FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
Title
PROCESS FOR THE PREPARATION OF BOSENTAN


Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh
Hall, Ahmedabad 380 009, Gujarat, India

The following specification particularly describes the invention:


PROCESS FOR THE PREPARATION OF BOSENTAN
FILED OF THE INVENTION
The present invention relates to an improved process for the preparation of bosentan. In particular it relates to a process for preparing bosentan comprising the reaction of sulfonamide intermediate of formula (II) with ethylene glycol in the presence of organic base. The invention also relates to a pharmaceutical composition comprising bosentan prepared according to the presence invention.
BACKGROUND OF THE INVENTION
Bosentan is the first oral endothelin antagonist approved for the treatment of PPH and PAH. It is a dual endothelin receptor antagonist. Endothelin-l (ET-1) is a neurohormone, the effects of which are mediated by binding to ETA and ETB receptors in the endothelium and vascular smooth muscle, ET-1 concentrations are elevated in the plasma and lung tissue of patients with PAH, suggesting a pathogenic role of ET-1 in this disease. Bosentan is a specific and competitive antagonist of endothelin receptor types ETA and ETB. Bosentan has a slightly higher affinity for ETA receptors than for ETB receptors. It is used for the treatment of endothelin- receptor mediated disorders, in particular circulatory and cardiovascular disorders such as hypertension, ischemia, pulmonary hypertension, vasospasm and angina pectoris. Bosentan is marketed as Tracleer ® in USA & Europe.
Bosentan is described chemically as 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidin-4-yl] -benzenesulfonamide is an endothelin receptor antagonist having the chemical structure of formula (I).
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OH (I)
US 5292740 is the basic product patent of bosentan, which discloses and claims endothelin receptor including Bosentan (I).
There are several approaches known in the art for preparing Bosentan, which can be described herein below.
US 5292740 disclose the process for the preparation of bosentan comprising the reaction of a dichloro intermediate of formula (III) with 4-tert-butylbenezene sulfonamide of formula (IV) in the present of base in suitable solvent to provide the sulfonamide intermediate of formula (II), which undergoes reaction with ethylene glycol in the presence of sodium metal used as a base at a temperature of 110° C with low yield. The said process can be schematically represented as below in scheme-1.

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Scheme-1
The process as disclosed in US 5292740 involves column chromatographic purification to purify Bosentan, which is generally not preferable at plant scale. Further, the said process involves the use of sodium metal, which is generally not recommended at plant scale because it is moisture sensitive, hazardous during handling and hence requires special storage. Moreover, one of the disadvantages of using a monoanion of ethylene glycol is the formation of undesired ethylene glycol bis-sulfonamide i.e. dimmer impurity in which two molecules of the pyrimidine monohalide are coupled with one molecule of ethylene glycol. The removal of this bis-sulfonamide impurity requires costly and laborious separation steps to obtain a pharmaceutically sutiable pure compound of formula (I).
To minimize the formation of dimmer impurity, the inventors of US 6136971 discovered alternate process for the preparation of bosentan by employing a mono-protected 1,2-diheteroethylene anion. According to US 6136791, the preferred protecting group is atert-butyl group, which is used to protect one hydroxyl group of ethylene glycol. The protecting
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group is then removed using formic acid to produce a formyloxy protected ethylene glycol sulfonamide derivative, followed by treatment with a base produces Bosentan of formula (I). The said process can be schematically represented as below in scheme-2.

Scheme-2
However, the process as disclosed in US 6136971 is laborious, as it involves a number of steps relating to the protection and deprotection of ethylene glycol as the tert-butyl ether, which renders the process unfavorable for commercial manufacture.
Drugs of the Future 2001, 26(12): 1149 also discloses the same process as disclosed in basic product patent and in US 6136791 for the preparation of bosentan.
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PCT publication WO 2009/004374 discloses another process for the preparation of bosentan involves the use of hydroxide ion, preferably sodium hydroxide as base during the reaction of ethylene glycol with sulfonamide intermediate of formula (II) to minimize the formation of dimmer impurity. The process as disclosed in the said prior art requires ~ 107 equivalence of ethylene glycol with respect to sulfonamide intermediate of formula (II), which is extremely high and not recommended at plant scale, in addition to large excess of ethylene glycol it also requires solvent like tetrahydrofuran during the reaction.
It is known that the formation of dimmer impurity can be minimized by using a large excess of ethylene glycol. However, the use of large excess of ethylene glycol invites undue purification steps, which makes process expensive and unfavorable for bulk manufacturing.
It is apparent from the above discussion that the known processes for the preparation of Bosentan are not satisfactory, in particular for plant scale production, as they are lengthy and economically not viable. Hence there still exists need of simple manufacturing process, which overcomes the problems associated with prior arts and still leads to the desired product.
Our inventors have been surprisingly find out when reaction of sulfonamide intermediate of formula (II) is carried out with ethylene glycol in the presence of organic base minimize the formation of dimmer impurity, doesn't require large excess of ethylene glycol and still provides bosentan with good purity and yield.
SUMMARY OF THE INVENTION
The first embodiment of the present invention is to provide an improved process for the preparation of bosentan (1), comprising the steps of:
(a) forming a reaction mixture by mixing an organic base and ethylene glycol;
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i

(b) adding 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidin-4-yl]-benzenesulfonamide (II) or its alkali salt to the reaction mixture obtained in step (a);
(c) heating the reaction mixture obtained in step (b); and
(d) isolating bosentan (I) from the mixture obtained in step (c).
Another embodiment of the present invention is to provide an improved process for the preparation of bosentan (I), which doesn't require column chromatographic purification.
Yet another embodiment of the present invention is to provide a bosentan (I) with good purity and good yield.
Yet another embodiment of the present invention is to provide a pharmaceutical composition comprising a bosentan (I) prepared according to present invention, and at least one pharmaceutically acceptable excipient.
Yet another embodiment of the present invention is to provide a use of bosentan obtained according to present invention, in the manufacture of a composition for the treatment or prevention of an endothelin-receptor mediated disorder.
Yet another embodiment of the present invention is to provide a method of treating or preventing an endothelin-receptor mediated disorder, comprising administering a therapeutically effective amount of bosentan (1) prepared to a patient in need thereof.
DEATILED DESCRIPTION:
The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
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As used herein, the term Bosentan refers to 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidin-4-yl]-benzenesuIfonamide having the following structural formula.

OH (I)
As used herein, the term sulfonamide intermediate of formula (II) refers to the 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidin-4-yl]-benzenesulfonamide having the following structural formula.

(II
The present invention provides an efficient and economical synthesis of bosentan starting from 4-tert-butyl-N- [6-chloro-5- (2-rnethoxyphenoxy) -2- (2-pyrimidinyl) -pyrimidin-4-yl] - benzenesulfonamide (II), which is feasible at the commercial scale.
The present invention relates, in general, to an improved process for the preparation of bosentan (I), comprising the steps of:
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(a) forming a reaction mixture by mixing an organic base and ethylene glycol;
(b) adding 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidin-4-y(]-benzenesu]fonamide (II) or its alkali salt to the reaction mixture obtained in step (a);
(c) heating the reaction mixture obtained in step (b); and
(d) isolating bosentan (I) from the mixture obtained in step (c).
In step (a) of the present invention, the reaction mixture is formed by mixing the organic base and ethylene glycol. The obtained reaction mixture can be optionally heated at 50°C-80°C for 1-3 hours to make uniform mixture of ethylene glycol and organic base and then the reaction mixture is cooled to 40-60°C.
The amount of ethylene glycol is not critical, but generally it can be from 40 - 55 equivalence with respect to sulfonamide intermediate of formula (II) or its alkali salt such as sodium or potassium, more preferable is potassium salt.
There is no limitation on the nature of the organic base employed. Examples of suitable organic bas'es include: guanidines such as tetramethylguanidine and diphenylguanidine; trialkylamines such as triethylamine, ethyldiisopropylamine, tributylamine, hexamethyltetramine, quinuclidine, 4-ethyImorpholine, and N-methylpiperidine; N,N,N'-trisubstituted amidines such as 1.5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); aliphatic polyamines such as tetramethylethylenediamine and tetraethylethylenediamine; aromatic amines such as dimethylaniline and dimethylaniline), and heterocyclic amines such as pyridine, 2-picoline, 2-ethylpyridine, 3-picoIine, 2,6-lutidine, pyridazine, pyrimidine, triazine, pyrazine, quinoline, isoquinoline, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, indole, and benzotriazole. Preferably, trisubstituted amidines such as 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) are used.
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The amount of base employed is not critical, but generally it can be from 3-5 equivalence with respect to sulfonamide intermediate of formula (II) or its alkali salt.
ID step (b) & (c) of the present invention, after cooling the reaction mixture obtained in step (a) at 40-60°C, the sulfonamide intermediate of formula (II) or its alkali salt, preferably potassium salt is added to the reaction mixture obtained in step (a). Optionally the catalyst like sodium iodide can be optionally added along with sulfonamide intermediate of formula (II). Then reaction mass is heated to a temperature in the range of between about 50°C-120°C, more preferably at 100-110°C till the completion of reaction.
The time required for the condensation may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents employed. However, the preferred period for condensation is from 7 to 12 hours.
After completion of condensation reaction, the reaction mixture obtained is cooled to temperature of between 0°C to 35°C. It is added with organic or inorganic acid to neutralize the excess of organic base that may be present in the reaction mixture.
There is no limitation on the nature of the acid employed, which may be an organic or inorganic acid. Examples of suitable inorganic acid include hydrochloric acid, hydrobromic acid, hydroiodic( acid, nitric acid, sulfuric acid, and phosphoric acid. In preferred embodiments, the acid may be an organic acid selected from the group comprising: an aliphatic carboxylic acid, an aromatic carboxylic acid, and a sulfonic acid. Examples of organic acids that may be useful in the working of the present invention comprise formic, acetic, propionic, succinic, camphorsulfonic, citric, fumaric, gluconic, lactic, malic, mucic, tartaric, para-toluenesulfonic, glycolic, maleic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, pamoic, methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic, stearic, sulfanilic. 2-ethanedioic, 3-propanedioic, 4-butanedioic, 5-pentanedioic, 6-hexanedioic, cis-butenedioic, methanoic, ethanoic, propanoic, butanoic, pentanoic, hexanoic, heptanoic, 1-hydroxypropanoic, and cinnamic acid. In a particularly preferred embodiment the acid is hydrochloric acid or tartaric acid.
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In step (d) of the present invention, the isolation of Bosentan (I) is simply carried out by maintaining the reaction mixture obtained in step (c) at 0°C to 35°C with stirring till the precipitate comes out. Generally, the isolation of compound of formula (I) is completed in less than 2 hour. The obtained crude Bosentan (1) can be optionally re-crystallized by using one or more suitable solvent like water, alcohol, ester or etc. at ambient temperature.
In another embodiment, the present invention provides a pharmaceutical composition comprising a bosentan (I) prepared according to present invention, and at least one pharmaceutically acceptable excipient.
An example of the invention is a method for the treatment of an endothelin-receptor mediated disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of bosentan according to any of the embodiments of the present invention or of a pharmaceutical composition described above.
The bosentan (1) prepared according to the present invention is ideal for pharmaceutical formulation. In addition to the active ingredient(s), the pharmaceutical compositions of the present invention may contain one or more excipients. Excipients are added to the composition for a variety of purposes.
Diluents increase the bulk of a solid pharmaceutical composition and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel ), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit ), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
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Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. Carbopol ), carboxymetbyl cellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel ), liquid glucose, magnesium aluminum silicate, maltodextrin, methyl cellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone™), pregelatinized starch, sodium alginate and starch.
The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium (e.g. Ac-Di-SoT , Primellose ), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon , Polyplasdone ), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab ) and starch.
Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye. which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable
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oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
Flavouring agents and flavour enhancers make the dosage form more palatable to the patient. Common flavouring agents and flavour enhancers for pharmaceutical products that may be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid.
Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colourant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
In liquid pharmaceutical compositions of the present invention, bosentan and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin,
Liquid pharmaceutical compositions may further comprise emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol.
Liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth-feel or organoleptic qualities of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid, bentonite, carbomer, carboxymethyl cellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethyl cellulose, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.

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Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar may be added to improve the taste.
Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole and ethylenediamine tetra acetic acid may be added at levels safe for ingestion to improve storage stability.
According to the present invention, a liquid composition may also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate.
Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
Solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. Dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts. Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and lozenges, as well as liquid syrups, suspensions and elixirs.
The dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell. The shell may be made from gelatin and optionally contain a plasticizer such as glycerin or sorbitol, and an opacifying agent or colourant. The active ingredient and
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excipients may be formulated into compositions and dosage forms according to methods known in the art.
A composition for tableting or capsule filling may be prepared by wet granulation. In wet granulation, some or all of the active ingredient and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water that causes the powders to clump into granules. The granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size. The granulate may then be tableted, or other excipients may be added prior to tableting, such as a glidant and/or a lubricant.
A tableting composition may be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients may be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.
As an alternative to dry granulation, a blended composition may be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
A capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting; however, they are not subjected to a final tableting step.
The details of the invention, its objects and advantages are explained hereunder in greater detail in relation to non-limiting exemplary illustrations.
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Emple-1:
Preparation of Diethylchloro malonate
A mixture of diethyl malonate (50 gm) and toluene (500 ml) under nitrogen atmosphere were slowly added with sulfuryl chloride (53.5 gm) over a period of 30 minutes at room temperature. The reaction mass was added with another amount of sulfuryl chloride (5.3 gm). After completion of the reaction, the reaction mixture was added into the RO water (350 ml) and layers were separated. The separated toluene layer was washed with water and saturated solution of sodium bicarbonate. The toluene layer was distilled off to get the title compound (Weight = 56 gm).
Example-2:
Preparation of Diethyl-(2-methoxy phenoxy) malonate
To a solution of 2-methoxy phenol (25 mg) and diethylchloro malonate (54.6 gm) in acetonitrile (250 ml) was added with potassium carbonate (42 gm) at room temperature. The reaction mass was stirred at room temperature for 4 hrs. After completion of the reaction, the reaction mass was filtered and obtained filtrate was distilled under vacuum to get oily mass. The obtained crude oil was dissolved in to toluene and washed the toluene layer with water and sodium hydroxide solution (2% w/w). The toluene layer was distilled completely under vacuum to get tiled compound (61.2 gm)
Example-3:
Preparation of 2-Amidinopyrimidine acetate
2-cyano pyrimidine (25 gm), ammonium acetate (22 gm) and 1, 4-diazabicyclo [2, 2, 2]-octane i.e. DABCO (1.2 gm) in ammonical methanol (10% ammonia content) were heated at 55°C for 22 hrs. After completion of the reaction, the reaction mass was cooled to about 5°C-10°C and the separated solid was filtered and washed with chilled methanol. The resultant solid was dried in air tray dryer at 50°C. (Weight = 35.5 gm, purity = 99.56%)
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Example-4:
Preparation of 5-(2~methoxyphenoxy)-2,2'-bipyrimidine-4,6 (1H, 5H)-dione
To a solution of 2-amidino pyrimidine acetate (3.0 gm) in methanol (30 ml) was added with diethyl-(2-methoxy phenoxy)malonate (5.5 gm) at room temperature. The reaction mass was cooled to about 0°C and added with sodium methoxide (2.2 gm). The reaction mass was stirred for 2 hrs at 0°C and then stirred the reaction mass at the room temperatures till the completion of reaction. After completion of the reaction, the reaction mass was cooled to about 0°C-5°C and pH of the reaction mass was adjusted to - 1.0 with dilute HCl. The resultant reaction mass was slowly added with water (100 ml) over a period of 30 minutes and stirred for 3 hrs at 10°C-15°C. The separated solid was filtered and washed with water. The wet solid was dried in oven at 45°C to afford the 4.3 gm crude of the title compound. The crude material was added in methanol (15 ml) and heated to about 60°C. Then reaction mass was cooled to room temperature and stirred for 10 hrs at room temperature. The separated solid was filtered to get the pure title compound (Weight = 3.6 gm & Purity = 98.29%)
Example-5:
Process for the preparation of compound of formula (III)
A mixture of 5-(2-methoxyphenoxy)-2, 2'-bipyrimidine-4.6 (1H, 5H)-dione (20 gm), acetonitrile (40 ml) and water (2 ml) were added with triethylamine (12.9 gm) at room temperature. The reaction mixture was added with phosphorus oxychloride (48 gm) in drop wise manner and heated to 85°C-90°C for 6-7 hrs. After completion of the reaction, the reaction mixture was slowly added in to the chilled water over a period of 30 minute at 0°C-10°C and stirred for 1 hour at the same temperature. The separated solid was filtered and washed with water till the pH of mother liquor became 6.0. The wet solid was dried in air tray dried at 50°C to get the compound of formula (III) (Weight = 21.35 gm, purity = 99.6%).
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Examplc-6:
Process for the preparation of Potassium salt of 4-tertbutyl bcnzenesulfonamide (IV).
A mixture of 4-tert-butyl benzenesulfonamide (25 gm) and isopropyl alcohol (125 ml) were added with potassium hydroxide (10 gm) at room temperature. The mixture was stirred for 2 hrs at room temperature and cooled to about 10°C. The separated solid was filtered and the obtained wet mass was dried in a vacuum oven at 50°C for 3 hrs to get the titled compound (Weight = 28.9 gm, purity = 99.8%).
Esample-7:
Process for the preparation of compound of formula (II)
A mixture of compound of formula (III) (30 gm) and potassium salt of 4-tertbutylbenzene sulfonamide (IV) (21.42 gm) in sulfolane (150 ml) were added with potassium hydroxide (8 gm). The reaction mixture was heated at 90°C-95°C for 2 hrs. After completion of the reaction, the reaction mass was slowly added with water (600 ml) manner at 25°C and the obtained solid was filtered. The resultant solid was dried in vacuum oven at 50°C to get the potassium salt of compound of formula (II) (Weight = 41.2 gm, purity = 99.45%).
Example-8:
Process for the preparation of Bosentan of formula (I)
A mixture of ethylene glycol (10 gm) and DBU (l,8-diazabicyclo[5.4.0]undec-7-ene) (4.0 gm) were heated at 70°C-75°C for 5 hrs. Then potassium salt of compound of formula (II) (5.0 gm) and sodium iodide (0.30 gm) were added to the reaction mixture and heated the reaction mixture at 110°C for 7-8 hrs. After completion of the reaction, the reaction mixture was added with chilled water (20 ml) and diluted hydrochloric acid to adjust the pH to 1-2 and stirred for 1 hrs at room temperature. The seperated solid mass was filtered, washed with water and dried in a vacuum oven to get Bosentan (I). The wet solid was added with ethanol (25 ml) at room temperature followed by heating at 75°C-80°C. The

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solution was cooled to about 34°C-40°C and slowly added with water (25 ml) over a period of 20 minutes followed by stirring for 5 hours at room temperature. The separated solid was filtered and washed with 1:1 mixture of ethanol (5ml) and water (5 ml). The wet material was dried in air to get the title compound (Weight = 4.0 gm, purity = 99.40%)
Dated this 02nd June, 2009
for Torrent Pharmaceuticals Limited, Praveen Chand Gandhi
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