DWIVEDI SHRIPRAKASH DHAR (IN)
JAIN KULDEEP NATWARLAL (IN)
DWIVEDI SHRIPRAKASH DHAR (IN)
| WO2006090268A2 | 2006-08-31 |
| US5545738A | 1996-08-13 |
We claim:
1. A process for preparing alfuzosin of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof
Formula (I) which comprises: a) reacting 4-amino-2-chloro-6,7-dimethoxyquinazoline of Formula (II) or its salts
(H)
with 3-methylaminopropionitrile of Formula (III)
CH 3 HN^^^ / CN
(III) in non-alcoholic solvent at an elevated temperature to give N-(4-amino-6,7- dimethoxyquinazol-2-yl)-N-methyl-2-cyanoethylamine of Formula (IV);
(IV)
b) catalytically hydrogenating the N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methyl- 2-cyanoethylamine of Formula (IV) under pressure, in a suitable solvent to give N 1 -(4- amino-6,7-dimethoxyquιnazol-2-yl)-N 1 -methylpropylene-diamine of Formula (V);
I l
c) reacting N 1 -(4-amino-6,7-dimethoxyquinazol-2-yl)-N 1 -methylpropylene- diamine of Formula (V) with tetrahydrofuroic acid in presence of a coupling agent to obtain alfuzosin of Formula (I); and if desired, converting said compound of Formula (I) to its pharmaceutically acceptable salts, solvates or hydrates thereof.
2. A process as claimed in claim 1, wherein said non-alcoholic solvent is selected from the group consisting of amides like formamide, dimethyl formamide; sulfoxides like dimethyl sulfoxides; sulfolanes or mixtures thereof.
3. A process as claimed in claim 1 or 2, wherein step (a) is carried out at elevated temperature from about 100 0 C to 15O 0 C, preferably 12O 0 C to 125 0 C.
4. A process as claimed in any preceding claim wherein said catalytic hydrogenation is carried out in the presence of a catalyst selected from one or more of Raney-Ni, platinum, palladium, and cobalt.
5. A process as claimed in any preceding claim wherein said catalytic hydrogenation is carried out in a suitable alcoholic solvent selected from C 1 -C 4 alcohol like methanol, ethanol, propanol, isopropanol and butanol.
6. A process as claimed in any preceding claim wherein coupling agent in step (c) is selected from the group consisting of N,N'-carbonyl dimidazole, alkyl chloroformates, dicyclohexyl carbodimide, thionyl chloride and mixtures thereof, preferably N,N'- carbonyl dimidazole.
7. A process as claimed in any preceding claim wherein said pharmaceutically acceptable salt is hydrochloride. 8. A process the preparation of substantially pure anhydrous Alfuzosin hydrochloride, which comprises i) treating alfuzosin with hydrochloric acid to obtain Alfuzosin hydrochloride ii) slurring alfusoin hydrochloride with a suitable organic solvent; iii) isolating substantially pure anhydrous alfuzosin hydrochloride.
9. A process as claimed in claim 8, wherein said hydrochloric acid is HCl gas or alcoholic hydrochloric acid such as methanolic HCl, ethanolic HCl or isopropanolic HCl
10. A process as claimed in claim 8 or 9, wherein said suitable organic solvent in step (ii) is selected from methanl, ethanol, isopropanol, n-propanol, butanol.
11. A process claimed in any one of claims 8 to 10 wherein said slurring is carried out in substantially anhydrous condition.
12. Anhydrous crystalline alfuzosin hydrochloride as claimed in any of the preceding claims, substantially free from its stable dihydrate form. 13. Anhydrous crystalline alfuzosin hydrochloride as claimed in claim 12, wherein anhydrous alfuzosin hydrochloride contains less than 2% of Alfuzosin dihydrate.
14. Anhydrous crystalline alfuzosin hydrochloride as claimed in claim 13, wherein anhydrous alfuzosin hydrochloride contains stable dihydrate from less than 1%.
15. Anhydrous crystalline alfuzosin hydrochloride as claimed in claim 14, wherein anhydrous alfuzosin hydrochloride contains stable dihydrate form below limit of quantification by X-ray powder diffraction.
16. Anhydrous crystalline alfuzosin hydrochloride as characterized by X-ray powder diffraction pattern as depicted in FIG.l.
17. Anhydrous crystalline alfuzosin hydrochloride as characterized by Differential Scanning Calorimetry (DSC) as depicted in FIG.2.
18. Anhydrous crystalline alfuzosin hydrochloride as claimed in claim 1 containing controlled level of residual alcohols.
19. Anhydrous crystalline alfuzosin hydrochloride containing residual alcohol less than or equal to 5000 ppm. 20. Anhydrous crystalline alfuzosin hydrochloride as claimed in claim 19, wherein the content of residual alcohol is less than 3000 ppm, preferably less than lOOOppm. 21. Anhydrous crystalline alfuzosin hydrochloride as claimed in claim 19-20, wherein alcohols includes methanol, ethanol, isopropanol, most preferably isopropanol. |
PROCESS FOR PREPARING ALFUZOSIN
FIELD OF THE INVENTION
The present invention relates to an improved processes for preparing alfuzosin and pharmaceutically acceptable salts, solvates, hydrates thereof. The present invention also relates to the processes for preparation of anhydrous alfuzosin hydrochloride having substantially free from other pseudopolymorphic crystalline forms particularly dihydrate form of alfuzosin hydrochloride. Alfuzosin is represented by below mentioned formula (I) and chemically known as N-(3-((4-Amino-6,7-dimethoxy-2- quinazolinyl)methylamino)propyl)tetrahydro-2-furan carboxamide.
BACKGROUND OF THE INVENTION The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should not be construed as an admission that such art is widely known or forms part of common general knowledge in the field. Alfuzosin is a selective antagonist of post-synaptic aplhal-adrenoceceptors, which are located in the prostate, bladder base, bladder neck, prostatic capsule, and prostatic urethra. Alfuzosin hydrochloride is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia and is sold under the brand name of Uroxatral®. See, e.g., The Merck Index, Thirteenth Edition, 2001, p. 235-36, monograph 235; and Physician's Desk Reference, "Uroxatral," 60 th Edition, pp. 2957- 2959 (2005).
U.S. Patent No. 4,315,007 disclosed 4-amino-6,7-dimethoxyquinazol-2-yl alkylene diamine derivatives. The compounds are antihypertensive agents. Among them alfuzosin, chemically N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methyl amino]propyl]tetrahydro-2-furancarboxamide is the most important antihypertensive agent.
Processes for the preparations of alfuzosin hydrochloride and related compounds were described in U.S. Patent No. 4,315,007 and GB Patent No. 2231571.
According to the disclosed process, N-(4-amino-6,7-dimethoxyquinazol-2-yl)-
N-methyl-2-cyanoethylamine intermediate is prepared by reacting 4-amino-2-chloro- 6,7-dimethoxyquinazθline with 3-methylaminopropionitrile of Formula (III) in isoamyl alcohol as solvent. However, use of isoamly alcohol, which is highly flammable in nature and should be avoided.
U.S. Patent No. 5,545,738 disclosed a dihydrate form of alfuzosin hydrochloride, which is also mentioned about the anhydrous, trihydrate and tetrahydrate forms of alfuzosin hydrochloride.
WO 2006/030449 Al discloses that alfuzosin base can be obtained in crystalline solid. The PCT publication relates more particularly to the purification of impure alfuzosin base, as it is practically advantageous when compared with the purification of a salt of it. The present invention provides processes for preparing crystalline alfuzosin base as one of the object of the invention. Another object of the present invention is to provide purification methods to obtain high purity alfuzosin base and pharmaceutically acceptable salts via crystalline alfuzosin base.
WO 2006/090268 A2 relates to the process for preparation of alfuzosin or its pharmaceutically acceptable salts. More particularly, the present invention provides the polymorphic Form A of Alfuzosin. The process for the preparation of Form I and Form II of alfuzosin hydrochloride are also within the scope of WO '268 A2.
U.S. Patent No. 5,545,738 discloses that alfuzosin hydrochloride exists in four psuedopolymorphic forms viz. Anhydrous, dihydrate, trihydrate and tetrahydrate forms. But, discloses that dihydrate form being the most stable form. Alfuzosin can be converted to its pharmaceutically acceptable salts i.e., hydrochloride by treatment with hydrochloric acid in isopropanol as one the solvent as mentioned in US '007. It has been found that detectable level of isopropanol solvent is found to be remained present in the final alfuzosin hydrochloride by chromatography techniques. Hence, it is also one of the object of the present invention to provide alfuzosin hydrochloride in anhydrous form having controlled level of residual solvents especially alcohols.
The process for obtaining the precursor i.e. N-(4-amino-6,7-dimethoxyquinazol- 2-yl)-N-methyl-2-cyanomethylamine as reported in the prior art used isoamyl alcohol as solvent. Thus, there is still a need to provide a cost-effective, environment friendly,
simple and efficient process to prepare substantially pure anhydrous alfuzosin hydrochloride sufficient enough for the large-scale productions.
Therefore, there is need to provide a simple process for preparation of anhydrous alfuzosin hydrochloride via cost-effective process for its precursor. The inventors of the present invention has found that the process provided herein as the scope of the invention would alleviates the hitherto problems associated with prior art for preparing anhydrous alfuzosin hydrochloride as described above. Object of Invention
It is an object of the present invention to overcome or substantially ameliorate one or more of the disadvantages of the prior art or at least to provide a useful alternative.
Another object of the present invention is to provide a process for the preparation of Alfuzosin and its pharmaceutically acceptable salts, solvates thereof.
It is an object of the present invention to provide a process for preparing anhydrous alfuzosin hydrochloride substantially free from psuedopolymorphs.
It is also an object of the present invention to provide alfuzosin hydrochloride having controlled level of residual solvents.
Further object of the present invention is to provide a process for preparing anhydrous alfuzosin hydrochloride via a cost-effective process to prepare a precursor. BRIEF DESCRIPTION OF FIGURES
FIG.l: X-ray diffraction of anhydrous alfuzosin hydrochloride FIG.2: X-ray diffraction of dihydrate alfuzosin hydrochloride FIG.3: DSC of anhydrous alfuzosin hydrochloride
Fig. 4: Figure of Linearity indicating the validation of the method of quantification of Alfuzosin hydrochloride dihydrate in anhydrous alfuzosin hydrochloride for establishing form Limit of Quantification (LOQ). DETAILED DESCRIPTION
According to the present invention, there is provided a process for preparing alfuzosin of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof
which comprises: a) reacting 4-amino-2-chloro-6,7-dimethoxyquinazoline of Formula (II) or its salts
(H)
with 3-methylaminopropionitrile of Formula (III)
(IH) in non-alcoholic solvent at an elevated temperature to give N-(4-amino-6,7- dimethoxyquinazol-2-yl)-N-methyl-2-cyanoethylamine of Formula (IV);
(IV) b) catalytically hydrogenating the N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methyl- 2-cyanoethylamine of Formula (IV) under pressure, in a suitable solvent to give N 1 -(4- amino-6,7-dimethoxyquinazol-2-yl)-N 1 -methylpropylene-diamine of Formula (V);
(V) c) reacting N 1 -(4-amino-6,7-dimethoxyquinazol-2-yl)-N 1 -methylpropylene- diamine of Formula (V) with tetrahydrofuroic acid in presence of a coupling agent to obtain alfuzosin of Formula (I); which can be subsequently converted to its pharmaceutically acceptable salts, solvates or hydrates thereof.
(D
According to the present invention, the reaction of 4-amino-2-chloro-6,7- dimethoxyquinazoline of Formula (II) or its salts with 3-methylaminopropionitrile is carried out in non-alcoholic solvent. The preferred non-alcoholic solvent is selected from the group comprising of amides such as formamide, dimethyl formamide; sulfoxides such as dimethyl sulfoxides; - sulfolanes or mixtures thereof. The most preferred solvent is dimethyl formamide. The reaction is carried out at an elevated temperature from about 100 0 C to 150 0 C, preferably 120 0 C to 125 0 C. According to the preferred embodiment of the present invention, catalytic hydrogenation of step (b) is carried out in presence of catalyst selected from Raney-Ni, platinum, palladium, cobalt and the like. The hydrogenation reaction is carried out in suitable alcoholic solvent selected from C 1 -C 4 alcohol like methanol, ethanol, propanol, isopropanol and butanol, preferably methanol. According to the preferred embodiment of the present invention, the condensation of N 1 -(4-amino-6,7-dimethoxyquinazol-2-yl)-N 1 — methyl- propylenediamine with tetrahydrofuroic acid is carried out in presence of a coupling agent selected from the group consisting of N,N'-carbonyl dimidazole, alkyl chloroformates, dicyclohexyl carbodimide, thionyl chloride and mixtures thereof, 'preferably N 3 N '-carbonyl dimidazole.
Thus obtained alfuzosin can be purified in suitable organic solvent selected from the group consisting ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone and methyl tert-butyl ketone; alcohols like methanol, ethanol, isopropyl alcohol and tert-butyl alcohol etc., esters like methyl acetate, ethyl acetate, n-butyl acetate, tert-butyl acetate etc., preferably ethyl acetate.
Thus, obtained Alfuzosin is subsequently converted to its pharmaceutically acceptable salt such as hydrochloride by method known perse.
In the preferred embodiment, the present invention provides a process for preparing alfuzosin hydrochloride salt of Formula (F):
(I')
The present invention further relates to the process for the preparation of substantially pure anhydrous Alfuzosin hydrochloride, which comprises i) treating alfuzosin with hydrochloric acid to obtain Alfuzosin hydrochloride ii) slurring alfusoin hydrochloride with a suitable organic solvent; iii) isolating substantially pure anhydrous alfuzosin hydrochloride
According to the present invention, Alfuzosin is treated with hydrochloric acid, preferably HCl gas or alcoholic hydrochloric acid such as methanolic HCl, ethanolic HCl, isopropanolic HCl.
The alfuzosin hydrochloride is slurried with suitable organic solvent selected from methanl, ethanol, isopropanol, n-propanol, butanol, in substaintally anhydrous condition to provide substantially pure anhydrous alfuzosin hydrochloride. According to the most preferred embodiment of the present invention,
"substantially" as herein described is used for anhydrous crystalline alfuzosin hydrochloride containing less than about 2% of stable dihydrate form, preferably less than about 1%, most preferably below limit of quantification when measured by X-ray powder diffraction analysis. Anhydrous crystalline alfuzosin hydrochloride contains controlled level of residual alcohols, preferably isopropyl alcohol less than or equal to 5000 ppm, more preferably less than or equal to 3000 ppm, most preferably less than or equal to 2000 ppm.
Anhydrous crystalline alfuzosin hydrochloride prepared by the process as the scope of the present invention having a particle size d(0.5) of less than about 200 microns, more preferably less than about 150 microns, most preferably less than about 50 microns.
The process for the preparation of Alfuzosin hydrochloride is described in below mentioned scheme- 1 :
Scheme-1
Having thus described the invention with reference to particular preferred embodiments and illustrative examples, those in the art would appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in numerous publications.
Table-1: Quantitative analysis study by X-ray diffraction technique comparison data to ensure presence of dihydrate alfuzosin hydrochloride below quantification limit (BQL).
As shown in the graph in Fig 4, correlation coefficient of 0.9912 displayed that the method has a linear response with respect to the concentration of the analyte. Also since the Relative Standard of Deviation (RSD) of 15.79% obtained at the 10% level lies beyond the acceptance criteria, the LOQ for the method was fixed at 20% level, i.e. 1.0% of alfuzosin dihydrate in Afluzosin anhydrous. EXAMPLES: -
Example-1: - Preparation of N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methyl-2- cyanoethylamine
A mixture of 475.0 g (1.0 mol) of 4-amino-2-chloro-6,7-dimethoxyquinazoline was taken in 832 niL DMF in RBF and heated it to 120 0 C to 125 0 C. 208 g (1.25 mole) of 3-methylaminopropionitrile was added within an hour. The reaction mixture was maintained for 30 minutes and cooled to room temperature. The reaction mixture was poured in aq. ammonia (1664.0 mL of ammonium solution in 6656.0 mL of water) and stirred for 2 hours at room temperature. The N-(4-mino-6,7-dimethoxyqumazol-2-yl)- N-methyl-2-cyanoethylamine thus obtained melts at about 27O 0 C, was filtered, washed with water and dried at 5O 0 C to 55 0 C to give 653.2 g of N-(4-mino-6,7- dimethoxyquinazol-2-yl)-N-methyl-2-cyanoethylamine.
Example-2: - Preparation of Ni-(4-amino-6,7-dimethoxyquinazol-2-yl)-Ni- methylpropylenediamine
(IV) (V)
In a 2 L autoclave, 1000 mL of methanol was taken. 150.0 g of ammonia was purged into autoclave at 0 0 C to 5 0 C. 10.0 g of Raney-Ni was added to above reaction mixture. 100.0 g of N-(4-mino-6,7-dimethoxyquinazol-2-yl)-N-methyl-2- cyanoethylamine was added and the reaction mass was heated upto 7O 0 C. 7 Kg pressure of hydrogen gas was applied to the reaction mass and was maintained for 5-6 hours. Raney-Ni was filtered from the reaction mixture after the completion of reaction and wash the 200 mL of methanol. 800.0 mL of methanol was distilled and the resulting slurry was stirred for 2 hours at 25°C to 3O 0 C. The solid was filtered and washed with 50 mL of methanol. The product thus obtained was dried at 50 0 C to 55 0 C to get 87.9 g ofN 1 -(4-aiτιino-6,7-dimethoxyquinazol-2-yl)-N 1 -methylpropylenediamine.
Example-3: - Preparation of Ni-(4-amino-6,7-dimethoxyquinazol-2-yl)-Ni-methyl- N 2 -(tetrahydrofuroyl-2-)-propyIenediamine monohydrochloride
(V) (F)
A solution of 40.0 g (1.0 mol) of tetrahydrofuroic acid and 55.9 g (1.0 mol) of carbonyldiimidazole in 600 ml. of tetrahydrofuran was stirred for 10 minutes at 2O 0 C, then heated at 4O 0 C for 30 minutes until no more carbon dioxide is liberated. Then added 89.2 g (0.0.90 mol) of the foregoing diamine and heated under reflux for 90 minutes. The reaction mixture was cooled to 4O 0 C to 5O 0 C. THF was distilled out completely. The residue was treated with 200.0 mL of water and 400.0 mL of methylene dichloride at 25 0 C to 3O 0 C. The separated aqueous layer was extracted with methylene dichloride. The combined organic layer was washed with water. The separated organic layer was subjected to distilled to remove methylene dichloride completely. The remaining methylene dichloride was codistilled with 40.0 mL of ethyl acetate. The residue were treated with 220.0 mL of ethyl acetate and refluxed for 1 hour. The reaction mass was cooled and stirred for 90 min. The diamine thus obtained was treated with alcoholic hydrogen chloride and transferred to monohydrochloride.
The dry solid 9.9 g thus obtained was treated with 50 mL of ethanol and refluxed for 30 min. The reaction mixture was gradually cooled to 2O 0 C to 25 0 C and stirred for 1 hour.
The product thus obtained was filtered and washed with chilled ethanol to give anhydrous alfuzosin hydrochloride, which melts at 235 0 C (decomposition).
The anhydrous alfuzosin hydrochloride thus obtained is substantially free from dihydrate alfuzosin hydrochloride and having controlled level of residual alcoholic solvents.