INTRODUCTION:

Carvedilol is multiple-action drug, and is a non-selective β-adrenergic blocking agent with α1-blocking activity β-Adrenergic blocking agents^[1-4], mostly comprising of β-amino alcohols, are of pharmaceutical significance and have received major attention due to their utility in the management of cardiovascular disorders^[5] including hypertension^[6], angina pectoris, cardiac arrhythmias and other disorders ^[7] related to the sympathetic nervous system.affects the response to certain nerve impulses in parts of the body^[8-9] .As a result, b-clockers decrease the heart’s need for blood and oxygen by reducing its workload. Carvedilol is also known to be vasodilator, resulting primarily from a-adrenoceptor blocade. The multiple actions of carvedilol are responsible for the antihypertensive efficacy of the drug and its effectiveness in managing congestive heart failure. Carvedilol also has much greater antioxidant activity than other commonly used b-blockers. Carvedilol has demonstrated significant clinical benefits in the management of patients with heart failure and in the post-myocardial infarction setting. It also possesses unique ancillary properties that may account for positive results in a number of clinical trials.Carvedilol has a chiral center and can exist either as individual stereoisomers or in racemic form.

Racemic carvedilol is the active ingredient of COREG®, which is indicated for the treatment of congestive heart failure and hypertension. The nonselective b-adrenergic activity is shown by the S(-) enantiomer and the a1 blocking activity is shown by both the R(+) and S(-) enantiomers at equal potency.

Fig.1 Structure of Carvedilol

Several methods have been reported in the literature for synthesis of Carvedilol^[10]. The innovator, Boehringer Mannheim GmbH, synthetic approach for the preparation of Carvedilol describes the opening of oxirane ring of 4-(oxiran-2-yl methoxy)-9H-carbazole, with 2-(2-methoxyphenoxy) ethanamine . In this process observed the formation of di-compound as impurity. Avoid the formation of impurity, various methods were performed and documented in the literature such as protecting the amine counterpart with benzyl, p-methoxybenzyl ,acetyl and and others. Despite their extensive success, many of the methods suffer from drawbacks such as incompletion of the reactions during deprotection, lower yields and others. Our research group has been extensively working on identifying and improving new synthetic methods specially We planned using convergent synthetic strategy of this molecule in which disconnection of carvedilol into two major fragments, Carbazole moiety (7) and amine moiety(11).

Carbazole 4 obtained by the reductive cyclization of biphenyl derivative 3, under reflux conditions with triethylphosphate^[11]. Compound 3 was prepared by coupling reaction between 2-methoxyphenylboronic acid 1 and 1-iodo-2-nitrobenzene 2 in the presence of Pd(PPh₃)₄. De-methylation of Carbazole 4 with BBr₃gave the corresponding 4-hyrdoxy carbazole 5. Treatment of the 4-hyrdoxy carbazole 5 with 3-chloro-1,2-propanediol in the presence of sodium carbonate in acetone at 65°C for 8hr afforded carbazole derivative^[12] with diol (6). Carbazole moiety (7) synthesized by the Regioselective monotosylation0^[13]of primary alcohol group of carbazole derivative (6) by the treatment of p-toluenesulfonylchloride, with triethylamine in dichloromethane as shown in Scheme-1.

Reaction Conditions: a)Pd(PPh₃)₄,2N Na₂CO₃,110 ^OC,2hrs. b)P(OEt)₃,155 ^OC,6hrs. c)1M BBr₃ in DCM,4hrs. d)3-chloro-1,2 propanediol ,Na₂CO₃,Acetone,8hrs,65 ^OC .e) p-toluenesulfonylchloride(8), Triethylamine, DCM,RT, 6hrs.

Synthesis of amine moiety (11) (Scheme-2), was achieved by starting from 2-methoxyphenol. Accordingly, treatment of 2-methoxy phenol with 1,2-dichloroethane (8) in the presence of sodium carbonate in acetone gave the chloro derivative^[14] (9). This on treatment with potassium phthalimide afforded corresponding phthalimide derivative (10), which was reacted with methylamine gave amine moiety (11).

Reaction conditions: f) 1,2-dichloroethane,Na₂CO₃, Acetone 60 ^OC, 8hrs. g) Potassium phthalimide , DMF, NaI, RT.h)Mono methyl amine in MeOH, RT 45min

Coupling of carbazole moiety (7) and amine moiety (11) in the presence of potassium carbonate afforded the target carvedilol in 86% yield whose data were identical in all respects with those reported in literature.

Reaction conditions:

i) Potassium carbonate, 110 ^OC.

In conclusion, we have found that highly efficient method to preparation of Carvedilol. The method offers several benefits which include time, yield and formation of single product without impurity and also synthesis of biologically active analogues of carvediol.

Experimental Results:

Synthesis of 2-methoxy-2'-nitrobiphenyl (3):

In a dry 50ml round bottom flask 2-methoxyphenylboronic acid 1(4gm, 26.4mmol) was dissolved in dry dimethylformamide25ml. The resulting solution was stirred with 1-iodo-2-nitrobenzene 2 (5.89gm,23.6) at room temperature for 20min. To the reaction mixture aqueous 2N Na₂CO₃ (5ml)solution was added and stirred was continued at room temperature. The reaction was degased by using with Argon gas for 10min., 1 mol% Pd(PPh₃)₄ complex was added to reaction mass and again degased further for 10 min. The resulting solution was heated to 110 ^OC and stirred at the same temperature for 2 hours monitored by TLC. The reaction mass was poured over ice cold water and extracted with ethylacetate (3X100ml). The combained organic extracts were washed with water (2X50ml). The organic extract was dried over anhydrous sodium sulfate and was purified by 230-400 silcagel column using 1:9 ethylacetate: n-Hexane as eluent to yield yellow colour solid (4.8gm,72%) which was characterized as 2-methoxy-2'-nitrobiphenyl (3) by its spectral and analytical data 3 was obtained. mp:130-131^OC. ¹HNMR (CDCl₃, 400MHz): δ7.9-8.0 (d,1H), 7.6-7.66(t,1H),7.42-7.5(t,1H),7.34-7.42(m,1H),7.3-7.3(d,1H,),7.05-7.12(t,1H), 6.88-6.93 (d,1H), 3.7(s,3H); IR (KBr) (cm^-1) 3467.2, 2932, 1608.9, 1526.7, 1357.7, 756. MS (ESI) : m/z 252 [M+Na]⁺

Preparation of 4-methoxy-9H-carbazole (4):

In a dry 50ml round bottom flask compound (3) (2.0gm)under nitrogen was refluxed for 8 hrs with P(OEt)₃(10ml) monitored by TLC. The reaction mass was quenched with ice and extracted into ethylacetate (3X100ml). The combined organic extracts were washed with water (3X50ml) followed by the brine (1X50ml). The organic layer was dried over anhydrous sodiumsulphate and distilled off the solvent to yield dark colour thick syrup, which was purified by 230-400 silica gel column chromatography using 2:8 ethylacetate:n-Hexane resulted in the formation of white colour compound(1.1gm,73%).The compound obtained was characterized as 4-methoxy-9H-carbazole 4 by the spectral and analytical data. mp: 171-172^OC; ¹HNMR(CDCl₃,400 MHz): δ8.3-8.32 (d,1H), 8.06 (brs,1H), 7.32-7.42 (m,3H), 7.2-7.45 (dd,1H), 7.04-7.06 (d,1H), 6.67-6.69(d,1H), 4.0(s,3H); IR(KBr) (cm^-1): 3392, 2932,2837, 1896,1790,1605, 1584, 1227, 1100, 755; MS (ESI): m/z 198 [M+H]⁺

Synthesis of 4-hydroxy carbazole (5):

In a 50 ml dry round bottom flask compound (4) (2gm,10mmol) was dissolved in dichloromethane (20ml) and the resulting solution was cool to 0^OC. Then1M BBr₃ in dichloromethane(20ml, 20mmol) was added by drop wise fashion over a period of 15min. After completion of addition, resulting reaction mass was stirred for 6 hrs monitored by TLC. The reaction mixture was quenched with ice pieces and was extracted with dichloromethane (3X100ml). The combined the organic extracts were washed with water (2X100ml) followed by brine(50ml). The organic layer was dried over anhydrous sodiumsulphate and solvent was distilled off to yield crude material, which was purified by 230-400 silica gel column chromatography using 3:7 ethylacetate: n-Hexane. The brown colour solid (1.6gm,88%) obtained was characterized by its spectral and analyticaldata as 4-hydroxycarbazole (5). mp:166-168 ^OC. ¹HNMR(DMSO_D₆,400MHz):δ11.1(brs,1H),9.9(s,1H),8.12-8.17(d,1H),7.39-7.41(d,1H),7.42-7.5(t,1H),7.08-7.2(m,2H), 6.89-6.91(d,1H), 6.54-6.45(d,1H); IR(KBr) (cm^-1): 3399,1886,1608, 1505,1207,1044,784; MS (ESI) : m/z 182 [M-H]⁺

Synthesis of 3-(9H-carbazol-4-yloxy) propane-1,2-diol (6):

In a dry 100ml round bottom flask under dry nitrogen atmosphere compound (5) (1gm, 5.5mmol) was dissolved in acetone (15ml), then to this sodium carbonate (Na₂CO₃) (1.2gm, 10.9mmol) was added. The resulting solution was stirred at room temperature for 10min and reaction mass temperature was increased to 70^OC and stirred the reaction mixture at the same temperature for 30 minutes. 3-chloropropane-1,2-diol (1.19gm,10.9mmol) dissolved in acetone(8ml) was added to the reaction mass at reflux temperature by drop wise fashion and resulting reaction mixture was refluxed for 8 hours under nitrogen, monitored by TLC. The reaction mixture was filtered through celite pad and washed the celite pad with excess acetone collecting the filtrate and remove the acetone to obtain crude material, which was purified by 230-400 silica gel column chromatography using 5:5 ethylacetate: n-Hexane. Solid obtained (1.2gm,85%) was characterized by its spectral and analytical data as 3-(9H-carbazol-4-yloxy)propane-1,2-diol(6).mp:150-151^OC;¹HNMR (DMSO-D₆, 400 MHz):δ11.2(brs,1H), 8.20-8.22 (d,1H),7.4-7.43(d,1H) 7.2-7.4(m,2H),7.0-7.2(m2H),6.6-6.7(d,1H), 5.1(d,1H), 4.7(t,1H),4.0-4.3(m,3H),3.55-3.7(m,2H); ¹³CNMR (DMSO-D₆₎: 155.03,141.9, 138.89,126.49, 124.5, 122.5,121.77,118.54,111.58,110.33,103.77,100.36,70.2,69.29,62.9; IR (KBr) (cm^-1) :3389, 2939, 1888, 1626, 1506, 1264, 1100, 1060, 752; MS (ESI): m/z 256 [M-H]⁺

Synthesisof3-(9H-carbazol-4-yloxy)-2-hydroxypropyl4-methylbenzenesulfonate (7):

Under dry nitrogen atmosphere Compound (6) (1gm, 3.8mmol) in a dry 100ml round bottom flask dissolved in dichloromethane(30ml), Triethylamine (0.84gm, 7.7mmol) was added at room temperature and resulting solution was stirred at room temperature 10 minutes. P-toulensulfonylchloride (0.723gm, 3.8mmol) was add to resulting mixture by portion wise and stirred at room temperature for 6 hours under nitrogen, monitored by TLC. The reaction mixture was quenched with water and extracted with dichloromethane (3×70ml) and combined the organic extracts were washed with water (2X50ml) followed by brine 50ml. The organic layer was dried over anhydrous sodium sulphate and solvent was distilled off under vacuum to yield crude material, which was purified by 230-400 silica gel column chromatography using 3:7 ethylacetate: n-Hexane as eluent. The compound obtained(1.2gm,76%) was characterized by its spectral and analytical data as 3-(9H-carbazol-4-yloxy)-2-hydroxypropyl-4-methylbenzenesulfonate (7).¹HNMR (CDCl₃, 400MHz): δ8.1(brs,1H), 7.98-7.97(d,1H), 7.73-7.75(d,2H), 7.0-7.43(m,7H), 6.67-6.69(d,1H), 4.15-4.5 (m,5H), 2.3(s,3H); MS (ESI) : m/z 412[M+H]⁺

Synthesis of 1-(2-chloroethoxy)-2-methoxybenzene (9):

In a 100ml round bottom flask sodium carbonate (25gm, 240mmol) was added to solution of 2-methoxy phenol (8) (10gm, 80mmol) in acetone(75ml). The reaction mixture was stirred at room temperature for 20 minutes and 1,2-dichloroethane (31gm, 320mmol) was added to above resulting mixture and the continent was heated to 60^OC and maintained the same temperature for 8hrs monitored by TLC. Distilled off the solvent under reduced pressure, the residue obtained was diluted with water and extracted with ethylacetate (3×150ml). The combined organic extracts were washed with water (2×50ml), dried over anhydrous sodiumsulphate. Distill off the solvent under reduced pressure yield oliy mass, which was characterized as compound (9) by its spectral and analytical data. ¹HNMR(400MHz,CDCl₃): δ7.49 -7.52(d,1H),7.4(s,1H),6.9-7.0(m, 2H), 4.37-4.41 (t,2H),3.96(s,3H),3.98-4.1(t,2H); ¹³CNMR (75MHz,CDCl₃): δ29, 56,69, 111, 112, 127, 130, 148, 155,191;IR(KBr)(cm^-1): 3075, 3040, 2977, 2925, 1679, 1596, 1583, 1510, 1436, 1392, 1263, 1132, 798, 737; MS(ESI): m/z187[M+H]⁺

Synthesis of 2-(2-(2-methoxyphenoxy)ethyl) isoindoline-1,3-dione (10):

In a 50ml round bottom flask compound (9) (5gm, 26.88mmol) was added to the mixture of potassium pthalamide (7.5gm, 40.3mmol) and dimethylformamide (25ml) at 25 ^OC. To this sodium iodide (catalytic) was added and heated to 65 ^OC monitored by TLC. The reaction mixture was cooled to room temperature and was quenched with water and then extracted with dichloromethane (3×100ml). The combined the organic extracts were washed with water (2X50ml) followed by brine (50ml). The organic layer was dried over anhydrous sodium sulphate. Distilled off the organic layer to obtain crude product, which was purified by 230-400 silica gel column chromatography using 4:6 ethylacetate:hexane as eluent. The compound obtained (7.5gm,95%) was characterized by its spectral and analytical data as 2-(2-(2-methoxyphenoxy) ethyl)isoindoline-1,3-dione (10). mp:136-137^OC;¹HNMR (400 MHz,DMSO-D₆): δ7.81-7.87 (m,4H), 6.68-6.71 (m, 4H), 6.40-6.41 (s, 1H), 6.25–6.28 (m, 1H), 4.11–4.15 (m, 2H), 3.92–3.96 (m, 2H), 3.4 (s, 3H); ¹³CNMR(75 MHz,DMSO-D₆):38,57,66, 115, 123,132,135, 143,149,152, 168; IR (KBr) (cm^-1): 2950, 1768, 1653, 1621, 1515, 1465, 1448, 1435, 1422, 1400, 1397, 1191, 1173, 1020, 983, 828 cm^-; MS: m/z 298 [M+H]⁺.

Synthesis of 2-(2-methoxyphenoxy) ethanamine (11):

In a 50ml round bottom flask compound (10) (3g, 10.01mmol) was reacted with 20%w/w monomethylamine (12ml in methanol) at 30 ^OC. The reaction mixture was stirred at 30 ^OC for 1hr, and concentrated completely at 45^OC under reduced pressure. The resulting residue was purified by using distillation resulting colour less liquid which was characterized by its spectral data as (11) as was obtained.

¹HNMR (CDCl₃,400MHz):δ 6.85-7.0 (m,4H),3.8-3.9(t,2H), 3.7(s,3H), 3.09-3.11 (m,2H); IR(KBr)(cm^-1): 3368, 2925, 1458, 1253, 740; MS (ESI): m/z 168.1 [M+H]⁺

Synthesis of Carvedilol:

In a 25ml round bottom flask compound (7) (1gm, 2.43mmol) was dissolved in dimethylfomamide (10ml) and potassium carbonate (0.670gm 4.86mmol) was added to the resulting reaction mixture with stirring. Stirred the reaction mass at 30 ^OC for 20 minutes and compound (11) (1.3gm 7.29mmol) was added. The resulting mixture was heated at 110^OC for 4hrs,monitored by TLC. The reaction mass was quenched with water and extracted with ethylacetate (3×100ml). The combined organic extracts were washed with water (2X100ml) and dried over anhydrous sodiumsulphate to obtain residue, which was purified by column chromatography using 2:8 methnol:dicholormethane as eluent. The compound obtained (0.85gm 86%) was characterized as Carvedilol by its spectral and analytical data. mp: 130-131^OC;¹HNMR (CDCl₃,400 MHz):δ 8.1(brs,1H), 8.2-8.22(d,1H), 7.2-7.42(m,4H), 7.1(d,1H), 6.8-7.0 (m,4H),6.6-6.65(d,1H), 4.2-4.4 (m,3H), 4.1-4.2(d,2H), 3.8(s,3H), 3.2-3.6 (brs, 1H), 2.95-3.2(m,4H);¹³C NMR (CDCl₃, 400 MHz) : δ155.00, 149.50, 148.12, 140.93, 138.71, 126.58, 124.87, 122.85, 122.38, 121.48, 120.89.119.5, 113.83, 112.54, 111.76, 110.0, 103.7, 101.06, 70.22, 68.58, 55.66, 51.9, 48.6;IR (KBr) (cm^-1): 3345,2923, 1630, 1607, 1503, 1454, 1445, 1334, 1253, 1100,1022, 747;MS (ESI): m/z 407 [M+H]⁺

ACKNOWLEDGEMENTS:

M. Yedukondalu thanks to JNTU Anatapur and Sridhar R. thanks to KL University.

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Received on 02.01.2013 Modified on 14.01.2013

Asian J. Research Chem. 6(3): March 2013; Page 195-199