Article pubs.acs.org/OPRD
Improved Process for Preparation of Gemfibrozil, an Antihypolipidemic Suri Babu Madasu,†,‡ N. A. Vekariya,*,† Hero Velladurai,† Aminul Islam,† Paul Douglas Sanasi,‡ and Raghu Babu Korupolu‡ †
Chemical Research and Development, Aurobindo Pharma Ltd., Survey No. 71 and 72, Indrakaran (V), Sangareddy (M), Medak District-502329, Andhra Pradesh, India ‡ Engineering Chemistry Department, AU College of Engineering, Andhra University, Visakhapatnam-530003, Andhra Pradesh, India ABSTRACT: An improved process for the preparation of gemfibrozil, an antihypolipodimic drug substance, with an overall yield of 80% and ∼99.9% purity (including three chemical reactions) is reported. Formation and control of possible impurities are also described. Finally, gemfibrozil is isolated from water without any additional solvent purification.
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INTRODUCTION Gemfibrozil is classified as a fibric acid derivative and is used in the treatment of hyperlipidaemias. It has effects on plasma-lipid concentrations similar to those described under bezafibrate. The major effects of gemfibrozil have been a reduction in plasma-triglyceride concentrations and an increase in highdensity lipoprotein (HDL) cholesterol concentrations. A reduction in very-low-density lipoprotein (VLDL)-triglyceride appears to be largely responsible for the fall in plasma triglyceride although reductions in HDL and low-density lipoprotein (LDL)-triglycerides have also been reported.1,2 The effects of gemfibrozil on total cholesterol have been more variable: in general, LDL-cholesterol may be decreased in patients with pre-existing high concentrations and raised in those with low concentrations.3 The increase in HDLcholesterol concentrations has resulted in complementary changes to the ratios of HDL-cholesterol to LDL-cholesterol and to total cholesterol.4,5 Gemfibrozil has successfully raised HDL-cholesterol concentrations in patients with isolated low levels of HDL-cholesterol but otherwise normal cholesterol concentrations.6 The Helsinki heart study7 assessed gemfibrozil for the primary prevention of ischaemic heart disease in middleaged men with hyperlipidaemia. The usual dose, by mouth, is 1.2 g daily in two divided doses given 30 min before the morning and evening meals. Gemfibrozil is available as tablets for oral administration (Lopid: USP). Reports are available in the literature related to the various synthetic routes for the preparation of gemfibrozil. These processes8 have restricted application in the industry because of less overall yield, number of purifications, and the stringent regulatory requirement to meet the quality of a finished drug substance. Moreover, the maximum daily dose of gemfibrozil is 1.2 g in divided doses. As per ICH guidelines, the acceptable level for known and unknown related impurities in the drug substance should be not more than 0.15% and 0.08%, respectively,9 based on maximum daily dose. To minimize the cost constraints and number of purifications, we avoided tedious work-up processes. In view of the high-volume requirement, huge revenues associated with this molecule, and disadvantages from the reported processes, there arises a © 2013 American Chemical Society
need to develop an alternative process for gemfibrozil, meeting with all regulatory aspects.
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RESULTS AND DISCUSSION Our improved process also starts with the O-alkylation using commercially available materials 2,5-dimethylphenol (2) and isobutyl 5-chloro-2,2-dimethylpentanoate (4b). In the literature O-alkylation of 2,5-dimethylphenol (2) with the methyl or isobutyl ester of 5-chloro-2,2-dimethylpentanoic acid (chloro alkyl ester side chain, 4) was reported10 by using o-xylene or toluene with polar solvent DMSO in the presence of the catalyst sodium iodide (Scheme 1). The addition rate of the Scheme 1. Reported Synthetic Route for Gemfibrozila
4a: R = −CH3; 4b: R = −CH2CH(CH3)2; 5a: R = −CH3; 5b: R = −CH2CH(CH3)2.
a
chloro alkyl ester side chain was very critical. It should be completed in a specified time. If the addition rate is faster, more unreacted 2 will be left due to the conversion of the chloro alkyl ester side chain into the acid derivative. If the addition rate is slow, formation of unknown impurities will be greater due to the higher temperature of the reaction. Moreover, iodo gemfibrozil impurity 7 (Figure 1) is forming in this route of synthesis in 0.25−0.50%, due to use of sodium iodide, and it is Received: February 11, 2013 Published: June 18, 2013 963
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aqueous toluene at reflux temperature, but the reaction was not completed. It was identified that the effect of water dilution plays an important role in the ester hydrolysis reaction with base. After doing a number of experiments, the ester hydrolysis reaction was optimized in toluene and highly concentrated aqueous sodium hydroxide solution at reflux temperature (Table 4). Moreover, the quantity of base can have a significant impact on the quality of the hydrolysis product. In this regard, we explored the mole ratio of sodium hydroxide required to accomplish the complete deprotection. The results obtained from this study showed the required mole ratio of sodium hydroxide. It was found that 4.7 mol of sodium hydroxide was optimum to bring about an efficient deprotection of the ester group (entry 5, Table 3). After completion of ester hydrolysis, workup was very simplified, as separation of the aqueous sodium hydroxide layer from the bottom, followed by addition of water and layers separation. The aqueous layer contained gemfibrozil sodium salt 6, which was further washed with toluene to remove nonpolar impurities which were carried from the condensation reaction, viz. gemfibrozil dimer 9 and gemfibrozil side chain dimer 10 (Figure 2; isolated by column chromatography and characterised). Thereafter, toluene was removed completely. Many processes were reported11,12 for isolation of gemfibrozil from gemfibrozil sodium in solvents such as methanol, hexanes, etc. We have significantly simplified isolation of gemfibrozil from water for obtaining a more cost-effective process without having any significant changes in the solid state parameters of the gemfibrozil drug substance. Gemfibrozil was isolated from the aqueous layer by addition of aqueous hydrochloric acid at pH 2.8−3.2 at room temperature and had a purity of ∼100% and high yields. Finally, the redesigned process furnished gemfibrozil (1) with an overall yield of 80% from the chloro isobutyl ester side chain after three synthetic reactions with about 99.9% purity and meeting all other quality parameters (Table 4).
Figure 1. Structure of iodo gemfibrozil 7.
difficult to remove this impurity even after crystallisation in methanol−water followed by hexanes. To overcome this, experiments were carried out in a biphasic system by using tetrabutylammonium bromide (TBAB) as the phase transfer catalyst. On the basis of experimental results (Table 1) it was found that higher temperature in closed autoclave conditions are required for O-alkylation. Experiments for O-alkylation of 2 were performed with a chloro methyl ester side chain (4a) as well as a chloro isobutyl ester side chain (4b) in aqueous sodium hydroxide using TBAB as phase transfer catalyst. Reaction with 4b is completed in 5 h, whereas, in the reaction with 4a, the amount of starting material 2 left unreacted was 45% (Table 2). It was observed that 4a itself became hydrolysed in aqueous basic medium, gave compound 8 (Scheme 3), and conformed by mass analysis (MS m/z: 165.31, 187.25 corresponding to M + 1 and M + 22 with chloro pattern). If excess sodium hydroxide is added to complete the O-alkylation reaction, gemfibrozil methyl ester (5b) is hydrolyzed into gemfibrozil and it is very difficult to isolate the gemfibrozil along with the gemfibrozil methyl ester during work. It was also found that hydrolysis of the gemfibrozil methyl ester required only 1.2 mol (less base) of sodium hydroxide but hydrolysis of the gemfibrozil isobutyl ester required 4.7 mol more (more base) of sodium hydroxide. It was concluded from above that half a portion of the chloro methyl ester side chain is becoming hydrolysed itself in aqueous basic medium at higher temperatures (under pressurised conditions) during the Oalkylation reaction in the presence of base. This is the reason for incomplete O-alkylation of 4a with 2, whereas O-alkylation of 4b with 2 gave fruitful results (Scheme 2). After optimizing O-alkylation of 2 with the chloro isobutyl ester side chain (4b), gemfibrozil isobutyl ester extracted with toluene and unreacted 2,5-dimethyl phenol (2) was recovered by washing with aqueous sodium hydroxide solution. Thereafter, the toluene layer was washed with 2% aqueous sodium metabisulphite solution followed by water. The toluene layer was as such taken for deprotection of the isobutyl group. After preparation of highly pure gemfibrozil isobutyl ester, our next target was deprotection of the isobutyl ester group. We used sodium hydroxide as a base for the deprotection of the ester group due to lower cost. Initially, the hydrolysis reaction was carried out in water at reflux with 2.5 mol of sodium hydroxide, but the reaction was not completed even after 10 h. Another trial for the hydrolysis reaction was done by using
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CONCLUSION An improved process has been developed for synthesis of gemfibrozil with an overall yield of 80% and ∼99.9% purity. The process described in this article has certain advantages over the reported processes, with the primary one being the work-up procedure during isolation of gemfibrozil. It is isolated from water without any additional solvent purifications.
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EXPERIMENTAL SECTION H NMR, 13C NMR, and DEPT spectral data were performed in dimethyl sulfoxide (DMSO-d6) with 500 and 300 MHz spectrometers. The chemical shift values were reported on the δ scale in parts per million (ppm), downfield from tetramethylsilane (TMS, δ = 0.0) as an internal standard. Spin multiplicities are given as s (singlet), d (doublet), dd 1
Table 1. O-Alkylation of 4b with 2 in Presence of TBAB
a
entry
solvents
NaOH (m/r)
TBAB (catalyst, % w/w)
temp (°C)
time (h)
purity by HPLC (%)a
yield (%)b
1 2 3 4 5
o-xylene o-xylene toluene water water
1.03 1.03 1.03 1.05 1.05
7 7 7 7 7
140−145 130−135 110−115 95−100 125−130c
6 6 10 10 5
63 61 72 65 88
57 56 65 60 80
It is conversion of product during reaction monitoring. bIsolated yields of gemfibrozil. cUnder pressure. 964
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Table 2. O-Alkylation of 4a/4b with 2 in Presence of TBAB in Water
a
entry
4
NaOH (m/r)
TBAB (catalyst, % w/w)
temp (°C)c
time (h)
purity by HPLC (%)a
yield (%)b
1 2 3 4
methyl (4a) methyl (4a) isobutyl (4b) isobutyl (4b)
1.05 1.05 1.05 1.05
7 10 7 10
125−130 125−130 125−130 125−130
6 6 5 5
47 45 88 88
45 43 80 80
It is conversion of product during reaction monitoring. bIsolated yields of gemfibrozil. cUnder pressure.
Scheme 2. Synthetic Route for Gemfibrozil with New Process Conditions
temperature. Sodium hydroxide (26.6 g, 0.665 mol) was added to the reaction mass slowly in 15−25 min at 25−40 °C. The resultant mixture was heated to 128−132 °C to complete the reaction in a closed autoclave; ∼2.0 kg/cm2 pressure developed. Thereafter, the reaction mass was allowed to return to room temperature, and the gemfibrozil isobutyl ester (5b) was extracted with toluene (1 × 280 mL; 1 × 140 mL). Unreacted 2,5-dimethylphenol (2) was removed by washing with 10% w/v aqueous sodium hydroxide solution (3 × 140 mL). Thereafter, the organic layer was washed with 2% w/v aqueous sodium metabisulphite solution (140 mL) and finally washed with water (140 mL). This toluene layer was taken as such for deprotection of the isobutyl group. A small sample was taken, and the toluene was evaporated completely under reduced pressure at 60−70 °C to get oily gemfibrozil isobutyl ester (5b), which was analyzed. Purity by HPLC: 99.0%; IR (film, cm−1): 3047.20, 3024.13, 2961.22, 2873.87, 1728.75, 1615.45, 1585.90, 1509.29, 1472.37, 1414.50, 1388.22, 1310.58, 1264.93, 1193.17, 1145.75, 1048.85, 995.50, 946.27, 803.05; 1H NMR (DMSO, 500 MHz, δ ppm): 0.89 (d, 6H), 1.16 (s, 3H), 1.63 and 1.67 (m, 4H), 1.85 (q, 1H), 2.08 (s, 3H), 2.24 (s, 3H), 3.78 (d, 2H), 3.90 (t, 3H), 6.62 (d, 1H), 6.69 (s, 1H), 6.97 (d, 1H); 13 C NMR and DEPT (DMSO, 500 MHz, δ ppm): 15.34
Scheme 3. Self Hydrolysis of Chloro Methyl Ester Side Chain (4a)
(doublet of doublet), t (triplet), and m (multiplet) as well as brs (broad). Coupling constants (J) are given in hertz. IR spectra were recorded in the solid state as KBr dispersions using a Perkin-Elmer spectrum one Fourier transform (FT)-IR spectrophotometer. The mass spectrum was recorded using a Perkin-Elmer PE SCIEX-API 2000, equipped with an ESI source used online with a HPLC system after the ultraviolet (UV) detector. HPLC chromatographic purity was determined by using the area normalization method. The thermal analysis was carried out on a DSC Q 1000 TA. The thermogram was recorded from 40 to 320 °C. The solvents and reagents were used without purification. Isobutyl 5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoate (Gemfibrozil Isobutylester, 5b). Chloro isobutyl ester side chain (4b) (140 g, 0.635 mol) and 2,5dimethylphenol (2) (79.8 g, 0.654 mol) were suspended in water (175 mL) containing TBAB (9.8 g, 7% w/w) at room
Table 3. Optimization of Sodium Hydroxide Mole Ratio (m/r) and Water Dilution for 5b Hydrolysis purity by HPLC (%)a
solvents ratio
a
entry
NaOH (m/r)
water (vol)
toluene (vol)
temp (°C)
time (h)
5b
1
yield (%)b
1 2 3 4 5 6
2.5 2.5 3.0 4.0 4.7 6.0
1.5 1.0 0.25 0.30 0.30 0.30
2.0 3.25 3.0 3.0 3.0
100 100 100−110 100−110 100−110 100−110
7 9 7 7 5 5
95.40 93.76 2.96 0.46 0.07 NDc
0.37 0.55 95.76 97.60 99.84 99.53
75 77 80 80
It is conversion of product during reaction monitoring. bIsolated yields of gemfibrozil. cNot detected. 965
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Figure 2. Structures of nonpolar impurities 9 and 10.
Table 4. Purity Data of 1 RSa by GC (ppm)
purity by HPLC (%) entry 1 2 3 a
1 100 100 100
5b
any other
2 c
ND NDc NDc
c
ND NDc NDc
toluene
c
isobutanol
c
ND NDc NDc
c
ND NDc 105
ND NDc NDc
yield (%)b
DSC (°C)
80.30 80.30 80.30
61.54 61.49 61.81
Residual solvents. bOverall yield. cNot detected.
(CH3), 18.72 (CH3, CH3), 20.90 (CH3), 24.56 (CH2), 24.75 (CH3, CH3), 27.23 (CH), 36.47 (CH2), 41.47 (C), 67.39 (CH2), 69.65 (CH2), 112.00 (CH), 120.43 (CH), 122.40 (C), 129.94 (CH), 135.90 (C), 156.35 (C), 176.56 (C); MS m/z (ESI): 307.23 [(MH)+]. 5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoic Acid (gemfibrozil, 1). To a solution of gemfibrozil isobutylester (5b) in toluene (∼570 mL; entire quantity obtained from an input of 140 g of 4b; 0.635 mol) was added a solution of sodium hydroxide (119.37 g, 2.984 mol) in water (64 mL) at room temperature. The resultant mixture was heated to 100− 112 °C for 7 h. After completion of reaction and cooling to 70−80 °C, the lower sodium hydroxide layer was separated, and the gemfibrozil sodium salt 6 was extracted by addition of water (840 mL) at 70−80 °C. The aqueous solution with washed with toluene (3 × 300 mL) at 70−80 °C, and toluene traces were removed by applying mild vacuum (300−500 mmHg) at 70−80 °C. The reaction mixture was allowed to cool to room temperature and was diluted with water (1000 mL). The solution pH was adjusted to 8.8−9.2 with hydrochloric acid at 25−30 °C (assay 10% w/w, ∼34 mL was consumed). The resultant reaction solution was treated with carbon enoanticroms (4.2 g; 3% w/w) and bed washed with water (140 mL), followed by passage through a 0.2 μm filter. The solution pH was further adjusted to 2.8−3.2 at 25− 30 °C (assay 10% w/w, ∼170 mL was consumed). The resultant reaction mixture was stirred at room temperature for 1 h, and the precipitated solid was filtered, washed with water (2 × 140 mL; 25−30 °C), and dried under vacuum at 50−60 °C to furnish 127.5 g (80.3%) of the title compound 1. Purity by HPLC: 100%; IR (KBr, cm−1): 2959.03, 2919.78, 2877.65, 1709.42, 1613.44, 1586.60, 1511.07, 1473.81, 1414.01, 1387.89, 1317.61, 1286.34, 1271.91, 1214.39, 1159.26, 1048.83, 996.57, 803.75; 1H NMR (DMSO, 500 MHz, δ ppm): 1.12 (s, 6H), 1.60 and 1.67 (m, 4H), 2.08 (s, 3H), 2.24 (s, 3H), 3.90 (t, 2H), 6.62 (d, 1H), 6.70 (s, 1H), 6.97 (d, 1H); 13C NMR and DEPT (DMSO, 500 MHz, δ ppm): 15.39 (CH3), 20.94 (CH3), 24.67 (CH2), 24.87 (CH3, CH3), 36.43 (CH2), 40.91 (C), 67.57 (CH2), 112.07 (CH), 120.45 (CH), 122.44 (C), 129.96 (CH), 135.93 (C), 156.43 (C), 178.56 (C); MS M/Z (ESI): 251.16 [(MH)+].
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors are grateful to colleagues in the Analytical Research Department of APL Research Centre, a division of Aurobindo Pharma Limited, Hyderabad for their valuable contribution to this work. The authors also thank the management for giving permission to publish this work.
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REFERENCES
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AUTHOR INFORMATION
Corresponding Author
*E-mail: navekariya1@rediffmail.com. 966
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