The present communication reports the preparation of carvedilol an adrenergic antagonist drug by a novel design of synthesis which has improved the yield. An optimized synthesis by screening different solvents and bases was proposed using R software. Finally better conditions for preparation of carvedilol in high yields were established.
Keywords: 4-hydroxy carbazole, epichlorohydrin, 4-(2, 3-epoxyprpoxy) carbazole, 2-(2-methoxyphenoxy) ethanamine, R software
Carvedilol (Figure I) is an adrenergic antagonist with both non-selective ?1, ?2 and ?1 receptor blocking agent and also a vasodilatation drug with antioxidant activity.
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. It appears to offer particular advantages in the treatment of co morbid conditions, including coronary artery disease, stroke hypertension, renal failure, diabetes and arterial fibrillation that can independently contribute to the progression of heart failure.
Carvedilol, also known as 1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-2- propanol.
It has a chiral center and can exist either as individual sterioisomersor in racemic form. There are many synthetic methods known in the literature for the synthesis of Carvedilol. Among them Innovator route for the preparation of Carvedilol is described.
.F. Wiedemann et al., reported the synthetic route41 to prepare Carvedilol by treating the compound, 4-hydroxy carbazole (2) with epichlorohydrin (3) in presence of sodium hydroxide gave 4-(2, 3-epoxyprpoxy) carbazole (4), which on treated with 2-(2-methoxyphenoxy)ethanamine (5) in neat reaction conditions afforded the desired compound Carvedilol (1).
The Figure 2 shows the preparation of carvedilol.
In the present work, synthesis of carvedilol was optimized by screening various bases, different solvents and established better conditions to improve yields by proper design of the experiments. General procedure for preparation of carvedilol involves 2 steps.
Base sodium hydroxide was added over to 4-hydroxy carbazole in DMSO solvent at cool temperature 10-15°c. Then added epichlorohydrin, stirred for 5-6 hours at ambient temperature. The reaction monitored by Thin layer chromatography. It was then quenched with cold water and filtered the precipitated solid.
Initially the synthesis was carried by taking DMSO as solvent and screened with different bases such as sodium carbonate, sodium bicarbonate, potassium hydroxide and potassium carbonate shown in Figure 3.
After the screening process, the synthesis was carried out by taking Potassium carbonate as a base and screened with different solvents such as N,N-dimethyl formamide, toluene, n-hexane and neat condition shown in Figure 4.
Optimised synthesis of 4-(2, 3-epoxyprpoxy) carbazole (Neat reaction) : To a stirred solution of potassium carbonate (6.0 g, 0.0436 mol) in 5 mL water, 4-hydroxy carbazole (2) (2 g, 0.0109 mol) was added over a period of 10-15 min. The reaction mass was cooled to 10-15°C. After stirring for 15 min, epichlorohydrin (2 g, 0.0218 mol) was added over 1 hr duration by maintaining the temp at 10-15°C. The reaction mass temperature was slowly raised to 50 -55°c and the suspension was maintained for 4 to 6 hrs under stirring at 50-55°c temperature. Reaction was monitored by TLC, checked absence of starting material, then the product was diluted with 10 mL water, filtered and washed with water. The obtained crude product was recrystallized in acetone resulted as an off-white crystalline powder with 60.5% yield.
Spectral data analysis of 4-(2, 3-epoxyprpoxy) carbazole: 1H-NMR (400 MHz, DMSO): ? 11.2 (s, 1H, -NH), 8.1 (d, 1H Ar), 7.6 (m, 1H , Ar), 7.4 (m, 2H, Ar), 7.2 (m, 2H, ArH), 6.7 (d, 1H , Ar), 4.2 (m, 2H, -CH2-), 4.1 (m, 1H, -CH-), 2.9 (d, 2H, -CH2- epoxy); MS: m/z (M++1) 240 ; Anal. Calcd for C15H13NO2: C 75.30, H 5.48, N 5.85%; Found: C 75.32, H 5.50, N 5.87%.
For the optimization of the synthetic scheme, R software is used as shown below.
Quality by design for step 1: Finally by DOE (Design of experiments) using R soft ware which is completely aligned with Quality by Design principles, better reaction conditions were established to improve yields.
In stage 1, the following parameters are selected [based on optimized process] for conducting design of experiments to establish the acceptable ranges
Experiment design is prepared by considering ±10% to standard ranges.
After optimization, 4-(2, 3-epoxyprpoxy) carbazole was prepared from 4-hydroxy carbazole with 2.0 mole equivalents epichlorohydrin and 4.0 mole equivalents potassium carbonate as a base in neat condition without using solvent. As per DOE, 16 experiments were conducted with different mole equivalents of epichlorohydrin, different mole equivalents of potassium carbonate and changing addition time of epichlohydrin. The above table 2 discloses the yield of total 16 experiments. Here the 10th experiment with epichlorohydrin 1.8 mole equivalents(less quantity compared to 8th experiment), potassium carbonate 4.4 mole equivalents and addition time 90 minutes resulted higher yield 78.4%. There is a good improvement in yield from 60.5% to 78.4% was observed. The application of DOE after optimization process, gave better yield of carvedilol step 1 which will show decrease on the cost factor in bulk manufacture.
Above compound epoxy propoxy carbazole (4), which on treatment with 2-(2-methoxyphenoxy) ethanamine (5) in solvent maintained for 3-4 hours at hot condition, monitored by TLC. Finally on pH adjustment, followed by filteration provided the desired compound Carvedilol.
Initially the synthesis was carried out by taking DMSO as solvent and screened with different bases such as sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate and aqueous ammonia as shown in Figure 5
After the screening process, the synthesis Figure 6 was carried out by taking aqueous ammonia as a base and screened with different solvents such as N,N-dimethyl formamide, toluene, n-hexane and neat condition.
Optimized synthesis of 1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-2- propanol:
To 4-(2, 3-epoxyprpoxy) carbazole(3) (1.0g,0.0041 mol) in N,N Di Methyl Formamide added 6.0 mL aqueous ammonia and then added 2-(2-methoxyphenoxy)ethanamine (4) (2.1g, 0.0125 mol) to the mixture. This was heated to 85°c for 5-6 hrs. Then cooled the reaction mass to 25-30°c, slowly extracted into DCM at neutral pH and distillation done. The gummy residue was dissolved in 4.0 ml acetone and filtered through hyflo bed and distilled off the organic layer under reduced pressure. The obtained crude material was purified by column chromatography by eluting with 25-30% ethyl acetate in toluene to get required compound as off white solid with 68.4% yield.
Spectral data analysis of 1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-2- propanol:
IR (Kbr): 3344 cm-1 (-OH); 1H NMR (CDCl3; 400 MHz ): ? 8.5 (m, 2H, -Carbazole), 7.4 (m, 4H, -Aromatic), 7.1 (m, 5H, -Carbazole), 6.4 (d, 1H, J=6.8 -carbazole), 4.1 (m, 5H, -CH2-CH-CH2), 3.85 (s, 3H, -OCH3), 2.92 (m, 2H, -CH2), 2.9 (m, 2H, -CH2), 2.1 (bs, -NH); 13C NMR (100 MHz, DMSO) (Fig.2.6): ? 48.48, 52.13, 54.95, 68.17, 68.69, 70.21, 100.13,103.63, 109.71, 111.93, 112.21, 114.25, 118.42, 120.76, 121.49, 122.17, 124.26, 126.04, 139.29, 141.53, 148.15, 149.71, 155.11; MS: m/z (M+1) 407.
Quality by design for step 2: Finally by DOE (Design of experiments) using R soft ware which is
Completely aligned with Quality by Design principles, better reaction conditions were established to improve yields. In stage 2, the following parameters are selected [based on optimized process] for conducting design of experiments to establish the acceptable ranges Quantity of ksm 2
Quantity of aqueous ammonia
Experiment design is prepared by considering ±10% to standard ranges.
After optimization, carvedilol was prepared from 4-(2, 3-epoxyprpoxy) carbazole, 3.0 mole equivalents 2-(2-methoxyphenoxy)ethanamine with 6 volumes aqueous ammonia as a base in N,N Di Methyl Formamide as a solvent media at temperature 85°c. As per DOE, 11 experiments were conducted with different mole equivalents of 2-(2-methoxyphenoxy)ethanamine, different volumes of aqueous ammonia and at different reaction temperatures. The above table 4 discloses the yield of total 11 experiments. Here the 5th experiment with 3.3 mole equivalents of 2-(2-methoxyphenoxy)ethanamine, 4.0 volumes of aqueous ammonia, at temperature 100°c resulted higher yield 80.5% .
There is a good improvement in yield from 68.4% to 80.5%. The application of DOE after optimization process, gave better yield which will show decrease on cost factor in bulk manufacture.
The carvedilol is of great interest due to its pharmacological properties. In the present communication a simple and convenient synthetic method which gives good yield of target molecule is reported. The main purpose of the present work is to optimize the best conditions for the synthesis of this molecule It also ensures the use of Quality design in establishing better conditions for synthesis after optimization. This is simple and convenient synthetic method which gives good yield of target molecules.
The authors are thankful to GITAM (Deemed to be University), Visakhapatnam for providing necessary facilities to carry out this research work and for kind encouragement. Dept of Chemistry, GIS, GITAM is grateful to DST for the DST-FIST programme.
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