WO2011114195A1

WO2011114195A1 - Synthesis of propiverine hydrochloride

Info

Publication number: WO2011114195A1
Application number: PCT/IB2010/051911
Authority: WO
Inventors: Ramesha Andagar Ramakrishna; Anjan Kumar Roy
Original assignee: Ramesha Andagar Ramakrishna; Anjan Kumar Roy
Priority date: 2010-03-15
Filing date: 2010-04-30
Publication date: 2011-09-22
Also published as: EP2470504A1; JP2012530050A; EP2470504A4; KR20120023059A; TWI435869B; EP2470504B1; TW201130799A

Abstract

The present invention provides a two step esterification process for the synthesis of Propiverine hydrochloride. In the synthetic scheme disclosed herein benzillic acid 1 is directly converted to di-propyl ester ether 7 from the known standard method. The intermediate thus obtained is reacted with N-Methyl 4-hydroxy piperidine in the presence of sodium t-butoxide at room temperature to get Propiverine base 5. This is then finally converted to Propiverine hydrochloride. The process of synthesis provides Propiverine hydrochloride in a very pure form (>99%) with a very good yield. The compound is very useful in treating urinary incontinence.

Description

Synthesis of Propiverine Hydrochloride

Technical Field

The present invention provides a process for synthesis of Propiverine Hydrochloride. Particularly the present invention provides a process for the synthesis of Propiverine hydrochloride by etherification-esterification followed by trans esterification.

More particularly the present invention provides a process for synthesis of Propiverine Hydrochloride by esterification and etherification is done in single step.

Particularly the invention provides a pure Propiverine Hydrochloride.

Background of invention

Propiverine Hydrochloride is a new class of drug used in treating "Urinary Incontinence". Propiverine is one the most frequently prescribed drugs in treatment of urinary incontinence. Comparable drugs which are available in the market are oxybutynin, tolterodine-tartrate and trospium chloride. Propiverine Hydrochloride has dual mode of action. First being, inhibition of calcium influx and modulation of intracellular calcium in urinary bladder smooth muscle cells causing musculotropic spasmolysis. Later being Inhibition of the efferent neurotransmission of the nervus pelvicus due to anticholinergic action. Propiverine Hydrochloride has been shown to be efficacious in symptomatic treatment of urinary incontinence and increased urinary frequency and urgency as may occur in patients with overactive bladder syndrome or neurogenic detrusor overactivity (detrusor hyperreflexia) from spinal cord injuries, e.g. transverse lesion paraplegia. Propiverine Hydrochloride is well tolerated by patients, specially on a long-term basis. All adverse events are dose-dependent, transient and reversible.

Synthesis of Propiverine Hydrochloride, has been described in several patents. Initial patent was published by Starke, Thomas and Friese (Dutch Patent No: 106 643,) in 1974. In the process described in this patent, benzillic acid is converted to methyl ester and then it is converted to hydroxyl N-methylpiperidino ester intermediate 3 (Figure 1 ). This reaction is always low yielding due to competing hydrolysis mediated by adjacent hydroxyl group of methyl benzillate. More over the conversion of intermediate 4 to Propiverine base 5 is also low yielding due to competing hydrolysis of the tert chloro present in 4. A the second patent to Luo, M, Ma X, Luo P ( No: CN 1285348,) the synthesis in almost similar reaction sequence as in the other mentioned patent .

In this patent benzillic acid is converted to Hydroxy ester intermediate 3 (Figure 2) directly. During which one of the main problem is the elimination of chloro of the piperidine moiety, thereby lower yield in the process. In the second step, there is a competing hydrolysis of the intermediate 4 with moisture to intermediate 3, thereby lowering the yield.

As per Korean patent KR2005001 1 138A, there is slight change in the process described. Methyl benzillate 6 is converted to propylmethyl benzillate 7 as in Figure 3 . Which is then hydrolyzed to benzillic acid propyl ether 8. Which is then finally converted to Propiverine base using Mitsunobu reaction. Mitsunobo reaction generates lots of waste in the form of triphenyl oxide and the handling of diethylazidodicarboxylate (DEAD) is dangerous. A slightly modified scheme of the above patent is presented in Korean patent KR2005001 1 139A (Figure 4). Where in propylmetyl benzillate 7 of Figure 3 is prepared using Mitsunobu reaction and then it is converted to Propiverine base using trans- esterifi cation with sodium ethoxide. Again the use of Mitsunobu reaction (Figure 4). is not cost effective and involves waste generation

In the present invention a new and simplified synthetic route for the synthesis of this Propiverine Hydrochloride is hereby disclosed which overcomes the drawbacks of the prior art patents.

It is an object of the present invention to provide new process for the synthesis of Propiverine Hydrochloride.

Another object of the present invention is to provide a process for synthesis of Propiverine hydrochloride by trans esterification catalyzed by potassium t-butoxide.

Still another object of the present invention is to provide a process for synthesis by etherification followed by esterification to get the critical intermediate.

Yet another object of the present invention is to provide a process to give High over all yield. Still further object of the present invention is to provide a pure product by the process of invention.

Brief Description of drawings

In the drawing accompanying this specification Figure 1 represents a prior art with two step esterifi cation as per Dutch patent.(DP 106643) In the figure (1 1 ) is Benzillicacid (12) is Benzillic acid ester and (13) is the hydroxyl ester intermediate. Combination step (22) refers to a low yielding stage due to presence of hydroxyl group at (12) and (13). This step (22) then leads to formation of propiverine chloro base at stage (23). This stage comprises of stages (14) a chloro intermediate and (15) propiverine base. Figure 2 represents another prior art esterification as per Chinese patent CN 1285348. In this figure Benzillicacid (11) reacts with 4-chloro -N methyl piperidine (16) to give hydroxyl ester intermediate (13). This stage is represented by (24). This stage further under catalytic action of SOCI₂ leads to stage (25) which comprises Chloro ester intermediate (17) which under action of propyl alcohol leads to formation of propiverine base (15). Figure 3 and 4 represent prior art as per Korean patent KR2005001 1 138 and KR2005001 1 139 respectively. In figure 3, (1 1 ) is benzillic acid leading to formation of methyl benzillate (18) under methyl alcohol and acid. (19) is propyl methylbenzillate which under alkaline hydrolysis forms benzillic acid propyl ether (20). This leads to stage (26) which is representative of a Mitsubishi reaction which generates Ph₃PO which has a very low atom economy. In figure 4 , (1 1 ) is Benzillic acid which under alcohol acid leads to stage (27) wherein (18) is methyl benzillate and under action of propyl alcohol and diethyl azido dicarboxylate (DEAD) leads to (19) the propyl methylbenzillate and further leads to formation of propiverine HCI (21 ) Figure 5 represents the synthesis of Propiverine Hydrochloride as an embodiment of the present invention. In this figure (30) is benzillicacid wherein R=H and for R=CH₃ the chemical represents methyl benzillate. This under action of N propyl alcohol SOCI₂ and organic acid leads to formation of propyl ester ether when R= Propyl and Methyl ester ether with R = CH₃ . This compound (310 under action of a catalyst leads to propiverine base which when chlorinated yields propiverine HCI (21 ). Summary of Invention

Accordingly the present invention provides a process for synthesis of propiverine hydrochloride which comprises comprises N-di-propyl ester ether 7 , the said ester being treated with N-methyl-4-piperidinol and a catalyst under constant stirring in inert gas for long duration , on completion of the said reaction inorganic chloride is added to neutralize the pH, the said reaction being subjected to vacuum to recover excess N-methyl-4- pipridinol giving a residue, the said residue being further extracted in a first organic solvent and washed in water, the said extraction being followed by treatment of the residue under reduced pressure to remove organic solvent to yield Propiverine base, the said raw product being further treated by dissolving in a second organic solvent and charcolozing and treating with hydrochloric acid to yield Propiverine hydrochloride.

In an embodiment of the present invention the catalyst used may be potassium t butoxide, sodium t-butoxide along with phase transfer catalysts.

In another embodiment of the present invention the phase transfer catalyst may be selected from a group consisting of Tetra butyl ammonium bromide , tetraphosphonium bromide , polyethylene glycol, ammonium or phosphonium salts).

In another embodiment of the present invention the inert gas used may be nitrogen, argon, helium.

In still another embodiment of the present invention the stirring may be done for a duration of 1 to 3 days.

In yet another embodiment of the present invention the inorganic chloride may be selected from a group of ammonium chloride to neutralize the reaction medium.

In still another embodiment of the present invention the first organic solvent may be toluene,

In still another embodiment of the present invention the second organic solvent may be acetone.

Accordingly the present invention provides a process for synthesis of N-Di-propyl ester ether 7 which comprises using benzillic acid 1 and alcohol in the presence of an inorganic acid reagents, organic reagents, inorganic salts, organic salts, the said process further comprising refluxing benzillic acid 1 with N-propyl alcohol in the presence of said catalysts and reagents in the ration in a range of 10-200% mole ratio, to produce N-di- propyl ester ether 7 as viscous liquid.

In an embodiment of the present invention the alcohol may be N propyl alcohol.

In another embodiment of the present invention inorganic acid may be sulphuric acid In yet another embodiment the organic reagent may be methane sulphuric acid

In still another embodiment the inorganic salt may be phosphorous oxychloride.

In still further embodiment of the invention the organic salts may be thionyl chloride.

In an embodiment of the present invention the yield of the ester is at least 90%.

Accordingly the present invention provides a pure Propiverine Hydrochloride.

In an embodiment of the present invention Propiverine hydrochloride may be used to treat Urinary Incontinence

Detailed Description of Invention

In the synthetic scheme disclosed herein (Figure 5), benzillic acid 1 is directly converted to di-propyl ester ether 7 from the known standard method. This does not involve any complicated reactions like the prior art method of Mitsunobu Reaction as in KR2005001 1 138A / does not generate much waste. The intermediate thus obtained is reacted with N-Methyl 4-hydroxy piperidine in the presence of sodium t-butoxide at room temperature to get Propiverine base 5. This is then finally converted to Propiverine hydrochloride.

Synthesis of N-di-propyl ester ether (2,2,diphenyl-2-propyloxy-propyl acetate) 7.

With reference to Fig 5 wherein R=H, R'= O-Propyl

N-Di-propyl ester ether 7 is synthesized from classical synthetic methods using benzillic acid 1 and excess N-propyl alcohol in the presence of reagents like sulfuric acid, methane sulfuric acid, phosphorous oxychloride, PCI5, thionyl chloride in almost 80-95% yield. Thus

Benzillic acid 1 (1 kg) is refluxed with 6 Lt of N-propyl alcohol in the presence of thionyl chloride (1.15 kg) for 10 h. After 10 h, excess n-propylalcohol is distilled under vacuum.

The resultant residue was washed with 10% sodium carbonate solution to pH neutral and extracted with toluene (3 Lt). Toluene is stripped under reduced pressure to get benzillicacid propyl ester ether 7 as the only product in almost 90% yield (1.23 kg) as viscous liquid. The NMR spectra of the compound obtained is as below:

1 H NMR (CDC ): 7.50-7.40 & 7.35-7.25 ( 2 multiplets, 10H), 4.12 (t, 2H), 3.19 (t, 2H), 1 .70- 1 .50 (3, 4H), 0.93 (t, 3H), 0.81 (t, 3H).

13C NMR (CDCI₃): 172.01 , 141 .30, 128.45, 127.70, 86.43, 66.95, 66.92, 23.23, 21 .84, 10.66, 10.33

In another embodiment procedure, benzillic acid (1 kg) 1 is treated with PCI5 (1 .82 kg) at 80-1 10 °C for 4 h. The residue thus obtained is refluxed with 6 Lt of N-propyl alcohol in the presence of thionyl chloride (1 .15 kg) for 10h. After 10 h, excess n-propylalcohol is distilled under vacuum. The resultant residue was washed with 1 0% sodium carbonate solution to pH neutral and extracted with toluene (3 Lt). Toluene is stripped under reduced pressure to get benzillicacid propyl ester ether 7 as the only product in almost 88 % yield (1 .20 kg) as viscous liquid. The NMR spectra of the compound obtained is as above. In another experiment, Benzillic acid 1 (1 kg) is refluxed phosphorous oxychloride (1 .50 kg) with 6 Lt of N-propyl alcohol for 24 h. The reaction mixture thus obtained is worked up as before to get N-di-propyl ester ether 7 as the only product in almost 90% yield (1 .23 kg) as viscous liquid. The NMR is same as described above

Benzillic acid methyl ester ( 0.241 kg) is treated with thionyl chloride ( 125 g) and heated at 50-60 °C for 3 h. The resultant chloro compound is refluxed with n-propyl alcohol for 10 h with n-propyl alcohol ( 6 Lt). After 1 0 h, excess n-propylalcohol is distilled under vacuum. The resultant residue was washed with 10% sodium carbonate solution to pH neutral and extracted with toluene (3 Lt). Toluene is stripped under reduced pressure to get benzillicacid propyl ester ether 7 (R - OCH3) as the only product in almost 88 % yield (1 .20 kg) as viscous liquid . The NMR spectra of the compound obtained is identical to the compound 7 (with R'=OCH3).

Following examples are given by way of illustration only and do not limit the scope of the invention

Synthesis of Propiverine base and Hydrochloride

Example 1

7 (1 .23 kg) is treated with N-methyl-4-piperidinol (3 kg) and catalytic amount of potassium t- butoxide (246 g) and tetrabutylammonium chloride (50 g) and stirred under nitrogen for 3 days at room temperature. At the end of 3 days TLC-Thin Layer Chromatography (1 :1 , acetone: chloroform) shows almost 80-90% reaction conversion. Once the TLC is acceptable, , ammonium chloride (400 g) is added to bring the pH to almost neutral. Excess N-methyl-4-pipridinol is recovered under high vacuum at a pressure of about 5 mm. The residue thus obtained is extracted in toluene (4 Lt) and washed with water(2 Lt) 3 times. Toluene was removed under reduced pressure to get crude product 1 .5 kg (almost 100%). Which can be converted to Propiverine hydrochloride by dissolving the residue in acetone(1 :6-7) and charcolizing (1 0% by weight) and treating with hydrochloric acid to get almost white Propiverine HCI 0.9 kg to1 .25 kg which melts at 216-218 °C, with an assay of 99.00-100.00% and HPLC purity of >99.50%. The NMR spectra obtained for the compound is as follows

1 H NMR (CDCI₃): 12.30 &12.40 (Broad singlet, 1 H), 7.45-7.25 (2 multiplets, 1 0H), 5.14, 5.00 (2 broad multiplets, 1 H),3.23 (triplet, 2H), 2.48 (Doublet, 3H), 1 .62 (quintet, 2H). 0.91 (triplet, 3H), 3.07,3.03,2.45,2.1701 .88 (5 multiplets, 8H)

13C NMR (CDCI₃): 170.34, 140.80, 128.33, 127.83, 128.17, 86.3,67.03,64.75,48.85, 43.45,26.57,23.18, 10.64.

Example 2

Benzillic acid (1 kg) 1 is treated with PCI5 (1 .82 kg) at 80-1 10 °C for 4 h. The residue thus obtained is refluxed with 6 Lt of N-propyl alcohol in the presence of thionyl chloride (1 .15 kg) for 10h. After 10 h, excess n-propylalcohol is distilled under vacuum. The resultant residue was washed with 10% sodium carbonate solution to pH neutral and extracted with toluene (3 Lt). Toluene is stripped under reduced pressure to get benzillicacid propyl ester ether 7 as the only product in almost 88 % yield (1 .20 kg) as viscous liquid. The NMR spectra of the compound obtained is as above. In another experiment, Benzillic acid 1 (1 kg) is refluxed phosphorous oxychloride (1 .50 kg) with 6 Lt of N-propyl alcohol for 24 h. The reaction mixture thus obtained is worked up as before to get N-di-propyl ester ether 7 as the only product in almost 90% yield (1 .23 kg) as viscous liquid. (1 .23 kg) of Ester ether was reacted with N-methyl-4-piperidinol (3 kg) as above and worked up as above to get about 0.88 kg of Propiverine Hydrochloride having a assay of 99-100%. Example 3

Benzillic acid methyl ester ( 0.241 kg) is treated with thionyl chloride ( 125 g) and heated at 50-60 °C for 3 h. The resultant chloro compound is refluxed with n-propyl alcohol for 10 h with n-propyl alcohol ( 6 Lt). After 10 h, excess n-propylalcohol is distilled under vacuum. The resultant residue was washed with 10% sodium carbonate solution to pH neutral and extracted with toluene (3 Lt). Toluene is stripped under reduced pressure to get benzillicacid propyl ester ether 7 (R'= OCH3) as the only product in almost 88 % yield (1.20 kg) as viscous liquid . 7 obtained from example 3 (1 .23 kg) was reacted with N- methyl-4-piperidinol (3 kg) as above and worked up as above to get about 0.89 kg of Propiverine Hydrochloride having a assay of 99-100%.

Example 4:

7 (1.23 kg) is treated with N-methyl-4-piperidinol (3 kg) and catalytic amount of sodium t- butoxide (250 g) and tetrabutylammonium chloride (50 g) and stirred under nitrogen for 3 days at room temperature. At the end of 3 days TLC-Thin Layer Chromatography (1: 1, acetone: chloroform) shows almost 80-90% reaction conversion. Once the TLC is OK, ammonium chloride (400 g) is added to bring the pH to almost neutral. Excess N-methyl- 4-pipridinol is recovered under high vacuum at a pressure of about 5 mm. The residue thus obtained is extracted in toluene (4 Lt) and washed with water(2 Lt) 3 times. Toluene was removed under reduced pressure to get crude product 1.5 kg (almost 100%). Which can be converted to Propiverine hydrochloride by dissolving the residue in acetone(l :6-7) and charcolizing (10% by weight) and treating with hydrochloric acid to get almost white Propiverine HCI 0.9 kg tol.20 kg which melts at 216-218 °C, with an assay of 99.00- 100.00% and HPLC purity of >99.50%. Example 5:

7 (1.23 kg) is treated with N-methyl-4-piperidinol (3 kg) and catalytic amount of sodium t- butoxide (250 g) and triphenylphosphonium bromide (50 g) and stirred under nitrogen for 3 days at room temperature. At the end of 3 days TLC-Thin Layer Chromatography (1:1, acetone: chloroform) shows almost 80-90% reaction conversion. Once the TLC is OK, ammonium chloride (400 g) is added to bring the pH to almost neutral. Excess N-methyl- 4-pipridinol is recovered under high vacuum at a pressure of about 5 mm. The residue thus obtained is extracted in toluene (4 Lt) and washed with water(2 Lt) 3 times. Toluene was removed under reduced pressure to get crude product 1.5 kg (almost 100%). Which can be converted to Propiverine hydrochloride by dissolving the residue in acetone(l :6-7) and charcolizing (10% by weight) and treating with hydrochloric acid to get almost white Propiverine HCI 0.9 kg tol.20 kg which melts at 216-218 °C, with an assay of 99.00- 100.00% and HPLC purity of >99.50%.

Example 6

7 (1.23 kg) is treated with N-methyl-4-piperidinol (3 kg) and catalytic amount of sodium t- butoxide (250 g) and polyethylene glycol-400 (50 g) and stirred under nitrogen for 3 days at room temperature. At the end of 3 days TLC-Thin Layer Chromatography (1: 1, acetone: chloroform) shows almost 80-90% reaction conversion. Once the TLC is OK, ammonium chloride (400 g) is added to bring the pH to almost neutral. Excess N-methyl-4-pipridinol is recovered under high vacuum at a pressure of about 5 mm. The residue thus obtained is extracted in toluene (4 Lt) and washed with water (2 Lt) 3 times. Toluene was removed under reduced pressure to get crude product 1.5 kg (almost 100%). Which can be converted to Propiverine hydrochloride by dissolving the residue in acetone(l :6-7) and charcolizing (10% by weight) and treating with hydrochloric acid to get almost white Propiverine HCI 0.9 kg tol.20 kg which melts at 216-218 °C, with an assay of 99.00- 100.00% and HPLC purity of >99.50%.

The main advantages of the present invention are:

1. The present invention gives pure Propiverine Hydrochlorid

2. The process gives high over all yield of the end product

3. The process is easily scaled up if required

Claims

CLAIMS WHAT IS CLAIMED IS:

1 . A process for synthesis of Propiverine hydrochloride which comprises N-di- propyl ester ether 7 , the said ester being treated with N-methyl-4-piperidinol and a catalyst under constant stirring in inert gas for long duration , on completion of the said reaction inorganic chloride is added to neutralize the pH, the said reaction being subjected to vacuum to recover excess N-methyl-4- pipridinol giving a residue, the said residue being further extracted in first organic solvent and washed in water, the said extraction being followed by treatment of the residue under reduced pressure to remove organic solvent to yield a raw product, the said raw product being further treated by dissolving in second organic solvent and charcolozing and treating with hydrochloric acid to yield Propiverine hydrochloride.

2. As claimed in claim 1 wherein , the catalyst used is potassium t-butoxide, sodium t-butoxide along with phase transfer catalysts.

3. As claimed in Claim 2 wherein, the phase transfer catalyst is selected from a group consisting of Tetra butyl ammonium bromide , tetraphosphonium bromide , polyethylene glycol, ammonium or phosphonium salts).

4.. As claimed in claim 1 wherein, the inert gas is nitrogen, argon, helium.

5. As claimed in claim 1 wherein the stirring is done for a duration of 1 to 3 days.

6 As claimed in claiml wherein , the inorganic chloride is ammonium chloride to neutralize the reaction medium.

7. As claimed in claim 1 wherein , the first organic solvent is toluene.

8. As claimed in claim 1 wherein , the second organic solvent is acetone

9. A process for synthesis of N-Di-propyl ester ether 7 of claim 1 , which comprises, using benzillic acid 1 and alcohol in the presence of an inorganic acid reagents, organic reagents, inorganic salts, organic salts, the said process further comprising refluxing benzillic acid 1 with N-propyl alcohol in the presence of said catalysts and reagents in the ration in a range of 10-200% mole ratio, the to produce N-di-propyl ester ether 7 as viscous liquid.

10. As claimed in claim 9 wherein the alcohol is N propyl alcohol, dichcloromethane, toluene, benzene and any combination thereof.

1 1 . As claimed in claim 9 wherein inorganic acid is sulphuric acid

12 As claimed in claim 9 wherein the inorganic salt is phosphorous oxychloride.

13 As claimed in claim 9 wherein , the organic salt is thionyl chloride.

14 As claimed in claim 9 wherein the yield of the ester is at least 90%.

15 Pure Propiverine Hydrochloride as claimed in claims 1 to 8, useful for treating urinary incontinence