Article pubs.acs.org/OPRD
Commercial Manufacturing of Propofol: Simplifying the Isolation Process and Control on Related Substances Chinmoy Pramanik,*,† Sandeep Kotharkar,† Pradip Patil,† Dinkar Gotrane,† Yogesh More,† Ajit Borhade,† Balaji Chaugule,† Tushar Khaladkar,† K. Neelakandan,† Ashok Chaudhari,† Mukund G. Kulkarni,‡ Narendra K. Tripathy,† and Mukund K. Gurjar† †
API R&D Centre, Emcure Pharmaceuticals Ltd., ITBT Park, Phase-II, MIDC, Hinjewadi, Pune-411057, India Department of Chemistry, University of Pune, Ganeshkhind, Pune-411 007, Maharashtra, India
‡
S Supporting Information *
ABSTRACT: A commercially viable manufacturing process for propofol (1) is described. The process avoids acid−base neutralization events during isolation of intermediate, 2,6-di-isopropylbenzoic acid (3) and crude propofol, and thus simplifies the synthesis on industrial scale to a considerable extent. Syntheses of five impurities/related substances (USP and EP) are also described.
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INTRODUCTION Propofol (1),1a,b chemically known as 2,6-disopropylphenol (Figure 1), is a short-acting, intravenous agent used extensively Figure 2. Alkylation of phenols using propylene in the presence of LA catalysts.
concern in this transformation is formation of several associated impurities, 2,4-diisopropyl and 2,4,6-triisopropyl phenol being the major side products; the corresponding isopropyl ether also forms in reasonable percentage. All these impurities need to be controlled at a limit of NMT 0.05% or less in the final API for it to be pharmaceutically acceptable.9,10 Later on, isopropanol was used as the propylating agent instead of direct propylene gas; in this method propylene is generated in situ using IPA and strong acid (H2SO412a,b or aluminosilicate catalyst12c). Another approach for the synthesis of propofol proceeds through alkylation of para-substituted phenols followed by removal of the para substituent to give propofol. Either 4chlorophenol13 or 4-hydroxy benzoic acid12a,b is used as starting material for this approach, and isopropanol in the presence of sulfuric acid is used for alkylation instead of propylene gas. Although the final purification by high-vacuum distillation to get highly pure propofol remains unchanged, this approach has two major advantages (i) since the para position is blocked (with −Cl or −COOH), para alkylation and thus related impurities such as 2,4-isopropyl and 2,4,6-triisopropyl derivatives are completely avoided; (ii) purification of the intermediate after the alkylation step is possible, and thus, an intermediate with high purity would be used in the second step (either dechlorination by hydrogenation or decarboxylation), and in turn the isolated crude propofol before vacuum distillation will be of much better quality.
Figure 1. Propofol.
in anaesthesia and intensive care medicine to provide dosedependent sedation and hypnosis.1c It is characterized by a rapid onset, a short duration of action, low toxicity, ability to control sedation and ease of administration.2−8 Propofol inhibits the NMDA receptor and modulates calcium influx through slow calcium ion channels.6 It is structurally unrelated to other common anaesthetic agents such as opioids, barbiturates, benzodiazepines, and halogenated liquids, but similar to the active nucleus of antioxidant substances such as alpha-tocopherol (Vitamin E), butylhydroxytoluene, and acetylsalicylic acid (aspirin).4,6,7 Propofol decreases cerebral oxygen consumption, reduces intracranial pressure, has potent anticonvulsant, antioxidant, and anti-inflammatory properties and is also a bronchodilator. Since propofol is administered intravenously as an emulsion, it is very important that the drug product should comply with stringent impurity limits (U.S. Pharmacopeia9 and European Pharmacopeia10). Friedel−Craft’s alkylation of phenol using propylene gas in the presence of Lewis acid (LA) catalysts is the most extensively used method for the synthesis of propofol (Figure 2) and is well documented in a number of publications and patents.11 After completion of the reaction, the final product is usually isolated and purified by high-vacuum distillation. Alkylation of phenol using propylene gas needs high temperature and high pressure; high safety risks are associated with these conditions. Apart from these shortcomings the major © 2013 American Chemical Society
Received: October 21, 2013 Published: December 19, 2013 152
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Figure 3. Synthesis of propofol from 4-hydroxybenzoic acid; earlier process.
Scheme 1
Along with these advantages, this process12b (Figure 3) suffers from some serious disadvantages for commercialization such as acid−alkali neutralization events involved in both steps (concentrated sulphuric acid is neutralized using sodium hydroxide after the alkylation step, and sodium hydroxide is neutralized with hydrochloric acid after the decarboxylation step), and tedious work-up and isolation procedures. The acid− base neutralization process on industrial scale (tonne scale) is accompanied by high exothermicity, associated safety risks, and also the risk of related impurities. The isolation and purification methods described for purification of the intermediate 3 and final product are quite lengthy and arduous for practice on an industrial scale. Various other procedures are also reported to obtain pharmaceutically acceptable propofol from commercial grade propofol,14 but these are also tedious and result in a higher cost of the final API.
crude 3 (3,5-di-isopropyl-4-hydroxybenzoic acid) into an organic solvent without neutralizing the sulfuric acid, it would simplify the work-up and isolation to a great extent. Thus, the reaction mixture after completion of the reaction was poured into ice−water, and various organic solvents were screened for efficient extraction. Toluene was discovered to be the solvent of choice for this purpose. As addition of the reaction mixture into water was exothermic in nature (addition of conc. sulfuric acid into water), to control the exotherm after completion of the reaction the reaction mixture was allowed to cool and was carefully poured (controlled addition) into a precooled mixture of water and toluene over a period of time. After separation of the layers, the organic layer was concentrated, and the residue was precipitated from methanol−water to give the desired intermediate with >95% HPLC purity. At this stage, various solvents were screened to remove small nonpolar impurities, and slurry wash using cyclohexane gave the best result by which the purity of this intermediate was improved to >98% by HPLC. In the earlier process, ethylene glycol was used for effecting the decarboxylation; owing to its higher boiling point (197 °C), we felt that it could interfere during the purification of the crude propofol by high-vacuum distillation and pose additional threat for the residual solvent test (ICH limit for ethylene glycol NMT = 620 ppm); hence, we intended to replace ethylene glycol with a similar solvent with a lower boiling point. Thus, 2-ethoxyethanol (much lower boiling point, 135 °C, ICH limit NMT = 160 ppm) was selected for the decarboxylation; in the presence of sodium hydroxide at 125−130 °C, the decarboxylation reaction proceeded smoothly (see Scheme 1). At this point, we wondered whether the product could be directly extracted from the existing basic medium instead of the usual practice of acidification followed by extraction into organic solvents (which would contain the product as well as the related acid impurities). Thus, we attempted the direct extraction of propofol (crude) with toluene simply after diluting the reaction mixture with water (without acidifying) and to our delight, observed that the product was extracted (almost quantitatively) into toluene. It was really satisfying even
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RESULTS AND DISCUSSION As a part of our ongoing efforts for development of commercially demanding critical generic drugs, we decided to undertake the synthesis of this product. From the literature, it was evident that there was a need for improvement of the manufacturing process, particularly, simplifying the isolation/ purification process for the intermediate as well as the isolation of the crude propofol before subjecting it to vacuum distillation for purification. We decided to use the 4-hydroxybenzoic acid approach12b for its obvious advantages but would try to simplify the isolation/purification of the intermediate 3 as well as the crude propofol. The new process should be practicable on commercial scale and should avoid highly exothermic neutralization processes. Accordingly, the first transformation (isopropylation) was efficiently accomplished starting with 4-hydroxybenzoic acid under similar/mild conditions using IPA/H2O and H2SO4. After the reaction was completed, for isolation and purification of the intermediate 3, major changes in the work-up procedure were thought to be essential to avoid the neutralization of excess sulfuric acid. We contemplated that if we could extract 153
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Figure 4. Propofol related critical impurities.
Scheme 2
Scheme 3
though surprising, to know that propofol did not seem to be forming any PhO-Na salt under the reaction/isolation conditions and could be extracted (as PhOH) into toluene without the need of any neutralization/acidification. It is
pertinent to mention that because of this significant modification in the workup/isolation stage, the isolated crude propofol thus obtained was devoid of almost all the related acid impurities as those were eliminated into the basic aqueous layer 154
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tion events involved in an earlier reported process, which simplified the isolation of intermediate 3 as well as crude propofol (1). Recently, we completed the validation of this process on multikilogram scale in our plant. In the coming months, we are also planning to further scale up the process as the market requirement of final API is expected to be huge.
and did not get extracted into the toluene layer. The crude propofol thus obtained can then be easily purified by highvacuum distillation (0.05 mm) wherein pure propofol distills out at 80−85 °C with HPLC purity >99.8% (Scheme 1). Impurity profiling (i.e., identification as well as quantification of impurities) of an active pharmaceutical ingredient is of fundamental significance for medical safety reasons and also for the drug effectiveness and is now receiving vital attention from regulatory authorities.15 A literature survey on propofol revealed that a number of process-related and degradation impurities have been reported in USP9 and EP;10 some of the critical ones are shown in Figure 4. Impurity standards (4, 5, and 6) are commercially available from USP/EP albeit in very small packs; thus, a number of packs are required for completing the analytical method development/validation and becomes hugely expensive. Alternatively, either all these can be isolated by preparative HPLC from the residue after vacuum distillation or can be easily prepared from propofol by straightforward transformations. We could prepare enough quantities of impurities 4, 5, and 6 starting from propofol using transformations depicted in Scheme 2. Thus, 4 was obtained on treatment of 1 with iron(III) chloride followed by reduction with sodium borohydride. Alkylation of phenolic hydroxyl using 2bromopropane and NaOH as base afforded compound 5, whereas treatment of 1 with CAN furnished quinone 6. Impurities 7 and 8 are part of the EP specification but are not commercially available, and these two impurities were not at all observed (by HPLC) either in crude propofol or in the residue after distillation. Since the availability of these impurities was a must to complete the analytical method validation, we intended to synthesize these two impurities in-house. While, several approaches can be devised for the synthesis of these impurities, we adopted common strategy which allowed us to get enough quantities of both of these impurities in quick time. We envisaged that compound 7 could be synthesized by treatment of boronate ester (11) with H2O216 (would result in dihydroxy compound 13) followed by isopropylidene protection, whereas C−C bond formation between 11 and 1-bromo-1-propene using Pd(0) (under Suzuki conditions)17 followed by hydrogenation of the double bond would provide us impurity 8. Thus, 2-isopropyl phenol (9) became our obvious starting material which was converted to MOM protected derivative 10. Treatment of 10 with n-BuLi followed by triethyl borate afforded the boronate 11. Subsequent in situ oxidative cleavage of boronate 11 with H2O2 afforded the desired hydroxyl derivative 12 which was easily manipulated to impurity-7 (MOM deprotection to give 13 followed by isopropylidene protection). Moreover, coupling of the same in situ boronate 11 with 1bromo-1-propene in presence of Pd(0) followed by MOM deprotection afforded the critical olefin intermediate 14 which was converted to impurity 8 by hydrogenation of the double bond as shown in Scheme 3. Thus, we were able to prepare good quantities of both of these impurities in relatively quick time which enabled our analytical team to complete all the activities.
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EXPERIMENTAL SECTION
All materials were purchased from commercial suppliers. Unless specified otherwise, all reagents and solvents were used as supplied by manufacturers. 1H NMR spectra and 13C NMR spectra were recorded on a Varian 400 MR spectrometer in CDCl3 and DMSO-d6, and mass spectra were determined on an API-2000LCMS mass spectrometer from Applied Biosystems. Elemental analysis was done with a VarioEL III instrument. In 1 H NMR, the unknown signal in the 1.5−1.6 ppm area is due the moisture present in CDCl3/sample. Preparation of 3,5-Diisopropyl-4-hydroxybenzoic Acid (3). Concentrated sulfuric aid (36 L) was added gradually to a flask containing water (2.5 L) cooled to 5 °C. 4Hydroxybenzoic acid (10 kg, 72.4 mol) was added, followed by slow addition of isopropyl alcohol (16.6 L, 217.08 mol) at the same temperature. The reaction mixture was heated to 55−60 °C (preferably 57−58 °C) till completion of reaction as indicated by HPLC. The reaction mixture was cooled to room temperature and carefully poured into a precooled (5 °C) mixture of water (100 L) and toluene (80 L) while maintaining temperature below 20 °C over a period of 1.5 h. The organic layer was separated, washed with brine (20%, 30 L), and concentrated under reduced pressure to provide a residue, which was dissolved in methanol (30 L) and gradually diluted with water (90 L) at 20 °C to precipitate the product, which was then filtered. The wet cake was slurry washed with cyclohexane (40 L) and dried to give the desired intermediate 3,5-diisopropyl-4-hydroxybenzoic acid (3) as white solid (14 kg, 84%). 1H NMR (DMSO-d6, 400 MHz): δ 12.37 (s, 1H), 8.87 (s, 1H), 7.61 (s, 2H), 3.34−3.27 (m, 2H), 1.16 (d, J = 6.8 Hz, 12H); 13C NMR (DMSO-d6, 100 MHz): δ 167.72, 155.29, 134.77, 124.94, 121.88, 26.12, 22.81. ESI-Mass: For C13H18O3, (M+)/z: 222.29, Found: (M − H)/z: 220.8, Melting point 143−145 °C. HPLC purity >98%. Preparation of 2,6-Diisopropylphenol (Propofol, 1). To a mixture of 3,5-diisopropyl-4-hydroxybenzoic acid (3) (10 kg, 45 mol) in 2-ethoxyethanol (30 L) was added sodium hydroxide (4.2 kg, 105.0 mol). The reaction mixture was heated at 125−130 °C until completion of the reaction as monitored by HPLC. The reaction mixture was cooled to room temperature and diluted with water (100 L) followed by toluene (60 L). The organic layer was separated, washed with brine (20%, 30 L), and concentrated under reduced pressure to provide an oily residue which was then distilled (0.05 mm, 80− 85 °C) under reduced pressure to provide propofol as a colorless liquid (6 kg, 74%). 1 H NMR (CDCl3, 400 MHz): δ 7.09 (d, J = 7.6 Hz, 2H), 6.93 (t, J = 7.6 Hz, 1H), 4.80 (s, 1H), 3.24−3.14 (m, 2H), 1.30 (d, J = 6.8 Hz, 12 H); 13C NMR (CDCl3, 100 MHz): δ 149.90, 133.64, 123.38, 120.62, 27.09, 22.70. ESI-Mass: For C12H18O, (M+)/z: 178.28, Found: (M − H)/z: 177.1, Anal. for C12H18O, calcd: C, 80.85; H, 10.18, Found: C, 80.73; H, 10.23. HPLC purity >99.8%.
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CONCLUSION In conclusion, our efforts resulted in a much more convenient and user-friendly process for commercial manufacturing of propofol. During the course of the work we could successfully eliminate a couple of highly exothermic acid−base neutraliza155
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ASSOCIATED CONTENT
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AUTHOR INFORMATION
Article
S Supporting Information *
Spectral data of selected intermediates and final compound. This material is available free of charge via the Internet at http://pubs.acs.org. Corresponding Author
*Fax: +91-20-39821445. E-mail: chinmoy.pramanik@emcure. co.in. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank Mr. Samit Mehta, our management and ARD group of Emcure Pharmaceuticals Ltd. for their willing support and constant encouragements.
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REFERENCES
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