at a temperature of 120oC-150° C, preferably in the range of 130° C-135° C for 6 hours. Thereafter, the reaction mixture is cooled to room temperature and quenched careftiUy with water. Then the mixture is neutralized to a pH of 7 with the help of organic acids such as acetic acid or inorganic acids such as hydrochloric acid, sulphuric acid or orthophosphoric acid, preferably glacial acetic acid. 3-halonevirapine (i)
is then collected by filtration and dried in vacuum.
*
The inert organic solvent used in this process includes toluene, diglyme, or tetrahydrofuran (THF).
The base used in the process includes alkali metallic hydrides such as sodium, potassium or lithium hydrides, sodium hexamethyldisilazane (NaHMDS), or potassium hexamethyldisilazane (KHMDS), preferably sodium hydride or sodiumhexamethyldisilazane (NaHMDS) or potassium hexamethyldisilazane (KHMDS).
Step 9
Preparation of nevirapine(I)
3"halonevirapine is taken in a suitable solvent and dehalogenated in the presence of a' metal catalyst for about 12 hours in the temperature of 30° C-100° C at a pressure of about 50-70 psi (344.7 kilo pascal- 482.6 kilo pascal). The catalyst is then filtered off and the solvent is removed under reduced pressure, the mixture is then added to water and stirred for 4 hours at about 5°C-10°C. The final product, nevirapine (I), is collected by filtration.
The suitable solvents used in the process include alcohols selected from ethanol, methanol, propanol or n-butanol, preferably ethanol or methanol.

The catalyst used in the said dehalogenation process may include a metal catalyst selected from palladium, nickel or tin, preferably palladium chloride.
Novel Intermediates:
The present invention also relates to certain novel picoline derivative compounds forming part of the invention:
Compound (d)

wherein, X1 a halogen is selected from a group consisting of fluorine, chlorine, bromine-* and iodine, preferably chlorine or bromine, most preferably bromine;
Rl is a linear, branched or cyclic hydrocarbon of one to eight carbon atoms, preferably R1 is a linear hydrocarbon of from one to four carbon atoms, most preferably R1 is methyl or ethyl, optionally substituted with one or more electron stabilizing groups selected from a list consisting of C6-C10 aryl, C1-C8 carboalkoxy,C1-C10 acyl (derived from aromatic or alkyl carboxylic acids), C1-C8 alkoxy, C1-C8 alkyl, C6-C10 arylthio, arylsulfinyl, arylsulfonyl, carboxyamido, nitro, phosphoryl and cyano.
Compound (e)
wherein, X1 is a halogen selected from a group consisting of fluorine, chlorine, bromine and iodine, preferably chlorine or bromine, most preferably bromine;

X3 is a halogen selected from a group consisting of fluorine, chlorine, bromine and iodine, preferably chlorine or bromine, most preferably chlorine;
Rl is a linear, branched or cyclic hydrocarbon of one to eight carbon atoms, preferably R1-is a linear hydrocarbon of from one to four carbon atoms, most preferably R1 is methyl or ethyl, optionally substituted with one or more electron stabilizing groups selected from a list consisting of C6-C10 aryl, C1-C8 carboalkoxy,C1-C10 acyl (derived from aromatic or alkyl carboxylic acids), C1-C8 alkoxy, C1-C8 alkyl, C6-C10 arylthio, arylsulfinyl, arylsulfonyl, carboxyamido, nitro, phosphoryl and cyano.
Compound (f)

X1 is a halogen selected from a group consisting of fluorine, chlorine, bromine and iodine, preferably chlorine or bromine, most preferably bromine;
X3 is a halogen selected from a group consisting of fluorine, chlorine, bromine and iodine, preferably chlorine or bromine, most preferably chlorine;
Rl is a linear, branched or cyclic hydrocarbon of one to eight carbon atoms, preferably R1 is a linear hydrocarbon of from one to four carbon atoms, most preferably R1 is methyl or ethyl, optionally substituted with one or more electron stabilizing groups selected from a list consisting of C6-C10 aryl, C1-C8 carboalkoxy,C1-C10 acyl (derived from aromatic or • alkyl carboxylic acids), C1-C8 alkoxy, C1-C8 alkyl, C6-C10 arylthio, arylsulfinyl, arylsulfonyl, carboxyamido, nitro, phosphoryl and cyano.


wherein, Xi is selected from a group consisting of fluorine, chlorine, bromine and iodine, preferably chlorine or bromine, most preferably bromine;
X2 is selected from a group consisting of fluorine, chlorine, bromine and iodine, preferably chlorine or bromine, most preferably chlorine;
X3 is selected from a group consisting of fluorine, chlorine, bromine and iodine, preferably chlorine or bromine, most preferably chlorine;
Rl is a linear, branched or cyclic hydrocarbon of one to eight carbon atoms, preferably R\ is a linear hydrocarbon of from one to four carbon atoms, most preferably R1 is methyl or ethyl, optionally substituted with one or more electron stabilizing groups selected from a list consisting of C6-C10 aryl, C1-C8 carboalkoxy,C1-C10 acyl (derived from aromatic or alkyl carboxylic acids), C1-C8 alkoxy, C1-C8 alkyl, C6-C10 arylthio, arylsulfmyl, arylsulfonyl, carboxyamido, nitro, phosphoryl and cyano.
Compound (h)


X1 is a halogen selected from a group consisting of fluorine, cniorme, Dromine and iodine, preferably chlorine or bromine, most preferably bromine;
X3 is a halogen selected from a group consisting of fluorine, chlorine, bromine and iodine, preferably chlorine or bromine, most preferably chlorine;
Rl is a linear, branched or cyclic hydrocarbon of one to eight carbon atoms, preferably R1 is a linear hydrocarbon of from one to four carbon atoms, most preferably R1 is methyl or ethyl, optionally substituted with one or more electron stabilizing groups selected from a list comprising of C6-C10 aryl, C1-C8 carboalkoxy,C1-C10 acyl (derived from aromatic or alkyl carboxylic acids), C1-C8 alkoxy, C1-C8 alkyl, C6-C10 arylthio, arylsulfinyl, arylsulfonyl, carboxyamido, nitro, phosphoryl and cyano.
Compound (i)

X1 is a halogen selected from a group consisting of fluorine, chlorine, bromine and iodine, preferably chlorine or bromine, most preferably bromine;
Rl is a linear, branched or cyclic hydrocarbon of one to eight carbon atoms, preferably R1 is a linear hydrocarbon of from one to four carbon atoms, most preferably R1 is methyl or ethyl, optionally substituted with one or more electron stabilizing groups selected from a list consisting of C6-C10 aryl, C1-C8 carboalkoxy,C1-C10 acyl (derived from aromatic or alkyl carboxylic acids), C1-C8 alkoxy, C1-C8 alkyl, C6-C10 arylthio, arylsulfinyl, arylsulfonyl, carboxyamido, nitro, phosphoryl and cyano.

The following non-limiting examples further illustrate and describe the novel process of preparation of nevirapine according to the present invention without limiting the scope of the invention.
Example 1
Preparation of 5-bromo-2-hydroxy-4-methyl-3-nitropyridine(d)
2-amino-5-bromo-4-methyl-3-nitropyridine (364g) was added to a stirred mixture of acetic acid (2200 mL) and sulfuric acid (210 mL). Sodium nitrite (205 g) in water (980 mL) was added drop wise to the above reaction mixture. The mixture was allowed to stir for one hour at room temperature. The reaction mixture was then heated to 70°C and held at that temperature for 2 hours. The reaction mixture was cooled to ambient temperature followed by the addition of cold water (1200 mL). The pH was adjusted to between 4 and 5 using sodium hydroxide solution. The precipitated crystals were suction filtered, washed with water and dried to give 355 g of 5-bromo-2-hydroxy-4-methyl-3-nitropyridine.
1H NMR (200 MHz, DMSO): 5 13.0 (brs, IH), 8.00 (s, IH), 2.20 (s, 3H).
Example 2
Preparation of 5-bromo-2-chloro-4-methyl-3-nitropyridine(e)
The product of the previous example, 5-bromo-2-hydroxy-4-methyl-3-nitropyridine (100 g) was added to a stirred solution of POCI3 (400ml). 43.3 g of triethylamine (TEA) was added to the mixture drop wise at a temperature of 60°C-70°C. The reaction mixture was heated to 110oC-112°C and held under those conditions for 5 hours. Excess POCI3 was removed by distillation. The reaction mixture was cooled to ambient temperature and poured into water (1600 mL). The contents were stirred for 1 hour. The precipitated crystals are suction filtered washed with cold water and dried to give 70 g of 5-bromo-2-chloro-4-methyl-3-nitropyridine.
Melting point: 223^C-225°C
'H NMR (200 MHz, CDCI3): 5 8.60 (s, IH), 2.45 (s, 3H).

Example 3
Preparation of 3-amino-5-bromo-2-chloro-4-methylpyridine (f)
5-bromo-2-chloro-4-methyl-3-nitropyridine (50g) in methanol (250 mL) was treated with iron powder (37.5g). The mixture was heated to 50°C - 60°C and catalytic amount of HCI was added to it at that temperature. The reaction mixture was held under these conditions for 4 hours. The mixture was cooled to ambient temperature and concentrated. Water (75 mL) was then added and pH is adjusted to 7 using 25% sodium hydroxide solution. The product was filtered fi-om the mixture, washed with cold water (50ml) and' dried to give 38 g of 3-amino-5-bromo-2-chloro-4-methylpyridine.
Melting point: 125*" C-128° C
*H NMR (200 MHz, CDCI3): 6 7.98 (s, IH), 4.20 (brs, 2H), 2.30 (s, 3H).
Example 4
Preparation of N-(5"bromo-2-chloro-4-methyl-3-pyridinyl)-2-chloro-3-pyridinecarboxamide (g)
Anhydrous pyridine (17.8 g) was added to a cooled solution of 2-chloro-3-amino-4-methyl-5-bromopyridine (50g) in dichloromethane (300 mL). The reaction mixture was further cooled to 0° C-10° C. To the reaction mixture 2-chloronicotinic acid chloride (47.8 g) in dichloromethane (25 mL) was added at that temperature and stirred for over one hour. Then the temperature of the reaction mixture was raised to 20° C to 30° C and the contents stirred for 6 hours. The resulting slurry was diluted using water (100 mL) and suction filtered. The filtered product was added to ethyl acetate (100 mL) and heated to 50° C - 60° C for 1 hour and then cooled to ambient temperature. The precipitate was suction filtered and dried to give 65g of N-(5-bromo-2-chloro-4-methyl-3-pyridinyl)-2-chloro-3-pyridinecarboxamide.
Melting point: 135° 'C-139°C

^H NMR (200 MHz, DMSO): 8 10.90 (s, IH;, 6.38,8.04 (m, ZH), 8.1^ (d, J = 5,78 Hz, IH), 7.60-7.70 (m, IH), 2.50 (s, 3H).
Example 5
Preparation of N-(5-bromo-2-chloro-4-methyl-3-pyridinyl)-2-cyclopropylamino-3-pyridinecarboxamide (h)
A mixture of N-(5-bromo-2-chloro-4-methyl-3-pyridinyl)-2-chloro-3-
pyridinecarboxamide (50g) and cyclopropylamine (150 mL) in 500 ml of toluene was heated to 130°C in an autoclave for 16 hours. The solvent, in this instance toluene was first concentrated and the resultant suspension was cooled to 0° C - 5° C and maintained at that condition for one hour. The precipitate was filtered and dried in vacuum at 80° C to give 45g of N-(5-bromo-2-chloro-4-methyl-3-pyridinyl)-2-cyclopropylamino-3-pyridinecarboxamide.
Melting point: 163° C-166°C
1H NMR (200 MHz, DMSO): 8 10.15 (brs, IH), 8.60 (s, IH), 8.38 (d, J = 5.23 Hz, IH), 8.18-8.25 (m, 2H), 6.70-6.82 (m, IH), 2.78-2.98 (m, IH), 2.30 (s, 3H), 0.68-0.82 (m, 2H), 0.38-0.50 (m, 2H).
Example 6
Preparation of 3-bromo-l l-cyclopropyl-5,1 l-dihydro-4-methyl-6H-dipyrido[3,2-b:2', 3'-e][l, 4]diazepin-6-one (i)
*
To a solution of 60% sodium hydride (19g) suspended in mineral oil and diglyme (250 mL) heated to 120°C under nitrogen was added a solution of N-(5-bromo-2-chloro-4-methyl-3-pyridinyl)-2-cyclopropylamino-3-pyridinecarboxamide (50g) in diglyme (50mL). The mixture was stirred at 130° C-135° C for 6 hours, cooled to ambient temperature and quenched carefiilly with water (500 ml). Then the mixture was neutralized to pH 7 using glacial acetic acid. The precipitate was collected and dried in vacuum to give 35 g of 3-bromo-l l-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][l,4]diazepin-6-one.

Melting point: 225° C-226° C
'H NMR (200 MHz, DMSO): 5 10.10 (s, IH), 8.55 (d, J^ 4.76 Hz, IH), 8.40 (s, IH), 8.10 (d, J= 9.52 Hz, IH), 7.18-7.30 (m, IH), 3.50-3.70 (m, IH), 2.40 (s, 3H), 0.80-1.00 (m, 2H), 0.30-0.50 (m, 2H).
Example 7
Preparation of nevirapine (I)
3-bromo-ll-cyclopropyl-5,ll-dihydro-4-methyl-6H-dipyrido[3,2:2',3'-e][l,4]diazepin-6-one (35g) was taken in ethanol (200 mL). This solution was hydrogenated with 3g of 10% carbon-black supported palladium catalyst for 12 hours at 80° c at 70 PSI (482.6 kilo Pascal). The catalyst was filtered through celite filter and ethanol was removed under reduced pressure. The mixture was added to water (50mL) and stirred for 4 hours at 5-10°C. The precipitate was collected by filtration and dried to give 20g of nevirapine. .
Melting point: 237°C-241°C

We Claim:
1. A process of making a compound of the formula

and their pharmaceutically acceptable salts comprising the following steps: a. halogenating compound (a) of the formula

b. nitrating compound (b) of the formula

wherein, Rl is a linear, branched or cyclic hydrocarbon of one to eight carbon atoms optionally substituted with one or more electron stabilizing groups;
X1 is a halogen selected from the group consisting of fluorine, chlorine, bromine and . iodine;
X is a halogen selected from the group of consisting of fluorine, chlorine, bromine ,and iodine;
X2 is a halogen selected from the group consisting of fluorine, chlorine, bromine and iodine;
X3 is a halogen selected from the group consisting of fluorine, chlorine, bromine and iodine.

2. The process of making a compound of formula I as claimed in claim 1 wherein, the said Rl is a linear hydrocarbon of from one to four carbon atoms optionally substituted with one or more electron stabilizing groups.
3. The process of making a compound of formula I as claimed in any of the preceding claims wherein, the said Rl is methyl or ethyl, optionally substituted with one or more electron stabilizing groups.
4. The process as claimed in any of the preceding claims wherein, the said electron stabilizing group is selected from a list consisting of C6-C10 aryl, Ci-Cg carboalkoxy,Ci-Cio acyl (derived from aromatic or alkyl carboxylic acids), CpCg alkoxy, CpCg alkyl, Ce-Cio arylthio, arylsulfinyl, arylsulfonyl, carboxyamido, nitro, phosphoryl and cyano.
5. The process as claimed in any of the preceding claims wherein, the said Xi is bromine.
6. The process as claimed in any of the preceding claims wherein, the said X is chlorine.
7. The process as claimed in any of the preceding claims wherein, the said X2 is chlorme.
8. The process as claimed in any of the preceding claims wherein, the said X3 is chlorine.
9. The process as claimed in any of the preceding claims wherein, the said inert solvent may include chlorinated solvents, esters or hydrocarbons.

10. The process as claimed in any of the preceding claims wherein, the said base includes pyridine, alkyl amine or N,N-dimethylaniline.
11. A compound of the formula


and their pharmaceutically acceptable salts, wherein,
Rl is a linear, branched or cyclic hydrocarbon of one to eight carbon atoms optionally substituted with one or more electron stabilizing groups;
Xi is a halogen selected from the group consisting of fluorine, chlorine, bromine and iodine.
12. The compound as claimed in claim 11 wherein the said Rl is a linear hydrocarbon of from one to four carbon atoms optionally substituted with one or more electron stabilizing groups.
13. The compound as claimed in claims 11 or 12 wherein, the said Rl is methyl or ethyl optionally substituted with one or more electron stabilizing groups.
14. The compound as claimed in claims 11, 12 or 13 wherein the said electron stabilizing group is selected from a list consisting of C6-C10 aryl, C1-C8 carboalkoxy,C1-C10 acyl (derived from aromatic or alkyl carboxylic acids), C1-C8 alkoxy, C1-C8 alkyl, C6-. C10 arylthio, arylsulfinyl arylsulfonyl, carboxyamido, nitro, phosphoryl and cyano.
15. The compound as claimed in claims 11, 12, 13 or 14 wherein, the said X1 is bromine.
16. A compound of the formula


and their pharmaceutically acceptable salts wherein,
Rl is a linear, branched or cyclic hydrocarbon of one to eight carbon atoms optionally substituted with one or more electron stabilizing groups;
X1 is a halogen selected from a group consisting of fluorine, chlorine, bromine and iodine;
X3 is a halogen selected from a group consisting of fluorine, chlorine, bromine and iodine.
17. The compound as claimed in claim 16 wherein the said Rl is a linear hydrocarbon of from one to four carbon atoms optionally substituted with one or more electron stabilizing groups
18. The compound as claimed in claims 16 or 17 wherein, the said Rl is methyl or ethyl optionally substituted with one or more electron stabilizing groups.
19. The compound as claimed in claims 16, 17 or 18 wherein the said electron stabilizing group is selected from a list consisting of C6-C10 aryl, C1-C8 carboalkoxy^C1-' C10 acyl (derived from aromatic or alkyl carboxylic acids), C1-C8 alkoxy, C1-C8 alkyl, Ce-Cio arylthio, arylsulfinyl arylsulfonyl, carboxyamido, nitro, phosphoryl and cyano.
20. The compound as claimed in claims 16,17,18 or 19 wherein, the said Xi is bromine.

21. The compound as claimed in claims 16,17,18,19 or 20 wherein, the said X3 is chlorine.
22. A compound of the formula

and their pharmaceutically acceptable salts wherein,
Rl is a linear, branched or cyclic hydrocarbon of one to eight carbon atoms optionally substituted with one or more electron stabilizing groups
Xi is a halogen selected from a group of consisting of fluorine, chlorine, bromine and iodine;
X3 is a halogen selected from a group of consisting of fluorine, chlorine, bromine and iodine.
23. The compound as claimed in claim 22 wherein the said Rl is a linear hydrocarbon of from one to four carbon atoms optionally substituted with one or more electron stabilizing groups
24. The compound as claimed in claims 22 or 23 wherein, the said Rl is methyl or
*
ethyl optionally substituted with one or more electron stabilizing groups.
25. The compound as claimed in claims 22, 23 or 24 wherein the said electron
stabilizing group is selected from a list consisting of C6-C10 aryl, C1-C8 carboalkoxy,C1-
C10 acyl (derived from aromatic or alkyl carboxylic acids), C1-C8 alkoxy, C1-C8 alkyl, C6-
C10 arylthio, arylsulfmyl arylsulfonyl, carboxyamido, nitro, phosphoryl and cyano.

26. The compound as claimed in claims 22,23,24 or 25 wherein, the said X1 is bromine.
27. The compound as claimed in claims 22,23,24,25 or 26 wherein, the said X3 is chlorine.
28. A compound of the formula

and their pharmaceutically acceptable salts wherein,
Rl is a linear, branched or cyclic hydrocarbon of one to eight carbon atoms optionally substituted with one or more electron stabilizing groups;
X1 is a halogen selected from a group consisting of fluorine, chlorine, bromine and iodine;
X2 is a halogen selected from a group consisting of fluorine, chlorine, bromine and iodine;
X3 is a halogen selected from a group consisting of fluorine, chlorine, bromine and iodine;
29. The compound as claimed in claim 28 wherein the said Rl is a linear hydrocarbon-'
of from one to four carbon atoms optionally substituted with one or more electron
stabilizing groups

30. The compound as claimed in claims 28 or 29 wherein, the said Rl is methyl or ethyl optionally substituted with one or more electron stabilizing groups.
31. The compound as claimed in claims 28, 29 or 30 wherein the said electron stabilizing group is selected from a list consisting of C6-C10 aryl, C1-C8 carboalkoxy,C1-C10 acyl (derived from aromatic or alkyl carboxylic acids), C1-C8 alkoxy, C1-C8 alkyl, Ce-C10 arylthio, arylsulfmyl arylsulfonyl, carboxyamido, nitro, phosphoryl and cyano.
32. The compound as claimed in claims 28,29,30 or 31 wherein, the said X1 is bromine.
33. The compound as claimed in claims 28,29,30,31 or 32 wherein, the said X2 is chlorine.
34. The compound as claimed in claims 28, 29,30,31,32 or 33 wherein, the said X3 is chlorine.
35. A compound of formula

and their pharmaceutically acceptable salts wherein,
Rl is a linear, branched or cyclic hydrocarbon of one to eight carbon atoms optionally substituted with one or more electron stabilizing groups;

Xi is a halogen selected from a group consisting of fluorine, chlorine, bromine and iodine;
X3 is a halogen selected from a group onsisting of fluorine, chlorine, bromine and iodine.
36. The compound as claimed in claim 35 wherein the said Rl is a linear hydrocarbon of from one to four carbon atoms optionally substituted with one or more electron stabilizing groups.
37. The compound as claimed in claims 35 or 36 wherein, the said Rl is methyl or ethyl optionally substituted with one or more electron stabilizing groups.
38. The compound as claimed in claims 35, 36 or 37 wherein the said electron stabilizing group is selected from a list consisting of C6-C10 aryl, C1-C8 carboalkoxy,C1-C10 acyl (derived from aromatic or alkyl carboxylic acids), C1-C8 alkoxy, C1-C8 alkyl, C6-C10 arylthio, arylsulfmyl arylsulfonyl, carboxyamido, nitro, phosphoryl and cyano.
39. The compound as claimed in claims 35, 36, 37 or 38 wherein, the said X1 is bromine.
40. The compound as claimed in claims 35, 36, 37, 38 or 39 wherein, the said X3 is chlorine.
41. A compound of formula


and their pharmaceutically acceptable salts wherein,
Rl is a linear, branched or cyclic hydrocarbon of one to eight carbon atoms optionally substituted with one or more electron stabilizing groups;
X1 is a halogen selected from a group consisting of fluorine, chlorine, bromine and iodine"
42. The compound as claimed in claim 41 wherein the said Rl is a linear hydrocarbon
of from one to four carbon atoms optionally substituted with one or more electron
stabilizing groups.
43. The compound as claimed in claims 41 or 42 wherein, the said Rl is methyl or
ethyl optionally substituted with one or more electron stabilizing groups.
44. The compound as claimed in claims 41, 42 or 43 wherein the said electron
stabilizing group is selected from a list consisting of C6-C10 aryl, C1-C8 carboalkoxy,C1-
C10 acyl (derived from aromatic or alkyl carboxylic acids), C1-C8 alkoxy, C1-C8 alkyl, C6-'
C10 arylthio, arylsulfmyl, arylsulfonyl, carboxyamido, nitro, phosphoryl and cyano.
45. The compound as claimed in claims 41, 42, 43 or 44 wherein, the said X1 is
bromine.
46. A process of making a compound of the formula I as substantially described
herein with reference to the accompanying description.