WO2005021521A1

WO2005021521A1 - Preparation of 1-[4-(2-methoxy-phenyl)-piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane hydrochloride

Info

Publication number: WO2005021521A1
Application number: PCT/IB2003/003585
Authority: WO
Inventors: Nitya Anand; Neelima Sinha; Sanjay Jain; Anita Mehta
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2003-08-28
Filing date: 2003-08-28
Publication date: 2005-03-10
Also published as: AU2003259394A1

Abstract

The present invention relates to processes for the synthesis of 1-[4-(2methoxyphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl) propane hydrochloride having protracted uro-selective (α1-adrenoceptor antagonistic activity. The compound holds promise for treating benign prostatic hyperplasia (BPH).

Description

PREPARATION OF l- 4- (2 -METHOXY- PHENYL) -PIPERAZIN-1-Y ! -3- ( 2 , 6-DIOXOPIPERIDIN-l-Y L) PROPANE HYDROCHLORIDE

FIELD OF THE INVENTION

5 The present invention relates to processes for the synthesis of l-[4-(2- methoxyphenyl) piperazin-l-yl]-(2,6-dioxopiperidin-l-yl) propane hydrochloride having protracted uro-selective α,-adrenoceptor antagonistic activity. The compound holds promise for treating benign prostatic hyperplasia (BPH).

BACKGROUND OF THE INVENTION

10 A review in J. Med. Chem., 1997, V.40, No. 9, pp 1291-1315, describes pharmacological options available for the treatment of benign prostatic hyperplasia. Most successful therapies have been based on α-adrenergic receptor antagonism and modulation of androgen levels by 5α-reductase inhibitors. However, 5α-reductase inhibitors are of limited effectiveness in terms of immediate symptomatic and urodynamic relief. On the 15 other hand, _\ -antagonists appear to be much more effective and provide immediate subjective symptomatic improvements and are therefore desirable modalities of treatment in the control of benign prostate hypertrophy, αi-adrenoceptors are also present in blood vessels and play an important role in the regulation of blood pressure. Thus, αi- adrenoceptor antagonists are of particular importance as they were originally developed as 20 antihypertensive agents and are likely also to have a beneficial effect on lipid dysfunction and insulin resistance, which are commonly associated with essential hypertension.

The more important of the αi-adrenoceptor antagonists which are currently used in the management of BPH are shown below:

PRAZOSIN 35

TERAZOSIN

DOXAZOSIN

(R)-(-)-TAMSULOSIN

AFLUZOSIN However, most of these known drugs are associated with vascular side effects (e.g. postural hypertension, syncope, dizziness, headaches, etc) due to lack of selectivity of action between prostatic and vascular αi-adrenoceptor antagonists which will confer urodynamic improvement without the side effects associated with existing drugs.

Various l-(4-arylpiperazin-l-yl)-ω-[N-(α,ω-dicarboxamido)]alkanes have been described in US Patent Nos. 6,083,950, 6,090,809, 6,410,735, 6,420,366 and 6,420,559. These compounds exhibit protracted uro-selective α_radrenoceptor antagonistic activity exceeding those of previously described compounds. These compounds exhibit significantly greater α,_A-adrenergic blocking potency than the known compounds in order to provide specific treatment for benign prostatic hyperplasia. This class of compounds are not associated with vascular side effects as they showed greater selectivity against oti adrenoceptors, which thus offers selective relief for prostrate hypertrophy as well as essential hypertension.

It is seen that 2,6-dioxopiperidine group enhances the adrenoceptor blocking activity, and also greatly increases the selectivity for α,_A in comparison to αis- adrenoceptor blocking activity, which is believed desirable for the compounds to be good candidates for the treating of Benign Prostatic Hyperplasia (BPH).

1 -[4-(2-methoxyphenyl)piperazin- l-yl]-3-(2,6-dioxopiperidin- 1 -yl]propane hydro- chloride of Formula I,

Formula I

a compound of this class showed greater selectivity against α_! adrenoceptors and it thus offers selective relief for prostrate hypertrophy as well as essential hypertension.

Particular syntheses of l-[4-(2-methoxyphenyl) piperazin-l-yl-3-(2,6-dioxo- piperidin-1-yl) propane hydrochloride of Formula I have been reported in U.S. Patent Nos. 6,083,950, 6,090,809, 6,410,735, 6,420,366 and 6,420,559, comprising reacting 1-chloro- 3 -(2,6-dioxopiperidine- l-yl)propane with l-(2-methoxyphenyl) piperazine in the presence of potassium carbonate and potassium iodide in dimethylformamide. The resulting reaction mixture is heated at 80°C for 17 hours. The crude organic compound thus obtained is purified by column chromatography using chloroform in methanol solvent mixture (99:1) as an eluent followed by addition of excess of etheral hydrochloride solution. The above mentioned method in the prior art for the synthesis of compound of Formula I suffer from particular limitations

In methods described in U.S. Patent Nos. 6,083,950, 6,090,809, 6,410,735, 6,420,366 and 6,420,559, for the synthesis of compound of Formula I, impurities, viz. dimer compound of Formula II,

Formula II

and the compound of Formula VI

Formula VI are formed. The necessity of their removal through column chromatography decreases the overall yield of final pure product.

The purification of compound involves column chromatography, which is cumbersome, tedious and not practicable on an industrial scale. The use of chloroform in bulk for reaction work up and purification of compound of Formula I by column chromatography poses a problem of handling at commercial scale.

The synthesis of the intermediate l-chloro-3-(2,6-dioxopiperidine-l-yl) propane for the synthesis of compound of Formula I has been described in Bull. Soc. Chern. Fr (1992), 129(3), 227-231, which comprises reacting glutarimide with 3-chloro-l-tosyloxy propane in benzene or toluene in the presence of potassium carbonate followed by addition of 1% 18-crown-6 as a phase transfer catalyst. The reaction mixture was refluxed to give the crude organic compound, which was purified by column chromatography. A general synthetic method for the synthesis of the intermediate l-chloro-3 -(2,6- dioxopiperidine- 1-yl) propane has also been reported in U.S. Patent Nos. 6,083,950, 6,090,809, 6,410,735, 6,420,366 and 6,420,559 wherein intermediate is shown generically in Formula VII.

The above-mentioned methods in the prior art for the synthesis of the intermediate l-chloro-3-(2,6-dioxopiperidine-l-yl) propane for the synthesis of compound of Formula I also suffer from the particular limitations: the method requires the use of benzene, which is highly inflammable, toxic and carcinogenic in nature, which thus poses a difficulty to handle at commercial scale; the method requires the use of toluene, which is highly inflammable and harmful; the use of high temperature conditions (i.e. refluxing) for the synthesis of an intermediate involves the risk of formation of undesired by products; the synthesis of the intermediate involves the use of 18-crown-6, which is easily absorbed through skin and is also reported to cause CNS effects thus it is difficult to handle at commercial scale; and the purification of compound involves column chromatography, which is cumbersome, tedious and not practicable on an industrial scale.

SUMMARY OF THE INVENTION

The present invention can solve problems associated with prior art methods and can provide an improved method for synthesis of the compound of Formula I

Formula I which method provides substantial benefits with respect to economics and convenience to operate at a commercial scale. More particularly, the present invention relates to a process for the preparation of the compound of Formula I which comprises condensing 2,6-dioxopiperidine (glutarimide)

with 1.3-dihalopropane, such as l-bromo-3-chloropropane in acetone to give the compound l-halo-3-(2,6-dioxopiperidin-l-yl)propane Formula III,

Formula III wherein X can be halo, such as bromo or chloro. Any excess of 1,3-dihalopropane can be removed by washing with hexane. The compound of Formula III is reacted with l-(2- methoxyphenyl) piperazine hydrochloride of Formula TV

Formula IV

to yield compound l-[ 4-(2-methoxyphenyl)piperazin-l-yl]-3-[2,6-dioxopiperidin-l-yl) propane of Formula V

Formula V

which is further reacted with hydrochloric acid in ethanol to give a compound of Formula I followed by crystallization with alcohol which removes the most prevalent impurities, including l-formyl-4-(2-methoxyphenyl)piperazine of Formula VI

Formula VI and l,3-bis-[4-(2-methoxyphenyl)piperazin-l-yl]propane of Formula II

Formula II

The alcohol for crystallization may be a lower alcohol, such as ethyl alcohol or isopropyl alcohol.

The reaction of 2,6-dioxopiperidine (glutarimide) and a 1,3-dihalopropane, such as l-bromo-3-chloropropane, to give l-halo-3-(2,6-dioxopiperidin-lyl)propane of

Formula III, can be carried out in the presence of a base and a phase transfer catalyst in a solvent. The base can be, for example, potassium carbonate, sodium carbonate or cesium carbonate, and the phase transfer catalyst can be, for example, tetrabutyl ammonium bromide or tetrabutyl ammonium iodide. The solvent in which the reaction is carried out can be, for example, acetone.

The reaction of l-halo-3-(2,6-dioxopiperidin-lyl) propane of Formula III with 1- (2-methoxy phenyl) piperazine hydrochloride of Formula IV can be carried out in the presence of a base and a catalyst in a solvent. The base can be, for example, potassium carbonate, sodium carbonate or cesium carbonate, and the catalyst can be, for example, sodium iodide and potassium iodide. The solvent can be, for example, dimethylformamide.

In the following section some particular embodiments are presented to illustrate the disclosure. However, this is not intended in any way to limit the scope of the present invention, which is set forth in the appended claims. DETAILED DESCRIPTION OF THE INVENTION

Example 1: Preparation of l-r4- 2-methoxyphenyDpiperazm-l-vn-3- 2.6-dioxopiperidin-l- yl) propane hydrochloride

Step 1: Preparation of l-haIo-3-(2,6-dioxopiperidin-I-yl) propane To a stirred suspension of 2,6-dioxopiperidine (glutarimide) (1.50 kg, 13.27 moles), potassium carbonate (5.50 kg, 39.86 moles, 3 equivalent) and tetrabutylammonium bromide (0.855 kg, 2.66 moles, 0.06 equivalent) in acetone (45.0 litre), was added l-bromo-3-chloropropane (4.18 kg, 26.54 moles, 2 equivalent) dropwise (about 125 minutes) at 25-30°C. The resulting mixture was stirred for about 21 hours (the progress of the reaction was monitored by TLC at the same temperature). Inorganic salts were filtered off through suction and washed with acetone (3x3.0 litre). Filtrate was concentrated in rotaevaporator (100 mm, at 50-55°C) to yield an oily residue. To this residue, hexane (7.5 litre) was added and stirred for 5-10 minutes. The reaction mixture was allowed to stand and the layers were separated and decanted. This process was repeated four times (7.5 litre of hexane was used each time) to remove excess of 1-bromo- 3-chloropropane. The compound was dissolved in ethyl acetate (22.4 litre), washed with water (4x9.0 litre), dried over anhydrous sodium sulphate (225 gm, 30 minutes). The sodium sulphate was filtered and the filtrate was concentrated in rotaevaporator to yield 1.82 kg of a mixture of l-bromo-3-(2,6-dioxopiperidin-l-yl)propane (A) and l-chloro-3- (2,6-dioxopiperidin-l-yl) propane (B) as an oil. The ratio of A and B was determined by Gas Chromatography, which was found to be 31% and 65%, respectively. This mixture was used as such in the next step.

Step 2: Preparation of l-[4-(2-methoxyphenyl) piperazin-l~yl]-3-(2,6-dioxopiperidin- 1-yl) propane The mixture of 1-bromo and 1 -chloro 3-(2,6-dioxopiperdin-l-yl) propane [1-halo-

3- (2,6-dioxopiperidin-l-yl) propane] (A and B) (1.75 kg, 8.37 moles), l-(2- methoxyphenyl) piperazine hydrochloride (1.72 kg, 7.52 moles, 0.9 equivalent), potassium carbonate (2.31 kg, 16.74 moles, 2 equivalent) and potassium iodide (0.083 kg, 0.5 moles, 0.20 equivalent) in N, N-dimethylformamide (7.2 litre) was heated at 75-80°C under stirring for 18 hours (the progress of the reaction was monitored by TLC). After cooling the reaction mixture to room temperature (about 30°C), water (36.0 litre) was added to the reaction mixture and was extracted with dichloromethane (2x4.5 litre). The combined organic phase was washed with water (2x9.0 litre) and dried over anhydrous sodium sulphate. The sodium sulphate was filtered and the filtrate was concentrated in rotaevaporator (100 mm, at 40-50°C) to give thick oil, which was dried under reduced pressure (1-2 mm) at 55-60°C for about 120 minutes to yield 2.71 kg of l-[4-(2- methoxyphenyl) piperazin-l-yl]-3-(2,6-dioxopiperidin-l-yl) propane (76% pure by reverse phase HPLC assay). The impurities present were characterized by NMR, Mass and reverse phase HPLC as l-formyl-4-(2-methoxyphenyl) piperazine and l,3-bis-[4-(2- methoxyphenyl) piperazin-1-yl] propane.

Step 3: Preparation of 1 [4-(2-methoxyphenyl) piperazin-l-yl]-3-(2,6-dioxopiperidin-l- yl) propane hydrochloride

To a crude mixture of l-[4-(2-methoxyphenyl) piperazin-l-yl]-3-(2,6- dioxopiperidin-1-yl) propane (5.05 kg, actual quantity 4.00 kg based on reverse phase HPLC assay, 11.59 moles) as obtained in step-2 absolute ethanol (5.3 litre) was added dropwise with subsequent addition of 2.82 M HCI-Ethanol (0.423 kg, 11.59 moles, 4.11 litre, 1 equivalent) under stirring at 15±5°C. The reaction mixture was stirred for an additional 15 minutes at the same temperature and was diluted with diethyl ether (35.0 litre). Stirring was continued for another 60 minutes at the same temperature and the solid separated was filtered through suction, washed with diethyl ether (2x3.5 litre) and dried in vacuum oven at 50-55°C under reduced pressure (1-2 mm) for 8 hours to obtain 4.08 kg (92.25%) of crude l-[4-(2-methoxyphenyl) piperazin-l-yl]-3-(2,6-dioxopiperidin-l-yl) propane hydrochloride. At this step the impurity l-formyl-4-(2-methoxy phenyl) piperazine was removed as it did not form the hydrochloride salt.

To remove the dimer impurity, l,3-bis-[4₇(2-methoxyphenyl]piperazinyl]propane, the product was crystallized. The product l-[4-(2-methoxyphenyl) piperazin-l-yl)-3-(2,6- dioxopiperazin-1-yl) propane hydrochloride product as obtained above was dissolved in isopropyl alcohol (50 litre) by heating at 75-80°C under constant stirring (a clear solution was obtained after 220 minutes). To this hot solution, activated carbon (200 gm) was added and the resulting mixture stirred for another 30 minutes at the same temperature. The mixture was filtered while hot through a hyflo bed and washed with isopropyl alcohol (6 litre). Filtrate was cooled to 15±5°C and stirring was continued for another 60 minutes at the same temperature. The solid obtained was filtered and washed with isopropyl alcohol (6 lit) and dried in a vacuum oven at 70-80°C for 8 hr. under reduced pressure (1-2 mm) to yield 3.20 Kg (80%) of pure l-[4-(2-methoxyphenyl) piperazin-l-yl]-3-[2,6- dioxopiperidin-1-yl) propane hydrochloride.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are within the scope of the present invention.

Claims

We Claim:

1. A process for preparing a compound of Formula I

Formula I which comprises condensing 2,6-dioxopiperidine (glutarimide)

with 1,3-dihalopropane in acetone to give l-halo-3-(2,6-dioxopiperidin-l- yl)propane of Formula III,

Formula III wherein X (halo) is chloro or bromo; followed by washing with a hydrocarbon, reacting the compound of Formula III with l-(2-methoxyphenyl) piperazine hydrochloride of Formula IV

Formula IV to provide the compound of Formula V

Formula V and reacting the compound of Formula V with ethanolic hydrochloric acid to yield a compound of Formula I.

2. The process of claim 1 wherein the reaction of 2,6-dioxopiperidine (glutarimide) and 1,3-dihalopropane to give l-halo-3-(2,6-dioxopiperidin-l-yl)propane of Formula III, is carried out in the presence of a base.

3. The process of claim 2 wherein the base is selected from potassium carbonate, sodium carbonate and cesium carbonate.

4. The process of claim 1 wherein the reaction of 2,6-dioxopiperidine (glutarimide) and 1,3-dihalopropane to give l-halo-3-(2,6-dioxopiperidin-l-yl)propane of Formula III, is carried out at a temperature ranging from 25-30°C.

5. The process of claim 1 wherein the reaction of 2,6-dioxopiperidine (glutarimide) and 1,3-dihalopropane to give l-halo-3-(2,6-dioxopiperidin-l-yl)propane of Formula III, is carried out in the presence of a suitable phase transfer catalyst.

6. The process of claim 5 wherein the phase transfer catalyst is selected from tetrabutyl ammonium bromide and tetrabutyl ammonium iodide.

7. The process of claim 1 wherein the washing is carried out with hexane.

8. The process of claim 1 wherein the reaction of compound of Formula III with l-(2- methoxy phenyl) piperazine hydrochloride of Formula IV to give a compound of Formula V is carried out in the presence of a base.

9. The process of claim 8 wherein the base is selected from potassium carbonate, sodium carbonate and cesium carbonate.

10. The process of claim 1 wherein the reaction of compound of Formula III with l-(2- methoxy phenyl) piperazine hydrochloride of Formula IV to give a compound of Formula V is carried out in the presence of a catalyst.

11. The process of claim 10 wherein the catalyst is selected from sodium iodide and potassium iodide.

12. The process of claim 1 wherein the reaction of compound of Formula III with 1 -(2- methoxy phenyl) piperazine hydrochloride of Formula IV to give a compound of Formula V is carried out in a solvent.

13. The process of claim 12 wherein the solvent is dimethylformamide.

14. The process of claim 1 wherein the purification of a compound of Formula I is carried out by crystallization in a alcohol.

15. The process of claim 14 wherein the alcohol is selected from isopropyl alcohol and ethyl alcohol.

16. The compound of Formula I prepared by the process of claim 1.