Field of the invention:
The present invention relates to an improved process for the preparation of Prazosin hydrochloride compound of formula-1 a and is represented by the following structural formula.
N . HC1
H3CO
NH2 Formula-la
The present invention also relates to novel crystalline form of Prazosin hydrochloride compound of formula-la.
Further the present invention also relates to furan-2-yl(piperazin-l-yl)methanone oxalate compound of formula-4a, which is useful in the preparation of compound formula-1 and its hydrochloride salt compound of formula-la.
Background of the invention:
Prazosin hydrochloride is marketed in US by Pfizer under the brand name of Minipress capsules for the treatment of hypertension, to lower blood pressure.
US Pat. Nos. 3,511,836, 3,635,979 and 3,663,706 discloses Prazosin and its acid addition salts.
Pharmacological studies on Prazosin hydrochloride, were reported by Scriabine etal., Experiential 1968, vol-24, pages-1150, and by Constantine etal., in "Hypertension: Mechanisms and Management", Onesti etal., editors, Grune and Stratton, Inc., 1973, p. 429-444.
The prior art process discloses various routes for the preparation of Prazosin hydrochloride. Those available routes have many disadvantages w.r.to impurities and yield.
US4092315 patent describes crystalline forms-a, p, y, monohydrate, dihydrate, polyhydrate, anhydrate, methanolate forms of Prazosin hydrochloride.

US4739055 patent describes anhydrous . stable crystalline 5-form of Prazosin hydrochloride.
JP03206088 patent describes e-form of Prazosin hydrochloride.
Polymorphs are distinct solids having the same molecular formula yet having distinct 5 advantageous physical properties compared to other polymorphic forms of the same compound. The difference in the physical properties of different polymorphic forms results from the orientation and intermolecular interactions of adjacent molecules in the bulk solid.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of 10 polymorphic forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption and: solid state NMR spectrum. One polymorphic form may give rise to thermal behavior different from that of another polymorphic form. Thermal behaviour can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning 15 calorimetry (DSC) which have been used to distinguish polymorphic forms.
The discovery of new polymorphic form of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product.
In view of the prior art processes, inventors of the present invention have developed 20 an improved process through novel salt of the intermediate and also developed novel crystalline form of the compound of formula-la.
Brief description of the invention:
The first aspect of the present invention is to provide an improved process for the 25 preparation of Prazosin hydrochloride compound of formula-la or its anhydrates or hydrates thereof.
The second aspect of the present invention is to provide furan-2-yl(piperazin-l-yi)methanone oxalate compound of formula-4a.

The third aspect of the present invention is to provide a process for the preparation of furan-2-yl(piperazin-l-yl)methanone oxalate compound of formula-4a.
The fourth aspect of the present invention is to provide a novel crystalline furan-2-yl(piperazin-l-yl)methanone oxalate compound of formula-4a, herein after designated as 5 crystalline form-M.
The fifth aspect of the present invention is to provide a process for the preparation of Prazosin free base compound of formula-1.
The sixth aspect of the present invention is to provide a novel crystalline form of Prazosin free base compound of formula-1, herein after designated as crystalline form-S.
10 The seventh aspect of the present invention is to provide a process for the preparation
of Prazosin hydrochloride compound of formula-la or its anhydrates or hydrates thereof.
The eighth aspect of the present invention is to provide novel crystalline form of
Prazosin hydrochloride compound of formula-la, herein after designated as crystalline form-
N,
15 The ninth aspect of the present invention is to provide an improved process for the
preparation of crystalline polyhydrate of Prazosin hydrochloride compound of formula-la.
Brief Description of the Drawings:
Figure 1: Illustrates the PXRD pattern of crystalline form-M of the compound of formula-4a.
20 Figure 2: Illustrates the PXRD pattern of crystalline form-S of Prazosin free base.
Figure 3: Illustrates the PXRD pattern of Prazosin hydrochloride obtained according to the example-5.
Figure 4: Illustrates the PXRD pattern of Prazosin hydrochloride obtained according to the example-6.
25 Figure 5: Illustrates the PXRD pattern of crystalline form-N of Prazosin hydrochloride. Detailed description of the invention:

As used herein the term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, pentane, cycloheptane, methylcyclohexane, ethylbenzene, m-, o-, or p-xylene, and the like; "ether solvents" such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-5 dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide
10 (DMSO), N-methylpyrrolidone.(NMP) and the like; "chloro solvents" such as dichloro methane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, amyl alcohol,
15 isoamyl alcohol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-. methoxyethanol, 1, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl •alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; "polar solvents" such as water or mixtures thereof.
The term "suitable base" used herein the present invention until unless specified is 20 selected from inorganic bases like "alkali metal hydroxides" such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride, lithium hydride 25 and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; ammonia, methanolic ammonia; and organic bases such as triethyl amine, methyl amine, ethyl amine, l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-Diazabicyclo (4.3.0)non-5-ene-(DBN), lithium dioisoporpylamide (LDA), n-butyl lithium, tribenzylamine,
5

isopropyl amine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, N-
ethylmorpholine, piperidine, dimethyl aminopyridine, morpholine, pyridine, 2,6-lutidine,
2,4,6-collidine, imidazole, 1-methyl imidazole, 1,2,4-triazole, l,4-diazabicycIo[2.2.2]octane
(DABCO) or mixtures thereof.
5 The term "salts" used in the present invention refers to acid addition salts selected
from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; organic acids such as acetic acid, maleic acid, malic acid, oxalic acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid; chiral acids such as S-(+) mandelic acid, R-(-) mandelic acid, L-(+)tartaric. acid, D-(-)tartaric acid, L-malic acid, D-
10 malic acid, D-maleic acid, (-)-naproxen, (t)-naproxen, (lR)-(-)-camphor sulfonic acid, (IS)-(+)-camphor sulfonic acid (lR)-(+)-bromocamphor-10-sulfonic acid, (IS)-(-)- bromocamphor-10-sulfonic acid, (-)-Dibenzoyl-L-tartaric acid, (-)-Dibenzoyl-L- tartaricacid monohydrate, (+)-Dibenzoyl-D -tartaric acid, (+)-Dibenzoyl-D -tartaric acid monohydrate, (+)-dipara-tolyl-D-tataric acid, (-)-dipara-tolyl-L-tataricacid, L(-> pyroglutamic acid, L(+)-pyroglutami'c
15 acid, (-)-lactic acid, L-lysine, D-lysine etc., and like.
As used herein the term "suitable hydrochloric acid source" is selected from HC1 gas, aqueous HC1, dry HC1, ethyl acetate-HCl, IPA-HC1, ethanol-HCI, methanol-HCI.
As used herein the term "suitable chlorinating agent" is selected from S02C12, SOCI2, (C0C1)2,P0C13, PCl3andPCl5.
20 The first aspect of the present invention provides an improved process for the
preparation of Prazosin hydrochloride compound of formula-la or its anhydrates or hydrates thereof,


H3CO

25 comprising of:

a) Reacting furan-2-carboxylic acid compound of formula-2 with a suitable chlorinating
agent in a suitable solvent provides the furan-2-carbonyI chloride compound of
formula-3,
b) reacting the compound of formula-3 in-situ with piperazine in presence of aqueous
5 hydrogen bromide in a suitable solvent provides the furan-2-yI(piperazin-l-
yl)methanone compound of formula-4,
c) treating the compound of formula-4 with oxalic acid in a suitable solvent provides
furan-2-yl(piperazin-l-yl)methanone oxalate compound of formula-4a,
d) reacting the compound of formula-4a with 2-chlorq-6,7-dimethoxyquinazolin-4-
10 amine compound of formula-5 in presence of a suitable base in a suitable solvent
provides Prazosin free base compound of formula-1,
e) optionally, purifying the compound of formula-1 using a suitable solvent provides pure compound of formula-1,
f) treating the compound of formula-1 with a suitable hydrochloric acid source in a
0
15 suitable solvent provides Prazosin hydrochloride compound of formula-la or
anhydrates or hydrates thereof,
g) optionally purifying the compound of formula-la using a suitable solvent.
Wherein,
is step-a) the suitable chlorinating agent is selected from S02C12, SOCl2, (COCI)2, POCl3, 20 PC13 and PC15;
in step-d) the suitable base is selected from organic or inorganic base;
in step-f) the suitable hydrochloric acid source is selected from HCl gas, aqueous HCl, dry HCl, ethyl acetate-HCl, IPA-HC1, ethanolic-HCl, methanolic-HCl;
in step-a) to step-g) the suitable solvent is selected from alcohol solvents, chloro solvents, 25 ketone solvents, polar aprotic solvents, nitrile solvents, ester solvents, hydrocarbon solvents, ether solvents and polar solvents like water or mixture thereof.
The preferred embodiment of the present invention provides a process for the preparation of anhydrous Prazosin hydrochloride compound of formula-la, comprising of:
7

a) Reacting furan-2-carboxylic acid compound of formula-2 with thionyl chloride in
presence of a mixture of dimethyl formamide and toluene provides furan-2-carbonyl
chloride compound of formula-3,
b) reacting the compound of formula-3 in-situ with piperazine in presence of aqueous
5 hydrogen bromide in methanol provides furan-2-yl(piperazin-l-yl)methanone
compound of formula-4,
c) treating the compound of formula-4 with oxalic acid in methanol provides furan-2-
yl(piperazin-l-yl)methanone oxalate compound of formula-4a,
d) reacting the compound of fqrmula-4a with 2-chloro-6,7-dimethoxyquinazolin-4-
10 amine compound of formula-5 in presence of sodium carbonate in isoamyl alcohol
provides Prazosin free base compound of formula-1,
e) purifying the compound of formula-1 using a mjxture of chloroform and methanol
provides pure compound of formula-1,
f) treating the compound of formula-1 with methanolic-HCl in methanol provides 15 Prazosin hydrochloride compound of formula-1 a,
g) purifying the obtained compound using isoamyl alcohol.
The preferred embodiment of the present invention provides a process for the preparation of crystalline polyhydrate of Prazosin hydrochloride compound of formula-la, 20 comprising of:
a) Reacting furari-2-carboxylic acid compound of formula-2 with thionyl chloride in
presence of a mixture of dimethyl formamide and toluene provides furan-2-carbonyl
chloride compound of formula-3,
b) reacting the compound of formula-3 in-situ with piperazine in presence of aqueous
25 hydrogen bromide in methanol provides furan-2-yl(piperazin-l-yl)methanone
compound of formula-4,

c) treating the compound of formula-4 in-situ with oxalic acid in methanol provides furan-2-yl(piperazin-l-yl)methanone oxalate compound of formula-4a,
d) reacting the compound of formula-4a with 2-chloro-6,7-dimethoxyquinazolin-4-amine compound of formula-5 in presence of sodium carbonate in isoamyl alcohol provides Prazosin free base compound of formula-1,
e) purifying the compound of formula-1 using a mixture of chloroform and methanol provides pure compound of formula-1,
f) treating the compound of formula-1 with hydrochloric acid in the mixture of water and dimethyl sulfoxide provides crystalline polyhydrate of Prazosin hydrochloride compound of formula-la.
The second aspect of the present invention provides furan-2-yl(piperazin-l-yl)methanone oxalate compound of formula-4a. The compound of formula-4a is more stable at room temperature and further, furan-2-yl(piperazin-l-yl)methanone oxalate compound of formula-4a of the present invention is useful in the preparation of highly pure compound of formula-1 and its hydrochloric acid salt compound of formula-la or its hydrates or anhydrates thereof.
The third aspect of the present invention provides a process for the preparation of furan-2-yl(piperazin-l-yl)methanone oxalate compound of formula-4a, comprising of treating compound of formula-4 with oxalic acid in a suitable solvent at a suitable temperature.
Wherein, the suitable temperature is about 0°C to reflux temperature of the solvent used, preferably 35°C to 70°C and the suitable solvent is selected from alcohol solvents, chloro solvents, ketone solvents, polar aprotic solvents, nitrile solvents, ester solvents, hydrocarbon solvents, ether solvents and polar solvents like water or mixture thereof; preferably alcohol solvents; more preferably methanol; oxalic acid used in the moles of 0.9 to 1.5 with respect to the compound of formula-4.

The preferred embodiment of the present invention provides a process for the preparation of furan-2-yl(piperazin-l-yl)methanone oxalate compound of formula-4a, comprising of:
a) Heating a mixture of furan-2-yI(piperazin-1 -yl)methanone, methanol and oxalic acid,
5 b) stirring the reaction mixture,
c) cooling the reaction mixture,
d) filtering the precipitated solid and drying provides furan-2-yl(piperazin-l-yl)methanone oxalate compound of formula-4a. ......
10 The fourth aspect of the present invention provides a novel crystalline of furan-2-
yl(piperazin-l-yl)methanone oxalate compound of formula-4a, herein after designated as crystalline form-M; which is characterized by its powder X-Ray diffractogram having peaks at 16.1, 17.2, 17.6, 22.1,22.4,23.5 and 25.1 ±0.2 degrees of two theta and PXRD pattern is same as depicted in figure-1.
15 The fifth aspect of the present invention provides a process for the preparation of
Prazosin free base compound of formula-1, comprising of
a) Reacting the furan-2-yl(piperazin-l-yl)methanone compound of formula-4 or its acid addition salts with 2-chloro-6,7-dimethoxyquinazolin-4-amine compound of formula-5 in presence of a suitable base in a suitable solvent provides compound of formula-1,
20 b) optionally purifying the compound of formula-1.
Wherein, the suitable base is selected from organic or inorganic base and the suitable solvent is same as defined in the first aspect of the present invention.
The preferred embodiment of the present invention provides a process for the
preparation of Prazosin free base compound of formula-1, comprising of reacting furan-2-
25 yl(piperazin-l-yl)methanone oxalate compound of formula-4a with 2-chloro-6,7-
dimethoxyquinazolin-4-amine compound of formula-5 in presence of sodium carbonate in
isoamyl alcohol provides the compound of formula-1.

The sixth aspect of the present invention provides crystalline Prazosin free base compound of formula-1, herein after designated as crystalline form-S; which is characterized by its powder X-Ray diffractogram having peaks at 10.5, 12.6, 14.0, 14.4, 17.7, 20.8, 21.1, 21.6, 22.0 and 25.3± 0.2 degrees of two theta and PXRD pattern is same as depicted in figure-2.
Crystalline form-S obtained according to the present invention is useful for the preparation of Prazosin HCl and its anhydrates or hydrates thereof.
The seventh aspect of the present invention provides a process for the preparation of Prazosin hydrochloride compound of formula-la or its anhydrates or hydrates thereof, comprising of:
a) Reacting the compound of formula-4a with 2-chIoro-6,7-dimethoxyquinazolin-4-amine compound of formula-5 in presence of a suitable base in a suitable solvent provides Prazosin free base compound of formula-1,
b) optionally, purifying the compound of formula-1 using a suitable solvent provides pure compound of formula-1,
c) treating the compound of formula-1 with a suitable hydrochloric acid source in a suitable solvent provides Prazosin hydrochloride compound of formula-la or anhydrates or hydrates thereof,
d) optionally purifying the compound of formula-la using a suitable solvent.
Wherein,
in step-a) the suitable base is selected from organic or inorganic base;
in step-c) the suitable hydrochloric acid source is selected from HCl gas, aqueous HCl, dry HCl, ethyl acetate-HCl, IPA-HC1, ethanolic-HCi, methanolic-HCl;
in step-a) to step-d) the suitable solvent is selected from alcohol solvents, chloro solvents, ketone solvents, polar aprotic solvents, nitrile solvents, ester solvents, hydrocarbon solvents, ether solvents and polar solvents like water or mixture thereof.

The preferred embodiment of the present invention provides a process for the preparation of crystalline Prazosin hydrochloride compound of formula-la, comprising of:
a) Reacting the compound of formula-4a with 2-chIoro-6,7-dimethoxyquinazolin-4-
amine compound of formula-5 in presence of sodium carbonate in isoamyl alcohol
5 provides Prazosin free base compound of formula-1,
b) purifying the compound of formula-1 using a mixture of chloroform and methanol provides pure compound of formula-1,
c) treating the compound of formula-1 with methanolic-HCl in methanol provides Prazosin hydrochloride compound of formula-la,
10 d) purifying the obtained compound in isoamyl alcohol and washing with
dichloromethane to get crystalline Prazosin hydrochloride compound of formula-la.
Another embodiment of the present invention provides a process for the preparation of crystalline Prazosin hydrochloride compound of formula-1 a, comprising of:
a) Reacting the compound of formula-4a with 2-chloro-6,7-dimethoxyquinazolin-4-
15 amine compound of formula-5 in presence of sodium carbonate in isoamyl alcohol
provides Prazosin free base compound of formula-1,
b) purifying the compound of formula-1 using a mixture of chloroform and methanol provides pure compound'of formula-1,
c) treating the compound of formula-1 with ethyl acetate-HCl in ethyl acetate provides
4-(2-
| furoyl) piperazine hydrochloride compound of formula-la is about 1 to 2% W/W.
Q.
of crystalline form-N of Prazosin hydrochloride compound of formula-la, comprising of:
CN 25 a) Reacting the compound of formu!a-4a with 2-chloro-6,7-dimethoxyquinazolin-4-
o Another embodiment of the present invention provides a process for the preparation
Q
is
o
LU
0 amine compound of formula-5 in presence of sodium carbonate in isoamyl alcohol

provides Prazosin free base compound of formula-1,
12
o
CN i
U)
3-
"<
b) purifying the compound of formula-1 using a mixture of chloroform and methanol provides pure compound of formula-1,
c) treating the compound of formula-1 with methanolic-HCI in methanol provides crystalline form-N of Prazosin hydrochloride compound of formula-la.
5
The eighth aspect of the present invention provides novel crystalline form of Prazosin
hydrochloride compound of formula-la, herein after designated as form-N; which is
characterized by its powder X-Ray diffractogram having peaks at 7.0, 9.1, 10.7, 11.7, 13.7,
14.7, 16.8, 17.5, 18.7, 21.4, 23.6, 25.8 and 33.1± 0.2 degrees of two theta and the PXRD
10 pattern as depicted in figure-5.
The ninth aspect of the present invention provides an improved process for the
preparation of crystalline polyhydrate of Prazosin hydrochloride compound of formula-la
comprising of treating.prazosin free base compound of formula-1 with dilute or concentrated
15 hydrochloric acid in the mixture of water and dimethyl sulfoxide to provide crystalline
polyhydrate of Prazosin hydrochloride.
Prazosin hydrochloride compound of formula-la obtained according to the present
invention is having purity >95%, preferably >99%; more preferably >99.5% as measured by
HPLC.
20 The PXRD analysis of the crystalline compound of the present invention was carried
out using BRUKER/AXS X-Ray diffractometer using CuKa radiation of wavelength 1.5406 A° and at a continuous scan speed of 0.037min.
The compound of the formula-la produced by the present invention can be further micronized or milled using conventional techniques to get the desired particle size to achieve 25 desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
30 Related substances by HPLC Method of Analysis:

Prazosin and its related substances were analyzed by HPLC with the following chromatographic conditions:
Apparatus: A liquid chromatograph is equipped with variable wavelength UV Detector and integrator. Column: Kromasil 100-5C18, 250 x 4.6 mm, 5 u.m (or) Equivalent; Wavelength: 5 254 nm; Column temperature: 25°C; Injection volume: 20 uL; Elution: isocratic; Mobile phase: Buffer and methanol (50:50); Diluent: mobile phase; Needle wash : Diluent. Buffer Preparation: Dissolve 3.48 g of sodium pentane sulphonate and 3.64 g of tetramethyl ammonium hydroxide in 1000 mL water and adjust to pH 5.0 with glacial acetic acid.
10 The present'invention'can be represented schematically as follows:
Scheme-1:

0H SOCl,
DMF Toluene

HN NH
Methanol Aqua. HBr

Formula-4

Oxalic acid

. Oxalate Formula-4a

H3CO.

N^ XI

H3CO'xV^^N NH,
Formula-5

Base

H3CO
H3CO
a
E o
o

15

NH2 Formula-la

HCI
Source

NH2 Formula-1

20

The best mode of carrying out the present invention was illustrated by the below mentioned examples. These examples are provides as illustration only and hence should not be construed as limitation of the scope of the invention.
14


Examples:
Example-1: Preparation of l-(furan-2-y!carbonyl) piperazine compound of formuIa-4
Dimethyl formamide (0.5 ml) was added to a mixture of 2-furoic acid (50 gm) and
5 toluene (250 ml) at 25-30°C and stirred for 15 minutes at the same temperature. Thionyl
chloride (55 gm) was slowly added to the reaction mixture at 25-30°C. Heated the reaction
mixture to 100-105°C and stirred for 8 hours at the same temperature. Cooled the reaction
mixture to 25-30°C under nitrogen atmosphere and obtained acid chloride is kept a side.
Water (92. ml) was added to. a solution of piperazine (74.4 gm) in methanol (285 ml) in
10 another round bottom flask. Heated the reaction mixture to 40-45°C. Aqueous hydrogen
bromide solution-(148.6 gms) was slowly added to the.reaction mixture at 40-45°C. Above
acid chloride solution was slowly added to the reaction mixture at 40-45°C. Further heated
the reaction mixture to 70-75°C and stirred for 6 hours at the same temperature. Cooled the
reaction mixture to 0-5°C and stirred for 1 hour at the same temperature/Filtered the
15 unwanted solid, washed with methanol. Distilled off the solvent from the filtrate under
reduced pressure. Water was added to the obtained compound at 25-35°C and stirred for 20
. minutes at the same temperature. Cooled the reaction mixture to 10-15°C and adjusted the
. pH of reaction mixture to 5-6 using aqueous sodium hydroxide solution. Aqueous layer was
washed with ethyl acetate and further basified aqueous layer with aqueous sodium hydroxide
20 solution. Aqueous layer was extracted with chloroform. Distilled off the solvent completely
from the organic layer to get the title compound.
Yield: 60 gms.
Example-2: Preparation of l-(furan-2-ylcarbonyl) piperazine oxalate compound of
25 formuIa-4a
Oxalic acid (230 gms) was added, to the mixture of methanol (1500 ml) and l-(furan-2-ylcarbonyl) piperazine (300 gms) at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 30 minutes at the same temperature. The reaction mixture was cooled to 25-30°C and stirred for 60 minutes at the same temperature. Filtered the precipitated solid, washed
30 with methanol and dried to get the title compound.
15

Yield: 400 gms, M.R.: 191-192°C;
The PXRD of the obtained compound is shown in figure-1.
ExampIe-3: Preparation of l-(furan-2-ylcarbonyl) piperazine oxalate compound of 5 formula-4a
Dimethyl formamide (0.5 ml) was added to a mixture of 2-furoic acid (50 gm) and toluene (250 ml) at 25-30°C and stirred for 15 minutes at the same temperature. Thionyl chloride (55 gm) was slowly added to the reaction mixture at 25-30°C. Heated the reaction mixture to 100-105°C and stirred for 8 hours at the same temperature. Cooled the reaction
10 mixture to 25-30°C under nitrogen atmosphere and obtained acid chloride is kept a side. Water (92 ml) was added to a solution of piperazine (74.4 gm) in methanol (285 ml) in another round bottom flask. Heated the reaction mixture to 40-45°C. Aqueous hydrogen bromide solution (148.6 gms) was slowly added to the reaction mixture at 40-45°C. Above acid chloride solution was slowly added to the reaction mixture at 40-45°C. Further heated
15 the reaction mixture to 70-75°C and stirred for 6 hours at the same temperature. Cooled the
reaction mixture to 0-5°C and stirred for 1 hour at the same temperature. Filtered the
^unwanted solid, washed with methanol. Distilled off the solvent from the filtrate under
reduced pressure. Water was added to the obtained compound at 25-35°C and stirred for 20
minutes at the same temperature. Cooled the reaction mixture to 10-15°C and adjusted the
20 pH of reaction mixture to 5-6 using aqueous sodium hydroxide solution. Aqueous layer was washed with ethyl acetate and further basified aqueous layer with aqueous sodium hydroxide

Formula-4,
20
c) treating the compound of formula-4 with oxalic acid in a suitable solvent to provide
oxalate salt of furan-2-yl(piperazin-l-yl)methanone compound of formula-4a
O
ryV>
HN^^J 0-./

. Oxalate Formula-4a,
20

~-T"
.i~, .-^.^-^,-^iwwt^i.-,
!^T:E?irF^EjFF^

d) reacting the compound of formula-4a with 2-chloro-6,7-dimethoxyquinazolin-4-amine compound of formula-5
H3C0Y^yNYcl
H3CO^^N NH2 Formula-5
in presence of a suitable base in a suitable solvent to provide Prazosin free base
compound of formula-1
:-0
O
-/—\ ° H3COx^^.N;
H3C(A ^ -N
NH2 . .Formula-1,"'
e) optionally, purifying the compound of formula-1 using a suitable solvent to provide
10 pure compound of formula-1,
f) treating the compound of formula-1 with a suitable hydrochloric acid source in a suitable solvent to provide Prazosin hydrochloride compound of formula-la or its anhydrates or hydrates thereof,
g) optionally purifying the compound of formula-la using a suitable solvent.
15
2. The process according to claim 1, wherein in step-a) the suitable chlorinating agent is
selected from S02C12, SOCl2, (COCl)2, POCl3, PC13 and PC15>
in step-d)the suitable base is selected from organic or inorganic base;
in step-f) the suitable hydrochloric acid source is selected from HC1 gas, aqueous HC1,
20 dry HC1, ethyl acetate-HCl, IPA-HC1, ethanolic-HCl, methanolic-HCl;
in step-a) to step-g) the suitable solvent is selected from alcohol solvents, chloro
solvents, ketone solvents, , polar aprotic solvents, nitrile solvents, ester solvents,
hydrocarbon solvents, ether solvents and polar solvents like water or mixture thereof.
25 3. Furan-2-yl(piperazin-l-yl)methanone oxalate compound of formula-4a.
21

4. A process for the preparation of furan-2-y!(piperazin-l-yl)methanone oxalate compound
of formula-4a comprising of:
a) Reacting furan-2-carboxylic acid compound of formula-2 with thionyl chloride in dimethyl formamide and toluene to provide furan-2-carbonyl chloride compound of formula-3,
b) reacting the compound of formula-3 in-situ with piperazine in presence of aqueous hydrogen bromide in methanol to provide furan-2-yl(piperazin-l-yl)methanone compound of formula-4,
c) treating the compound of formula-4 with oxalic acid in methanol to provide furan-2-yl(piperazin-l-yl)methanone oxalate compound of formula-4a.
■ * ' - y ' ' '
5. A process for the preparation of prazosin free base compound of formula-1 comprising
of:
a) Reacting furan-2-yl(piperazin-l-yl)methanone or its acid addition salts with 2-
chloro-6,7-dimethoxyquinazolin-4-amine compound of formula-5 in presence of the
suitable base selected from organic or inorganic base; in a suitable solvent selected
from alcohol solvents, chloro solvents, ketone,solvents, polar aprotic solvents, nitriie
solvents, ester solvents, hydrocarbon solvents, ether solvents and polar solvents like
water or mixture thereof to provide Prazosin free base compound of formula-1,
b) optionally converting the obtained compound in step-a) into its acid addition salts.
6. Crystalline form-S of prazosin free base compound of formula-1, wherein said crystalline form-S is characterized .by its powder X-Ray diffraction pattern having peaks at about 10.5, 12.6, 14.0, 14.4, 17.7, 20.8, 21.1, 21.6, 22.0 and 25.3± 0.2 degrees of two theta.
7. Crystalline form-N of Prazosin hydrochloride compound of formula-la is characterized by its powder X-Ray diffraction pattern having peaks at about 7.0, 9.1, 10.7, 11.7, 13.7, 14.7, 16.8, 17.5, 18.7, 21.4, 23.6, 25.8 and 33.1± 0.2 degrees of two theta.
8. A process for the preparation of crystalline form-N of Prazosin hydrochloride compound
of formula-la comprising of treating prazosin free base compound of formula-1 with
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methanolic HC1 in methanol to provide crystalline form-N of Prazosin hydrochloride compound of formula-la.
9. A process for the purification of prazosin free base comprising of:
5 a) Dissolving prazosin free base in alcohol solvent or mixture of alcohol solvent and
chloro solvent,
b) optionally filtering the reaction mixture obtained in step-a),
c) isolating the pure prazosin free base from the reaction mixture obtained in step-a) or step-b); wherein isolating refers to distilling off the solvent completely or partially
10 from the reaction mixture, followed by cooling and filtering the reaction mixture to
get pure prazosin free base.
10. A process for the preparation of crystalline polyhydrate of Prazosin hydrochloride
compound of formula-la comprising of treating prazosin free base compound of
15 formula-1 with dilute or concentrated hydrochloric acid in the mixture of water and
dimethyl sulfoxide to provide crystalline polyhydrate of Prazosin hydrochloride.
Dated this day cf\ of August 2016.
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AuthorizexFSignatory
(Srinivasan Thirumalai Rajan)
25 MSN Laboratories Private Limited

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