WO2016098128A1

WO2016098128A1 - Process for the preparation of bepridil

Info

Publication number: WO2016098128A1
Application number: PCT/IN2015/050204
Authority: WO
Inventors: Muthukrishnan Murugan; Mujahid MOHAMMAD
Original assignee: Council Of Scientific & Industrial Research
Priority date: 2014-12-16
Filing date: 2015-12-16
Publication date: 2016-06-23

Abstract

Bepridil is used for its anti-arrhythmia and calmodulin antagonistic activities. The present application discloses a novel, easy and direct process for the preparation of bepridil. Further, it also discloses a process for the preparation of R-enantiomer of bepridil with high ee.

Description

PROCESS FOR THE PREPARATION OF BEPRIDIL

FIELD OF THE INVENTION

The present invention relates to a novel, easy and direct process for the preparation of bepridil. Particularly, a process for the preparation of the R- enantiomer of bepridil with high ee is disclosed.

BACKGROUND OF THE INVENTION

Calcium channel blockers are an important group of drugs and they have prevalent use in treating hypertension, heart failure, cardiac arrhythmias etc. Bepridil (Trade name: Vascor®) is a long acting calcium-blocking agent with significant antianginal activity.

(R) enantiomer of Bepridil

It has antihypertensive and selective anti-arrhythmia activities and acts as a calmodulin antagonist. Although, it contains one chiral center, it is generally administered as a racemates.

However, literature search reveals that (R)-isomer of bepridil is more active than (-S)- isomer, in certain cases. Importantly, many racemic drugs, which previously received FDA approval, are being re-evaluated to determine the potential benefits of the pure enantiomers. Furthermore, in recent years, there is raising interest in exploiting bepridil' s utility as it exhibits promising results in the new therapeutic areas such as alzheimer's, antiviral, atrial fibrillation and in certain neurological disorders. Literature search reveals there is no direct method available for the preparation of Bepridil enantiomers, although the compounds have been used.

US 3962238 A disclose ethers of n-propanolamine, preparation thereof and their use in treatment of cardiovascular conditions.

"Pharmaceutical Sunbstances: Sythesis, patents, applications" 4^th edition by Kleemann in Page 217-218 discloses the following Scheme I:

ine

1 -(2-chloro-3-iso-butoxypropyl)pyrrolidine (II)

Bepridil

Scheme 1

Eur. Pat. Appl., 0332159, titled, "(3-Alkoxy-2-aminopropyl)phenylheterocycles, particularly benzoxazine and indoline derivatives, and their preparation, pharmaceutical compositions, and use as cardiovascular agents" by Leinert, Herbert et al reports the following reaction:

Scheme 2 Article titled, "Hb zeolite: An Efficient and Reusable Catalyst for Ring-Opening of Epoxides with Amines under Microwave Irradiation" By Kureshy, Rukhsana I. et al in Catalysis Letters, 134(3-4), 318-323; 2010 reports the following

Scheme 3

WO 2007/062862 discloses use of a calmodulin inhibitor/antagonist, like bepridil, phenoxybenzamine, cetiedil, chlorpromazine or W7, for the preparation of a pharmaceutical composition for the treatment, amelioration and/or prevention of neurodegenerative disorders.

WO 2011008230 A3 relates to use of rapamycin derivatives and ethers of N- propanolamines for decreasing infection by a pathogen. More particularly, the invention relates to use of O-alkylated rapamycin derivatives, as well as bepridil, for decreasing viral infection.

As studies on this potential molecule are still going on, it is essential to develop a new method for preparation enantiomers of bepridil to cater the need of biological studies.

OBJECTS OF THE INVENTION

The main object of the present invention is to provide a novel, easy and efficient process for preparation of bepridil.

Another object of the present invention is to provide a process for preparation of R- enantiomer of bepridil which can be used for an anti-arrhythmia and calmodulin antagonistic activity. SUMMARY OF THE INVENTION

Accordingly, the present invention provides a novel, easy and direct process for preparation of bepridil with high enantiopurity, wherein the R- enantiomer can be used for an anti-arrhythmia and calmodulin antagonistic activity.

In an embodiment, the present invention provides a novel, easy and direct process for preparation of enantiomerically pure forms of bepridil.

In another embodiment the present invention provides an easy and direct process for the preparation of Bepridil (1),

1 comprising the steps of: a. treating isobutanol with epichlorohydrin (2) using KOH in presence of phase transfer catalyst TBAI to obtain 2-(isobutoxymethyl)oxirane (3); b. subjecting the epoxide (3) to regioselective ring opening with aniline in presence of catalytic LiBr using methanol as a solvent to give the intermediate amino alcohol (4); c. N-benzoylation of compound (4), using benzoyl chloride and triethyl amine condition to afford N-Benzoylated derivative (5); d. treating compound (5) with succinimide under standard Mitsunobu protocol to produce compound ( 6) and benzoyl migrated product 7; e. reducing the amide compound (6) using borane-DMS under reflux condition to furnish the target molecule Bepridil (1). BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS

Fig. 1 depicts 1H NMR of (R)-bepridil (R)-l in CDCI₃. Fig. 2 depict ¹³C NMR of (R)-bepridil (R)-l in CDCI₃.

Fig. 3 depict Racemic Chiral HPLC Analysis of (R)-Bepridil (R)-l. Fig. 4 depict Racemic Chiral HPLC Analysis of (R)-Bepridil (R)- 1.

Abbreviations:

DIAD: Diisopropyl azodicarboxylate KOH: Potassium hydroxide

BH3-DMS: Borane dimethylsulfide complex DMS: Dimethylsulfide TBAI: Tetrabutylammonium Iodide LiBr: Lithium Bromide

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

In view of above, the present invention provides a novel, easy and direct process for the preparation of bepridil, wherein the R- enantiomer is known to be used for anti- arrhythmia and calmodulin antagonistic activity.

In an embodiment, the present invention provides a novel, easy and direct process for the preparation of bepridil. In another embodiment the present invention provides an easy and direct process for the preparation of Bepridil (1),

1

comprising the steps of: a. treating isobutanol with epichlorohydrin (2) using KOH in the presence of phase transfer catalyst TBAI to obtain 2-(isobutoxymethyl)oxirane (3); b. subjecting the epoxide (3) to regioselective ring opening with aniline in the presence of catalytic LiBr using methanol as a solvent to give the intermediate amino alcohol (4); c. N-benzoylation of compound (4), using benzoyl chloride and triethyl amine condition to afford N-Benzoylated derivative (5); d. treating compound (5) with succinimide under standard Mitsunobu protocol to produce compound (6) and benzoyl migrated product 7; e. reducing the amide compound (6) using borane-DMS under reflux condition to furnish the target molecule Bepridil (1).

In a preferred embodiment, the present invention provides a novel, easy and direct process for the preparation of R-Bepridil (R-l),

R-l

with ee>99%, comprising the steps of: a. treating isobutanol with R-epichlorohydrin (R-2) using aq. KOH in the presence of phase transfer catalyst TBAI to obtain (S)-2-(isobutoxymethyl)oxirane (S)- 3; b. subjecting the epoxide (S)-3 to regioselective ring opening with aniline in the presence of catalytic LiBr using methanol as a solvent to give the intermediate amino alcohol (S)-4; c. N-benzoylation of compound (S)-4, using benzoyl chloride and triethyl amine condition to afford N-Benzoylated derivative (S)-5; d. treating compound (S)-5 with succinimide under standard Mitsunobu protocol to produce compound (R)-6 and benzoyl migrated product 7; e. reducing the amide compound (R)-6 using borane-DMS under reflux condition to furnish the target molecule (R)-Bepridil (R-l).

The above process is shown below in Scheme 4:

( <RR)>--22 O'C, 1h, 85%

R-epichlorohydrin

(Rj-Λ (ee >99%)

Scheme 4

In an aspect, the present invention provides a process wherein (S)-enantiomer of bepridil is prepared by using (S)-epichlorohydrin instead of (R)-epichlorohydrin in step (a) of said process.

In another aspect the present invention, there is provided a process for the synthesis of (R)-enantiomer of bepridil which can be used for an anti-arrhythmia and calmodulin antagonistic activity.

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention. EXAMPLES

Experimental

Solvents were purified and dried by standard procedures prior to use. IR spectra were

1 13 obtained from Perkin-Elmer Spectrum one spectrophotometer. H NMR and C NMR spectra were recorded on a Bruker AC-200 NMR spectrometer. Spectra were obtained in CDCI₃. Monitoring of reactions was carried out using TLC plates Merck Silica Gel 60 F254 and visualization with UV light (254 and 365 nm), I₂ and anisaldehyde in ethanol as development reagents. Optical rotations were measured with a JASCO P 1020 digital polarimeter. Mass spectra were recorded at ionization energy 70 eV on API Q Star Pulsar spectrometer using electrospray ionization. Enantiomeric excess was determined by chiral HPLC.

Example 1: 5 -2-(isobutoxymethyl)oxirane (S)-3

To a stirred solution of aqueous potassium hydroxide (15 mL, 50% w/w), R- epichlorohydrin (7.2 mL, 92.4 mmol) and tetrabutylammonium iodide (0.5 g, 1.5 mmol) was added isobutanol (5 mL, 30.8 mmol) at temperature below 25 °C and the resulting mixture was stirred at room temperature for 24 h. After completion of the reaction cold water (20 mL) was added and the reaction mixture was extracted with diethyl ether (3 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over Na₂S04, and evaporated under reduced pressure. The residue was purified by vacuum distillation (75 °C, 8 mbar) as colorless oil (2.5 g, 62%).

[a]²¹ _D = +3.45 (c 1.99, CHC1₃). IR (CHC1₃): v_max 2960, 2873, 1522, 1474, 1421, 1097 cm^"1. 1H NMR (200 MHz, CDC1₃): δ_Η 0.89 (d, J = 6.7 Hz, 6H), 1.81 - 1.94 (m, 1H), 2.59- 2.63 (dd, J = 4.9, 2.6 Hz, 1H), 2.77- 2.82 (dd, J = 4.9, 4.1 Hz, 1H), 3.12-3.18 (m, 1H), 3.23 (d, J = 3.4 Hz, 1H), 3.28 (d, J = 3.5 Hz, 1H), 3.33-3.42 (dd, 7 = 1 1.5, 5.7 Hz, 1H), 3.67-3.74 (dd, J = 11.5, 3.0 Hz, 1H). ¹³C NMR (50 MHz, CDC1₃): 5_C 78.4 (CH₂), 71.5 (CH₂), 50.9 (CH), 44.2 (CH₂), 28.4 (CH), 19.2 (CH₃, 2 carbons). MS: m/z 153 [M+Na]⁺.

A. (S)-l-isobutoxy-3-(phenylamino)propan-2-ol (S)-4

To a stirred solution of epoxide (S)-3 ( 1 g, 7.68 mmol) and aniline (0.858 g, 9.21 mmol) in methanol (20 mL) under N₂ atmosphere was added lithium bromide (0.13 g, 1.5 mmol) and the resulting mixture was stirred for 12 hours at room temperature. After completion of the reaction, (indicated by TLC) methanol was evaporated under reduced pressure. Water (15 mL) was added and extracted with ethyl acetate (15 mL x 3). The organic phase was washed by brine, dried over Na₂S0₄ and concentrated in vacuo. The crude product was purified using column chromatography (silica gel, petroleum ether/ethyl acetate, 85: 15) to yield (S)-4 as an oil ( 1.54 g, 90%).

[a]²² _D = +2.54 (c 2.5, CHC1₃); IR (CHC1₃). v_max 3751, 3682, 3660, 3573, 3020, 2400, 1699, 1603, 1511, 1419, 1215, 1017, 929, 669 cm^"1. 1H NMR (200 MHz, CDC1₃): δ_Η 0.94 (d, = 6.7 Hz, 6H), 1.79-1.99 (m, 1H), 3.10-3.35 (m, 5H), 3.42-3.57 (m, 2H), 3.96- 4.07 (m, 1H), 6.62-6.75 (m, 3H), 7.1 1-7.25 (m, 2H). ¹³C NMR (50 MHz, CDC1₃): 5_C 148.3 (C), 129.2 (CH, 2 carbons), 1 17.7 (CH), 113.1(CH, 2 carbons), 78.4 (CH₂), 73.0 (CH₂), 69.0 (CH), 46.7 (CH₂), 28.4 (CH), 19.2 (CH₃, 2 carbons). MS: m/z 224 [M+H]⁺, 246 [M+Na]⁺. ee >99% [HPLC conditions: Chiralcel OD-H (250 x 4.6 mm) column; eluent: pet ether/ethanol/trifluoroacetic acid (85: 15:0.1); flow rate 0.5 mL/min; detector: 254 nm] [(Sj-isomer IR = 11.10 min, (i?j-isomer IR = 12.17 min].

B. (S)-N-( 2-hydroxy-3-isobutoxypropyl)-N-phenylbenzamide ( S)-5 To a stirred solution of (S)-4 ( 1.2 g, 5.37 mmol) in dry dichloromethane (10 mL) was slowly added benzoyl chloride (0.68 mL, 5.91 mmol) at 0 °C, under N₂ atmosphere. After, 10 mins triethyl amine (1.49 mL, 10.75 mmol) was added dropwise over 15 minutes. The resulting mixture was stirred for 1 hour at 0 °C. After completion of the reaction (indicated by TLC) cold water ( 15 mL) was added and the crude mixture was extracted with dichloromethane (15 mL). The organic layer was washed with IN HC1 (15 mL), sat NaHC0₃ solution (3 X15 mL), and dried over Na₂S0₄ and concentrated in vacuo. The crude product was purified using column chromatography (silica gel, petroleum ether/acetone, 90: 10) to yield (S)-5 as an oil ( 1.5 g, 85%).

[a]²² _D = +67.37 (c 2.32, CHC1₃). IR (CHC1₃): v_max 3683, 3020, 1578, 1521, 1401, 1017, 928 cm^"1. 1H NMR (200 MHz, CDC1₃): δ_Η 0.85 (d, = 6.7 Hz, 6H), 1.68-1.85 (m, 2H), 3.16 (d, = 6.6 Hz, 2H), 3.47 (d, = 5.3 Hz, 2H), 3.94- 4.02 (m, 1H), 4.06-4.13 (m, 1H), 4.24 (dd, = 13.2, 7.4 Hz, 1H), 7.09-7.33(m, 10 H). ¹³C NMR (50 MHz, CDC1₃) 5c 172.5 (CO), 143.9 (C), 135.4 (C), 129.9 (CH), 129.1 (CH, 2 carbons), 128.9 (CH, 2 carbons), 127.7 (CH, 2 carbons), 127.6 (CH, 2 carbons), 126.7 (CH), 78.3 (CH₂), 72.7 (CH₂), 69.7 (CH), 55.0 (CH₂), 28.3 (CH), 19.2 (CH₃, 2 carbons). MS: m/z 328 [M+H]⁺, 350 [M+Na]⁺.

C. (R)-N-( 2-( 2,5-dioxopyrrolidin-l-yl)-3-isobutoxypropyl)-N-phenylbenzamide (R)-6

A solution of DIAD (0.52 mL, 2.68 mmol) in dry THF (5 mL) was added dropwise to a solution of (S)-5 (0.8 g, 2.44 mmol), succinimide (0.266 g, 2.68 mmol) and triphenyl phosphine (0.7 g, 2.68 mmol) in dry THF (20 mL) at 0 °C under N₂ atmosphere. The reaction mixture was stirred at ambient temperature for 12 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate, 65:35) to yield (R)-6 as oil (0.4 g, 40%).

[a]²² _D = +106.8 (c 0.9, CHC1₃). IR (CHC1₃): v_max 3682, 1704, 1524, 1398, 1018 cm^"1. ^XH NMR (200 MHz, CDC1₃): δ_Η 0.81 (d, = 6.5 Hz, 6H), 1.65-1.85 (m, 1H), 2.39 (s, 4H), 3.05-3.21 (m, 2H), 3.78 (d, = 1.7 Hz, 1H), 3.81 (d, = 2.3 Hz, 1H), 4.05 (d, J = 11.6 Hz, 1H), 4.64- 4. 82 (m, 2H), 7.02-7.26 (m, 10H). ¹³C NMR (50 MHz, CDC1₃): 5_C 177.8 (CO, 2 carbons), 171.1 (CO), 143.3 (C), 135.5 (C), 129.7 (CH), 129.0 (CH, 2 carbons), 128.5 (CH, 2 carbons), 127.7 (CH, 2 carbons), 127.3 (CH, 2 carbons), 126.6 (CH), 77.6 (CH₂), 67.3 (CH₂), 51.0 (CH), 47.3 (CH₂), 28.3 (CH), 27.9 (CH₂, 2 carbons), 19.1 (CH₃, 2 carbons). MS: m/z 409 [M+H]⁺, 431 [M+Na]⁺.

D. (S)-l-isobutoxy-3-(phenylamino)propan-2-yl benzoate -7

Colorless oil ( 0.2 g, 25% ). (a)²⁵ _D +34.5 (1.18, CHC1₃). IR (CHC1₃): v_max 3633, 3020, 2963, 2873, 1716, 1603, 1510, 1423, 1272 cm^"1. 1H NMR (200 MHz, CDC1₃): δ_Η 0.91 (d, = 6.7 Hz, 6H), 1.61 (brs, 1H), 1.80-2.00 (septet, 1H), 3.27 (dd, = 6.5, 1.3 Hz, 2H), 3.58 (dd, = 5.8, 2.0 Hz, 2H), 3.66- 3.82 (m, 2H), 5.36-5.47 (m, 1H), 6,67-6.75 (m, 3H), 7.15-7.23 (m, 2H), 7.41-7.49 (m, 2H), 7.54-7.63 (m, 1H), 8.03-8.08 (m, 2H). ¹³C NMR (50 MHz, CDC1₃) 5_C 166.2 (CO), 147.9 (C), 133.4 (CH), 130.0 (C), 129.7 (CH, 2 carbons), 129.2 (CH, 2 carbons), 128.3 (CH, 2 carbons), 117.6 (CH), 112.8 (CH, 2 carbons), 78.5 (CH₂), 72.2 (CH), 70.2 (CH₂), 44.7 (CH₂), 28.4 (CH), 19.2 (CH₃, 2 carbons). MS: 350 [M+Na]⁺.

E. (R)-N-benzyl-N-(3-isobutoxy-2-(pyrrolidin-l-yl)propyl)aniline (R-bepridil) (R)-l

To a solution of compound (R)-6 (0.180 g, 0.44 mmol) in dry THF (5 mL) at 0 °C was slowly added BH₃-DMS complex (0.2 mL, 2.20 mmol) under N₂ atmosphere. Subsequently, the reaction mixture was refluxed for 12 h. After completion of the reaction, methanol (5 mL) was added carefully at 0 °C and stirred the content for 20 min. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (40 mL). After an aqueous workup the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate, 70:30) to yield (R)-l as an oil (0.113 g, 70%). (Refer Fig: 1 to 4)

[a]²² _D = -5.2 (c 1.26, MeOH); IR (CHC1₃). v_max 3061, 3026, 2957, 2799, 1943, 1806, 1735, 1682, 1598, 1505, 1452, 1354, 1294, 1224, 1112, 987, 873, 746, 694 cm^"1.

1H NMR (400 MHz, CDC1₃): δ_Η 0.95 (d, = 6.3 Hz, 3H), 0.97 (d, = 6.6 Hz, 3H), 1.77-1.82 (m, 4H), 1.83-185 (m, 1H), 2.78-2.92 (m, 5H), 3.05 (d, = 6.4Hz, 2H), 3.44- 3.53 (m, 2H), 3.58-3.70 (m, 2H), 4.61-4.72 (quartet, = 17.3 Hz, 2H), 6.69 (t, = 7.3 Hz, 1H), 6.81 (d, = 8.2 Hz, 2H), 7.18-7.24 (m, 5H), 7.29-7.32 (m, 2H). ¹³C NMR (50 MHz, CDCI₃): 5c 148.5 (C), 138.7 (C), 129.1 (CH, 2 carbons), 128.5 (CH, 2 carbons), 128.2 (CH), 126.6 (CH, 2 carbons), 116.2 (CH), 112.3 (CH, 2 carbons), 78.4 (CH₂), 73.4 (CH₂), 68.9 (CH₂), 60.9 (CH), 54.7 (CH₂), 51.2 (CH₂, 2 carbons), 27.2 (CH), 23.4 (CH₂, 2 carbons), 19.6 (CH₃, 2 carbons). MS: m/z 367 [M+H]⁺.

ee >99% [HPLC conditions: Chiralcel OD-H (250 x 4.6 mm) column; eluent: n- hexane/ethanol (96:4); flow rate 0.5 mL/min; detector: 254 nm] [(Z?)-isomer IR = 13.05 min, (Sj-isomer IR = 15.01 min]

ADVANTAGES OF THE INVENTION

a. Easy process to provide access to Bepridil enantiomers in high optical purity. b. The need for preparation process of single enantiomers of bepridil is the need of biological studies, and is fulfilled herewith.

c. (R)-enantiomer of bepridil can be used for an anti-arrhythmia and calmodulin antagonistic activity.

Claims

We claim:

1. A process for the preparation of Bepridil (1),

1

comprising the steps of: a. treating isobutanol with epichlorohydnn (2) using aq. KOH in presence of phase transfer catalyst TBAI to obtain 2-(isobutoxymethyl)oxirane (3);

b. subjecting the epoxide (3) to regioselective ring opening with aniline in presence of catalytic LiBr using methanol as a solvent to give the intermediate amino alcohol (4); c. N-benzoylation of compound (4), using benzoyl chloride and triethyl amine condition to afford N-Benzoylated derivative (5); d. treating compound (5) with succinimide under standard Mitsunobu protocol to produce compound (6) in and benzoyl migrated product 7; e. reducing the amide compound (6) using borane-DMS under reflux condition to obtain Bepridil (1).

2. The process as claimed in claim 1, wherein the said process is used for the preparation of R-Bepridil (R-l),

with ee > 99%, comprising the steps of: a. treating isobutanol with R-epichlorohydrin (R-2) using aq. KOH in presence of phase transfer catalyst TBAI to obtain (S)-2- (isobutoxymethyl)oxirane (S)- 3; b. subjecting the epoxide (S)-3 to regioselective ring opening with aniline in presence of catalytic LiBr using methanol as a solvent to give an intermediate amino alcohol (S)-4; c. N-benzoylation of compound (S)-4, using benzoyl chloride and triethyl amine condition to afford N-Benzoylated derivative (S)-5; d. treating compound (S)-5 with succinimide under standard Mitsunobu protocol to produce compound (R)-6 and benzoyl migrated product 7; e. reducing the amide compound (R)-6 using borane-DMS under reflux condition to obtain (R)-Bepridil (R-l).

3. The process as claimed in claim 1, wherein said process is for synthesis (R)- enantiomer of bepridil which can be used for an anti-arrhythmia and calmodulin antagonistic activity.