Claims:We Claim:
1) An improved process for the preparation of Prazosin Hydrochloride compound of structural formula (1) or its pharmaceutically acceptable salts

(1)
comprising the steps of:
a. reacting 2-Furoic acid with chlorinating agent in presence of catalyst and an organic solvent to give 2-Furoyl chloride
(4)
which is then reacted with N-protected piperazine compound of formula (4) in presence of solvent and a base to get an intermediate compound of Formula (5) whereas R is an amine protecting group

b. the obtained intermediate is treated with deprotecting agent to get the compound of formula (6)

(6)

c. reacting the compound of formula (6) with the chloro compound of formula (7)

(7)
in presence of base and solvent to get the compound of Formula (1).

2) The process for the preparation of Prazosin Hydrochloride (1) according to Claim – 1, wherein the intermediate 2-Furoyl chloride is carried in-situ for further reaction without isolation.

3) The process for the preparation of Prazosin Hydrochloride (1) according to Claim – 1, wherein the base is selected from inorganic base groups comprising potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate and potassium carbonate or organic base groups comprising triethylamine and pyridine.

4) The process for the preparation of Prazosin Hydrochloride (1) according to Claim – 1, wherein the organic solvent is selected from group comprising toluene, ethylacetate, methanol, n-butanol, tetrahydrofuran, dichloromethane, dimethylacetamide (DMA), chlorobenzene, dimethyl sulfoxide (DMSO) and water and/or mixtures thereof.

5) The process for the preparation of Prazosin Hydrochloride (1) according to Claim – 1, wherein R can be an amine protecting group selected from tert-butyl carbamate, benzyl carbamate, acetamide, trifluoroacetamide, phthalimide, benzylamine and tritylamine.

6) The process for the preparation of Prazosin Hydrochloride (1) according to Claim – 1, wherein the catalyst used in step – a) is selected from dimethyl formamide, N, N - dimethyl aniline, Dimethyl acetamide and N-methyl morpholine.

7) The process for the preparation of Prazosin Hydrochloride (1) according to Claim – 1, wherein the deprotecting agent used in step – b) is selected from group comprising isopropanolic hydrochloric acid, aqueous hydrochloric acid, Sulfuric acid, Trifluoro acetic acid, Methane sulfonic acid and acetyl chloride in Methanol.

8) The process for the preparation of Prazosin Hydrochloride (1) according to Claim – 1, wherein the chlorinating agent is selected from thionyl chloride, sulfuryl chloride, oxalyl chloride, PCl5 and POCl3.

9) An improved process for the preparation of Prazosin Hydrochloride compound of structural formula (1)

(1)
comprising the steps of:
a. reacting 2-Furoic acid with thionyl chloride in presence of catalyst and an organic solvent to give 2-Furoyl chloride wherein the catalyst is DMF
(4)
which is then reacted with N-protected piperazine compound of formula (4) in presence of solvent and a base to get an intermediate compound of Formula (5) whereas R is the tert-butyl carbamate as protecting group of amine

b. the obtained intermediate is treated with IPA.HCl to get the compound of formula (6)

(6)

c. reacting the compound of formula (6) with the chloro compound of formula (7)

(7)
in presence of Sodium carbonate and solvent to get the compound of Formula (1).

10) The process for the preparation of Prazosin Hydrochloride (1) according to Claim – 9, wherein the organic solvent is selected from group comprising toluene, ethylacetate, methanol, n-butanol, tetrahydrofuran, dichloromethane, dimethylacetamide (DMA), chlorobenzene, dimethyl sulfoxide (DMSO) and water and/or mixtures thereof.
, Description:FIELD OF THE INVENTION
The present invention relates to a commercially viable improved process for the preparation of Prazosin Hydrochloride (I) which is useful in the treatment of patients with hypertension to lower blood pressure as lowering the blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily stokes and myocardial infarctions.

BACKGROUND OF THE INVENTION
Prazosin Hydrochloride is chemically described as hydrochloride salt of 1-(4-amino-6,7-dimethoxy2-quinazolinyl)-4-(2-furoyl) piperazine and is represented by structural formula I.

(1)

Prazosin Hydrochloride a quinazoline derivative is the first of a new chemical class of antihypertensive. The trade name of Prazosin Hydrochloride is MINIPRESS® approved by the FDA for the treatment of patients with hypertension to lower their blood pressure.
The formation of linkage between amide bond group which plays a vital role in several important natural products as well as artificial compounds more particularly in the development of antihypertensive medicines and Quinazolinyl chloride intermediate to obtain the compound of Formula (I).
The synthesis of Quinazolinyl chloride intermediate has been detailed in number of the prior arts such as DE 2847623 and Journal of Medicinal Chemistry 1987, 30, 49 have described the synthetic procedure fully.
Also there are number of known methods for the synthesis of amides available in the literature. Some of the well-known methods are reacting primary or secondary amines with the esters will end up with the amide formation. Whereas the said methods have disadvantages such as the reaction to be carried out in presence of solvents and in the heating condition in case of primary amines wherein the usage of catalysis such as Lewis acids, strong bases and enzymes in addition to the solvents are unavoidable in case of secondary amine.
In recent days, there are number of researchers have developed a variety of processes to prepare the Prazosin and its intermediates as anti-hypertension medicines. Few examples are as disclosed:
Bioorg. Med. Chem. Lett. 24 (2014) 3739 discloses the process for the preparation of amide intermediate by condensing the Boc-Piperazine compound with the acid compound by using coupling reagents and the reported yield was 64%. However the present invention prepares the same intermediate in the conventional method using acid chloride coupling with the Boc-piperazine without usage of coupling reagents results in the more yield percentage (Yield: 94.8% & Purity in Area % by HPLC: 99.93%). The process as disclosed in the journal is as follow:

Bioorg. Med. Chem. Lett. 22 (2012) 5545 and Bioorg. Med. Chem. Lett. 22 (2012) 2807 disclose the process for the preparation of amide intermediate by condensing acid or acid chloride with Boc-protected piperazine to give corresponding Boc amide which is deprotected using Hydrogen chloride in ether to give the required compound. The process as disclosed in the present invention gives the required product with the better yield and higher purity than reported (Yield: 94.8% & Purity in Area % by HPLC: 99.93%). The process as disclosed in the journals is as follow:

J. Med. Chem. 2012, 55(21), 9181 discloses the synthesis of amide intermediate by coupling Boc-piperazine with the corresponding acid using HBTU in DCM to give the corresponding Boc amide which is purified by preparative HPLC. The deprotection of Boc amide is carried using TFA in DCM and further purified by automated preparative HPLC. The yield mentioned is very less. Comparing the process for the preparation of amide intermediate as disclosed in the present invention appears to be commercially feasible in terms of cost, better yield and purity.

Synthetic Communications 2004, 34, 2917 discloses the process for the preparation of amide intermediate using the corresponding acid and unprotected piperazine compound in presence of Triphenyl Phosphine (TPP) and N-Bromo Succinimide (NBS) to give corresponding amide derivative. Nonetheless, the said process requires further purification like column chromatography in order to achieve the high purity compound (Yield: 94.8% & Purity in Area % by HPLC: 99.93%) and The route of synthesis of amide intermediate as delineated in the disclosure as below:

Wen Chih Chou et al., in the patent US 6313293 B2 describes the process for the preparation of N-(furan-2-carbonyl) piperazine by treating corresponding acid with piperazine using HMDS at 110°C. During the said process, the possibility for the formation of dimer impurity i.e. impurity B is more.

Despite various prior disclosures of the processes for preparing Prazosin, they still suffer with one or more drawbacks as mentioned above including commercially non-viable processes, handling concerns in plant besides multistep impurities removal etc. Considering the therapeutic importance of Prazosin, there still exist needs to develop and provide an improved commercially viable process, which is robust and amenable to scale up resulting in improved quality characteristics of active pharmaceutical ingredient.

The inventors of the present invention surprisingly have come up with an improved process for the preparation of Prazosin Hydrochloride and have shown significant advantageous over the prior disclosures in terms of yield, purity, duration of synthesis, safety and commercially viable process with lesser price which makes the said product an economically available to the customers.
OBJECTIVE OF THE INVENTION
An object of the present invention is to provide an improved process for the preparation of Prazosin Hydrochloride compound of formula (1).

SUMMARY OF THE INVENTION
The invention disclosed in the specification relates to commercially viable process for preparation of antihypertensive compound Prazosin, which is approved for the treatment of patients with hypertension to lower blood pressure as lowering the blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily stokes and myocardial infarctions.
In one aspect according to the present invention, it relates to a new process for preparing Prazosin Hydrochloride (I),

(I)

comprising the steps of:
a. reacting 2-Furoic acid with chlorinating agent in presence of catalyst and an organic solvent to give 2-Furoyl chloride

(4)

which is then reacted with N-protected Piperazine compound of formula (4) in presence of solvent and a base to get an intermediate whereas R is an amine protecting group

b. the obtained intermediate is treated with deprotecting agent to get the compound of formula (6)

(6)

c. reacting the compound of formula (6) with chloro compound of formula (7)

(7)

in presence of base and solvent to get the compound of Formula (1) or it’s pharmaceutically acceptable salts.

The above process is illustrated in the figure (1):

Figure – 1

DETAILED DESCRIPTION OF THE INVENTION
In their endeavor for the present invention, it provides an improved commercially useful process for preparation of Prazosin Hydrochloride (I).
In one embodiment according to the present invention, it provides process for preparing Prazosin Hydrochloride (I),

(1)

Said process according to the present invention for the preparation of Prazosin Hydrochloride (1) or its pharmaceutically acceptable salts, comprising the steps of:
a. reacting 2-Furoic acid with chlorinating agent in presence of catalyst and an organic solvent to give 2-Furoyl chloride

(4)

which is then reacted with N-protected Piperazine compound of formula (4) in presence of solvent and a base to get an intermediate whereas R is an amine protecting group

b. the obtained intermediate is treated with deprotecting agent to get the compound of formula (6)

(6)

c. reacting the compound of formula (6) with chloro compound of formula (7)

(7)

in presence of base and solvent to get the compound of Formula (1).

The individual steps of the process according to the present invention are detailed herein below; however more specifics are demonstrated by virtue of working examples given in the example section.

The process step (a) of reacting 2-Furoic acid with chlorinating agent is carried out in presence of solvent and catalyst to give 2-Furoyl Chloride. The obtained 2-Furoyl chloride is carried in-situ without any further isolation or purification to react with N-protected Piperazine in presence of base and solvent to give compound of Formula (5).

In one embodiment of the present invention, catalyst used in step (a) is selected from the group comprising Dimethyl formamide, N, N - dimethyl aniline, Dimethyl acetamide and N-methyl morpholine.
In one of the specific embodiment of the present invention, Dimethyl formamide is used as a catalyst.
In another embodiment, the chlorinating agent used in step (a) are selected from thionyl chloride, sulfuryl chloride, oxalyl chloride, PCl5 and POCl3.
In one specific embodiment of the present invention, thionyl chloride is used.
The amine protecting group as mentioned in step (a) are selected from tert--butyl carbamate, benzyl carbamate, acetamide, trifluoroacetamide, phthalimide, benzylamine and tritylamine.
In yet another specific embodiment, the amine protecting group used is tert--butyl carbamate.
The suitable solvents that can be used in step (a) are selected from the group comprising ethylacetate, toluene, methanol, n-Butanol, tetrahydrofuran, dimethylacetamide, chlorobenzene, dimethyl sulfoxide, methylethylketone and water and/or mixtures thereof in any proportion without limitation.
In particular embodiment of the present invention, toluene is used.
The process step (a) is performed at a reflux temperature ranging between 40-70°C.
In one of the particular embodiment according to present invention, the process step (a) reaction was performed at temperature 50-55°C for time duration of 10-15 hrs.
The base used in step (a) is selected from inorganic base groups comprising potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate and potassium carbonate or organic base groups comprising triethylamine and pyridine.
The mole ratios of reactants and the reagents used therein can be appropriate based on the resultant product and the side products or by products.
The process step (b) is treating the obtained intermediate of compound of Formula (5) from step (a) with deprotecting agent in presence of solvent to get the compound of Formula (6).
The deprotecting agent used in step (b) is selected from the group comprising isopropanolic hydrochloric acid, aqueous hydrochloric acid, Sulfuric acid, Trifluoro acetic acid, Methane sulfonic acid and acetyl chloride in Methanol.
In one of the specific embodiment, isopropanolic hydrochloric acid (IPA.HCl) is used.
The suitable solvents that can be used in step (b) are selected from the group comprising ethylacetate, toluene, methanol, n-Butanol, tetrahydrofuran, dimethylacetamide, chlorobenzene, dimethyl sulfoxide, methylethylketone and water and/or mixtures thereof in any proportion without limitation.
In particular embodiment of the present invention, ethylacetate is used.

The process step (c) is reacting to the compound of Formula (6) with the chloro compound of Formula (7) in presence of base and solvent to get the compound of Formula (1) or its pharmaceutically acceptable salts.
The suitable solvents that can be used in step (c) are selected from the group comprising ethylacetate, toluene, methanol, n-Butanol, tetrahydrofuran, dichloromethane, dimethylacetamide, chlorobenzene, dimethyl sulfoxide, methylethylketone and water and/or mixtures thereof in any proportion without limitation.
In particular embodiment of the present invention, dichloromethane is used to extract free base of an intermediate compound of Formula (6).
In another embodiment of the present invention, n-Butanol is used to dissolve the free base intermediate compound of Formula (6).
In specific embodiment of the present invention, dimethyl acetamide is used to dissolve the chloro compound of Formula (7).
The base used in step (c) is selected from inorganic base groups comprising potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate and potassium carbonate or organic base groups comprising triethylamine and pyridine.
In one of the embodiment of the present invention, Sodium Carbonate is used.
In yet another embodiment of the present invention, the chloro compound of Formula (7) is dissolved in dimethylacetamide and carried out particle free operation and then transferred to n-butanol mass of free base of an intermediate compound of Formula (6).
The process step (c) is performed at a temperature ranging between 70-140°C.
In one of the particular embodiment according to present invention, the process step (c) is performed at temperature 90-100°C for a time duration of about 10-14 hrs.
In one specific embodiment of the present invention, the intermediate of compound of Formula (3) and Formula (6) has been carried into the next step without any further isolation or purification.
The mole ratios of reactants and the reagents used therein can be appropriate based on the resultant product and the side products or byproducts.
For example, the working-up of reaction mixtures, especially in order to isolate desired compounds, follows customary procedures, known to the organic chemists skilled in the norms of the art and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like.
Advantageously, the process of present invention avoids the use of hazardous reagents thus making the process ecofriendly.
The reagents used herein the process of present invention are cheaper, commercially available and may not form impurities or side products unlike in the prior art processes.
After completion of the reaction, the desired compounds can be obtained from the reaction mixture by conventional means known in the art. For example, the working-up of reaction mixtures, especially in order to isolate desired compounds, follows customary procedures, known to the organic chemists skilled in the norms of the art and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like.
The processes reported for the preparation of Prazosin Hydrochloride (I) in the art results in the formation of various impurities and byproducts leading to include additional purification steps intermittently at several stages thus resulting in very poor yields of the final product.
Advantageously, the process of present invention provides substantially pure Prazosin Hydrochloride (I) with higher yields and purities by using novel intermediate process.
The present invention provides simple, ecofriendly, economical, reproducible, robust process for the preparation of Prazosin Hydrochloride (I) which is well feasible on a commercial scale.
Advantageously, the process of present invention described herein has simple reaction steps, produces the intermediate surprisingly in high yields and purities than the processes reported in the literature and well amenable on commercial scale.

As used herein, the term "HPLC" refers to High-performance liquid chromatography. As used herein, the term "area % by HPLC" refers to the area in an HPLC chromatogram of one or more peaks compared to the total area of all peaks in the HPLC chromatogram expressed in percent of the total area.

Substantially pure Prazosin Hydrochloride obtained by the process of present invention was analyzed by high performance liquid chromatography (HPLC) method with the conditions as given below,

Chromatographic conditions: The liquid chromatograph is equipped with a UV/PDA Detector.
Column : YMC Triart C18 ExRs 150*4.6mm, 3.5 µm
Wavelength : 254nm
Flow rate : 1.0 mL / min
Load : 10 µL
Run time : 65 minutes
Column Oven Temperature : 40°C
Mode of elution : Gradient
Diluent : Water:Acetonitrile:HClO4(900:100:0.1)% v/v/v
Sample conc. : 0.25 mg / mL

Time %A %B
0.0 85 15
4.0 85 15
40.0 42 58
55.0 42 58
56.0 85 15
65.0 85 15

Buffer: Transfer 1.0 mL of HClO4 in 1000 mL of Milli-Q-water mixed filter through 0.45µ membrane filter.
Mobile phase-A: Buffer
Mobile phase-B: Acetonitrile and Buffer 70:30 (%v/v).
In another embodiment, the Prazosin Hydrochloride (I) obtained by the processes of the present invention may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or liquid paraffin.
The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyloleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
Pharmaceutically acceptable excipients used in the compositions comprising Prazosin Hydrochloride (I) obtained as per the process of present invention include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

Table – 1: Stability Study Data for Prazosin Hydrochloride
Stability study initiated on Jul 12, 2018
Storage Condition: Temperature is 40°C ± 2°C & Humidity is 75% ± 5%RH

S # Parameters Initial 1st Month 2nd Month 3rd Month 6th Month Remarks
1. Description
(Spec: White or almost white powder) White powder White powder White powder White powder White powder No changes
2. Loss on Drying (Spec: NMT 2.0% for anhydrous & 8.0-15.0% for polyhydrate form) 1.2% 1.8% 1.35% 1.3% 1.6% No significant changes observed
3. Related Substances (by HPLC) (Spec: Acceptance Criteria: NMT 0.4%
Individual impurities: NMT 0.2% each
Total: 0.5%) 0.5% 0.5% 0.5% 0.5% 0.5% No changes observed
4. Assay on Potentiometry (Spec: Not less than 97.00% and not more than 103.00%) 99.9% 99.2% 99.8% 99.8% 99.7% No significant changes observed
5. PXRD (To conforms the Crystalline form) Conforms Conforms Conforms Conforms Conforms No significant changes observed

The stability study for the timeline of six months has been carried out for the Final API of Prazosin Hydrochloride with various factors including LOD, Impurities, Assay and Polymorph. The study revealed that the Final API Prazosin Hydrochloride is stable in all aspects and those results complied with the ICH guidelines and monograph during the course of study which is palpable from the above table.
The product of the present invention appears to be stable for its shelf life since the stability study has shown that the product is consistently robust throughout the six months without any predominant or significant changes. The polymorphic form of the product also appears to be constantly stable over the period of six months without getting converted into any other forms during the long term storage by absorbing the moisture content. Due to its stability, robust, commercially viable and also its therapeutic importance, the product of the instant invention still holds the need.

Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.

EXAMPLES

Example-1: Preparation of Furan-2-yl (piperazine-1-yl) methanone: (6):
To the stirred 2-furoic acid (2) (100 g, 1.0 eq.), DMF (0.5 ml) and thionyl chloride (127.36 g, 1.2 eq.) in toluene (200 ml, 2.0 V) is added at 75-80 °C and stirred for about 4-5 hrs. Then the reaction mass is cooled to 25-35 °C. This acid chloride reaction mass is added to a solution of N-Boc piperazine (149.54 g, 0.9 eq.), triethyl amine (135.42 g, 1.6 eq.) in toluene (1000 ml, 15.0 V) at 10-50 °C (addition is continuous even though exothermic up to 50 °C). The mass is stirred at 25-30 °C until TLC complies. Then water (200 ml, 2.0 V) is charged at 25-35 °C. The organic and aqueous layers are separated at 50-55 °C. Then the organic layer is washed with 10% Na2CO3 solution (200 ml, 2.0 V) at 50-55 °C, followed by washed with 20% sodium chloride solution (200 ml, 2.0 V). The solvent is distilled under vacuum at below 60 °C and co-distilled with ethyl acetate (100 ml, 1.0 V). The obtained solid is stirred in ethyl acetate (300 ml, 3.0 V) at RT for about 60-120 min. Then the solid is filtered and washed with ethyl acetate (200 ml, 1.0 V). The solid is dried under vacuum at below 50 °C.

The solid is stirred in ethyl acetate (1000 ml, 10.0 V) and Na2CO3 (142 g, 1.50 eq.) at 50-55 °C for about 2-3 hrs. The solid is filtered and collected the ethyl acetate layer. Similarly the product is extracted in to ethyl acetate (2x500 ml, 2x5.0 V) at 50-55 °C and finally washed with ethyl acetate (100 ml, 1.0 V). The ethyl acetate layers are combined and distilled out the solvent under vacuum at below 55 °C to get crude material. To the obtained crude material water is added (500 ml, 5.0 V) and extracted the product into chloroform (1000 ml, 10.0 V). The product is extracted from aqueous layer into chloroform (3x500 ml, 3x5.0 V). The chloroform layers are combined and washed with 25% sodium chloride solution. The solvent is distilled under vacuum at below 55 °C to get PSN-1A (6) as crude material. Yield: 106 g (66.25 %) & Purity by HPLC: 99.71%.
1H-NMR (400 MHz, DMSO-d6): d 7.478-7.481 (t, 1H, ArH), 6.977-6.984 (d, 1H, -ArH), 6.472-6.482 (q, 1H, -ArH), 3.771 (b, 4H, Piperazine protons), 2.918-2.938 (t, 4H, Piperazine Protons), 1.770 (s, 1H, -NH). Mass M/Z: 180.82 (m+)

Example-2: Preparation of Prazosin Hydrochloride (1):
PSN-1A (39.46 g, 1.05 eq.) is stirred in 1-butanol (500 ml, 10.0 V) and activated carbon (5 g) at 45-50 °C for about 30-40 min. Then the mass is filtered through hyflo bed and washed with 1-butanol (100 ml, 2.0 V). The butanol layer is stirred with PSN –Chloro compound (50 g, 1.0 eq.) at 115-120 °C until TLC complies. Then the mass is cooled to 80-85 °C. The solid is filtered and washed with 1-butanol (100 ml, 2.0 V) and dried at 70-75 °C (Yield: 83 g, 94.85%). HPLC: 99.781%.
1H-NMR (DMSO-d6): d 12.62 (s, 1H, HCl), 9.014, 8.651(s, 2H, -NH2), 7.904 (s, 1H, -furan proton), 7.797 (s, 1H, -Aromatic proton), 7.708 (s, 1H, -Aromatic proton), 7.095-7.103 (d, 1H, -furan proton), 6.671-6.675(d, 1H, -furan proton), 4.026 (m, 8H, -Piperazine protons), 3.861-3.872 (m,10H,6methoxy & 4 Piperazine protons).
IR (cm-1): 1595.41(Amide CO stretching), 3300.51(Aromatic NH2 stretching), 1634.58 (C=N of Quinazoline Stretching).Mass (m/z): 384.16 (m+1).

Example-3: Preparation of Furan-2-yl (piperazine-1-yl) methanone (6):
2-furoic acid (100 g, 1.0 eq.), DMF (0.5 ml) and thionyl chloride (127.36 g, 1.2 eq.) are stirred in toluene (200 ml, 2.0 V) at 75-80 °C for about 4-5 hrs. The reaction mass is cooled to 25-35 °C. The acid chloride reaction mass is added to a solution of N-Boc piperazine (149.54 g, 0.9 eq.), triethyl amine (135.42 g, 1.6 eq.) in toluene (1000 ml, 15.0 V) at 10-50 °C (addition is continuous even though it is exothermic up to 50 °C). The mass is stirred at 55-60 °C for about 2-3 hrs then water is charged (200 ml, 2.0 V) at 55-60 °C and stirred for about 20-30 min. Organic and aqueous layers are separated at 55-60 °C. The organic layer is washed with 10% citric acid solution (200 ml, 2.0 V) at 55-60 °C followed by 20 % sodium chloride solution (200 ml, 2.0 V). Then IPA.HCl (300 ml, 3.0 V) is charged to organic layer at 25-35 °C and stirred at 50-55 °C for about 4-5 hrs (until TLC complies). The mass is cooled down to 25-35°C and filtered the solid then washed with ethyl acetate (100 mL, 1.0 V) to get Hydrochloride salt i.e. PSN-1A. The solid obtained is dried at 55-60°C. (Yield: 150.0g, 77.58% and Purity by HPLC-99.869%).Mass (m/z): 180.82 (m+)

Example – 4: Preparation of Prazosin Hydrochloride (1):
PSN-1A (10 g, 1 eq.) is stirred in water (40 ml, 4.0 V) and activated carbon (1 g) for about 20-30 min. The mass is filter through hyflo bed and washed with water (10 ml, 1.0 V). The water layer is taken into RBF and Na2CO3 (9.77 g, 2.0 eq.) is charged and stirred for about 15-20 min. The product is extracted into dichloro methane (5x50 ml, 5x5.0 V) at 25-35 °C and combined the organic layers and washed with 20% NaCl solution (20 ml, 2.0 V). The combined organic layers are dried over Na2SO4 (1 g, 10%) and distilled the solvent under vacuum to get the free base as crude. The obtained free base is stirred in 1-butanol or Isopropyl alcohol (70 ml, 7.0V) at 45-50 °C for about 20-30 min and filtered the mass through hyflo bed and washed with 1-butanol or Isopropyl alcohol (20 ml, 2.0 V) and kept the Butanol layer or Isopropyl alcohol layer aside in the RBF.
To a solution of PSN-Chloro compound (8.3 g, 0.75 eq.) N,N-dimethyl acetamide (DMAC) (80 ml, 8.0 V) and activated carbon (0.5 g, 5%) are added and stirred at 50-55 °C for about 30-60 min. The mass is filtered through hyflo bed and washed the bed with N, N-dimethyl acetamide (20 ml, 2.0 V). The butanol layer or Isopropyl alcohol layer is stirred with DMAC layer at 90-95 °C until TLC complies. Then the mass is cooled down to 50-55 °C and filtered the solid then washed with 1-butanol or Isopropyl alcohol (20 ml, 2.0 V) and dried the solid at 70-75 °C.
The above wet material is charged into RBF and isopropyl alcohol (90.0 ml 9.0V) water (40.0 ml 4.0V) is added into it. It is heated to Reflux and maintained for 4.0-5.0 hours at reflux temperature then cooled down to 50-55°C and maintained for 30-60 minutes at 50-55°C. The product is filtered and washed with isopropyl alcohol (20.0 ml 2.0V). The material is unloaded and stirred with isopropyl alcohol (130.0 ml 13.0V) at reflux temperature for 4-5 hours then cooled to 50-55°C and stirred for 30-60 minutes at 50-55°C. The compound is filtered and washed with isopropyl alcohol (20.0 ml 2.0V). The Wet material is dried at 80-85°C (12.0g 68.50%). (Yield: 12 g, 68.50%). HPLC: 99.954%. Mass (m/z): 384.16 (m+1).

Example – 5: Alternate Purification process:
PSN-1A (10 g, 1 eq.) is stirred in water (40 ml, 4.0 V) and activated carbon (1 g) for about 20-30 min. The mass is filter through hyflo bed and washed with water (10 ml, 1.0 V). The water layer is taken into RBF and Na2CO3 (9.77 g, 2.0 eq.) is charged and stirred for about 15-20 min. The product is extracted into dichloro methane (5x50 ml, 5x5.0 V) at 25-35 °C and combined the organic layers and washed with 20% NaCl solution (20 ml, 2.0 V). The combined organic layers are dried over Na2SO4 (1 g, 10%) and distilled the solvent under vacuum to get the free base as crude. The obtained free base is stirred in 1-butanol or Isopropyl alcohol (70 ml, 7.0V) at 45-50 °C for about 20-30 min and filtered the mass through hyflo bed and washed with 1-butanol or Isopropyl alcohol (20 ml, 2.0 V) and kept the Butanol layer or Isopropyl alcohol layer aside in the RBF.
To a solution of PSN-Chloro compound (8.3 g, 0.75 eq.) N,N-dimethyl acetamide (DMAC) (80 ml, 8.0 V) and activated carbon (0.5 g, 5%) are added and stirred at 50-55 °C for about 30-60 min. The mass is filtered through hyflo bed and washed the bed with N, N-dimethyl acetamide (20 ml, 2.0 V). The butanol layer or Isopropyl alcohol layer is stirred with DMAC layer at 90-95 °C until TLC complies. Then the mass is cooled down to 50-55 °C and filtered the solid then washed with 1-butanol or Isopropyl alcohol (20 ml, 2.0 V) and dried the solid at 70-75 °C.
The above obtained wet material is stirred with isopropyl alcohol (130.0 ml 13.0V) at reflux temperature for 4-5 hours then cooled down to 50-55°C and stirred for 30-60 minutes at 50-55°C. The compound is filtered and washed with isopropyl alcohol (20.0 ml 2.0V). The Wet material is dried at 80-85°C (12.0g 68.50%). HPLC: 99.914%

Example – 6: Preparation of Prazosin Hydrochloride (1):
PSN-1A (5 g, 1 eq.) and PSN-Chloro compound (5.23 g, 0.95 eq.) are stirred in mixture of N,N-dimethyl acetamide (50 ml, 10.0 V) & water (25 ml, 5.0 V) at 90-95 °C until TLC complies. Then the mass is cooled to 80-85 °C and filtered the solid then washed with water (20 ml, 4.0 V) followed by acetone (10 ml, 2.0 V). The solid obtained is dried at 50-55 °C (Yield: 6.26 g, 64.87%). HPLC: 96.236%; Mass (m/z): 384.16 (m+1).

Example – 7: Preparation of Prazosin Hydrochloride (1):
PSN-1A (5 g, 1 eq.) and PSN-Chloro compound (5.23 g, 0.95 eq.) are stirred in mixture of DMF (50 ml, 10.0 V) & water (25 ml, 5.0 V) at 90-95 °C until TLC complies. Then the mass is cooled to 80-85 °C and filtered the solid then washed with water (20 ml, 4.0 V) followed by acetone (10 ml, 2.0 V). The solid obtained is dried at 50-55 °C (Yield: 7.00 g, 72.53%). HPLC: 94.621%. Mass (m/z): 384.16 (m+1).

Example – 8: Preparation of Prazosin hydrochloride (1):
PSN-1A (12 g, 1 eq.) in water (60 ml, 5.0 V) and Na2CO3 (9.77 g, 2.0 eq.) in water (60 ml, 5.0 V) are stirred together for about 15-20 min. The product is extracted into dichloro methane (5x60 ml, 5x5.0 V) at 25-35 °C. The organic layers are combined and washed with 20% NaCl solution (24 ml, 2.0 V). The organic layer is dried over Na2SO4 (1.2 g, 10%) and the solvent is distilled under vacuum to get the free base as crude. The obtained free base is stirred in 1-butanol (84 ml, 7.0V) at 45-50 °C for about 20-30 min. The mass is filtered through hyflo bed and washed with 1-butanol (24 ml, 2.0 V). The Butanol layer is kept aside in the RBF.
To a solution of PSN-Chloro compound (10.0 g, 0.75 eq.) N,N-dimethyl acetamide (DMAC) (96 ml, 8.0 V) and activated carbon (0.6 g, 5%) are added and stirred at 50-55 °C for about 30-60 min. The mass is filtered through hyflo bed and washed the bed with N, N-dimethyl acetamide (24 ml, 2.0 V). The DMAC layer is distilled under vacuum at below 100 °C and Co-distilled with Butanol (24ml, 2.0 V). The obtained solid is stirred with above butanol layer at 115-120 °C until TLC complies. Then the mass is cooled to 80-85 °C and filtered the solid then washed with 1-butanol (24 ml, 2.0 V). The obtained solid is dried at 70-75 °C (Yield: 16 g, 69.08%). HPLC: 99.909%. Mass (m/z): 384.16 (m+1).

Example – 9: Preparation of Prazosin Hydrochloride (1):
PSN-Chloro compound (150 g, 1.0 eq.) is stirred in DMF (1200 ml, 8.0 V) at 55-60 °C for about 30-45 min. The mass is filtered through hyflo and washed with DMF (300 ml, 2.0 V). The solvent is distilled under vacuum at below 100 °C. To the distillate, DMF is charged (300 ml, 2.0 V) and stirred at 25-35 °C for about 45-60 min. The solid obtained is filtered and washed with DMF (75 ml, 0.5 ml) and dried the solid at 75-80 °C.
PSN-1A (142.34 g, 1.05 eq.) and Na2CO3 (132.66, 2.0 eq.) in ethyl acetate (900 ml, 6.0 V) are stirred at 50-55 °C for about 2-3 hrs. The solid is filtered and collected the ethyl acetate layer. Similarly the product is extracted into ethyl acetate (3x450 ml, 3x3.0 V) at 50-55 °C from the solid. Finally the solid is washed with ethyl acetate (150 ml, 1.0 V). The ethyl acetate layers are combined and the solvent is distilled under vacuum at below 55 °C to get crude. The crude is stirred in water (450 ml, 3.0 V) at 25-35 °C and extracted the product into chloroform (900ml/6.0 V & 4x450ml/4x3.0V) at 25-35 °C. The chloroform layers are combined and washed with 20% NaCl solution (300 ml, 2.0 V). The solvent is distilled under vacuum at below 55 °C to get crude compound. The crude in 1-butanol (1050 ml, 7.0 V) and activated carbon are stirred (15 g, 10%) at 40-45 °C for about 20-30 min. The mass is filtered through hyflo bed and washed with 1-butanol (300 ml, 2.0 V). This butanol layer is stirred with above obtained chloro compound at 115-120 °C until TLC complies then cooled to 80-85 °C. The solid is filtered and washed with butanol (150 ml, 1.0 V) and dried at 75-80 °C (Yield: 215 g, 81.90% and Purity by HPLC: 99.93%). Mass (m/z): 384.16 (m+1).

Example – 10: Preparation of Furan-2-yl (piperazine-1-yl) methanone by HMDS route:
To 2-Furoic acid (50 g, 1.0 eq.) in a RBF, Piperazine (76.7 g, 2.0 eq.) and Hexamethyldisilazane (HMDS) (185 ml, 3.7 V) are added and stirred at 115-120 °C U/N2 atmosphere for about 4-5 hrs. Toluene (100 ml, 2.0 V) is charged to the reaction mass at below 100 °C and the solvent is distilled under vacuum at below 100 °C. DCM (200 ml, 4.0 V) and water (150 ml, 3.0 V) are charged into the distillate at 25-35°C and Con. HCl (100 ml, 2.0 V) is added at 25-35 °C. The organic and aqueous layers are separated and kept the aqueous layer aside. The product is extracted from DCM layer with 20% aqueous HCl solution (100 ml, 2.0 V) and combined the aqueous layers to adjust the pH to 10-11 with potassium carbonate. The reaction mass is extracted with Dichloromethane (4x250 ml, 4x5.0 V) and combined the organic layers then washed the organic layer with 20% sodium chloride solution (100 ml, 2.0 V). The solvent is distilled u/v at below 45°C to get Furan-2-yl (piperazine-1-yl) methanone (PSN-1A) free base (Yield: 28 g, 35% and Purity by HPLC: 94.25%). Mass (m/z): 180.82 (m+).
Optionally, The above obtained wet material is stirred with isopropyl alcohol (130.0 ml 13.0V) at reflux temperature for 4-5 hours then cooled down to 50-55°C and stirred for 30-60 minutes at 50-55°C. The compound is filtered and washed with isopropyl alcohol (20.0 ml 2.0V). The Wet material is dried at 80-85°C (12.0g 68.50%). HPLC: 99.914%
While the foregoing pages provide working example and detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are illustrative only of the core of the invention and non-limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.