|SYSTEMATIC (IUPAC) NAME|
(Z)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e] oxepin-2- acetic acid
|TRADE NAMES||Patanol and others|
|Ophthalmic, intranasal, oral|
- Olopatadine and pharmaceutically acceptable salts thereof are described in patents EP 214779 , US 4871865 , EP 235796 andUS 5116863 . Patent EP 214779 describes two general processes for the production of Olopatadine, one of them involving a Wittig reaction and the other a Grignard reaction followed by a dehydration step.
- Patent US 5116863 describes the production of Olopatadine hydrochloride by several different processes, two of which include a Grignard reaction for introducing the side chain in position 11 and a third process (called “Process C” in said patent) in which said side chain is introduced in position 11 by means of a Wittig reaction. In a specific embodiment (Example 9), the Wittig reaction is performed on the 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid (3) substrate, also known as Isoxepac, which is reacted with (3-dimethylaminopropyl)-triphenylphosphonium bromide hydrobromide, in the presence of n-butyl lithium giving rise to a Z/E mixture of Olopatadine together with salts of phosphorus which, after purifying by means of transforming it into the methyl ester of Olopatadine (2) and subsequent hydrolysis, provides Olopatadine hydrochloride (1), as shown in reaction scheme 1.
- In the process shown in reaction scheme 1, the Wittig reagent [(Ph)3P+(CH2)3N(Me)2Br–HBr] is used in excess of up to 5 equivalents per equivalent of Isoxepac (3), a dangerous reagent (n-butyl lithium) is used; the process is very long and includes a number of extractions, changes of pH, in addition to esterification and subsequent saponification, the process therefore having very low yields and being rather expensive. The Z/E isomer ratio obtained in said process is not described.
- Ohshima E., et al., in J. Med. Chem., 1992, 35:2074-2084(designated inventors in US 5116863 ) describe several methods for synthesizing Olopatadine hydrochloride and other compounds of similar structure by means of Grignard reactions in some cases, and by means of Wittig reactions in other cases, for introducing the side chain (3-dimethylaminopropylidene). Following the synthetic scheme shown in reaction scheme 1, they start from type (3) compounds with free carboxylic acid and use (i) as base, n-butyl lithium, in a ratio relative to the type (3) compound of 7.5 equivalents of base/equivalent of type (3) compound and (ii) as Wittig reagent, (3-dimethylaminopropyl)-triphenylphosphonium bromide hydrobromide, in a ratio relative to the type (3) compound of 4.9 equivalents of the Wittig reagent/equivalent of type (3) compound. Once the Wittig reaction is carried out, in order to be able to better isolate the products, the acid is subsequently esterified; thus, and after purification by means of column chromatography, the obtained Z/E isomer ratio is 2:1. In said article, the authors (page 2077) acknowledge that when they try to perform this same Wittig reaction starting from a type (3) compound having an ester group instead of a carboxylic acid, the reaction does not occur and the starting material is recovered without reacting. This process has several drawbacks since it needs large amounts both of the Wittig reagent and of the base, n-butyl lithium (dangerous reagent, as already mentioned), it needs esterification, column purification, saponification and purification again, whereby the global process is not efficient.
- Application WO 2006/010459 describes obtaining Olopatadine hydrochloride by means of a process in which a Wittig reaction is also performed but, this time, on an open substrate with final cyclization to form oxepin by means of Pd catalyst as can be seen in reaction scheme 2.
- The process shown in reaction scheme 2 has several drawbacks: high number of synthesis steps, the use of palladium catalysts which increase the cost of the process, the obtained Z/E isomer ratio is only 2.5:1 in favor of the Z isomer, and, finally, the need of using ionic exchange resins and chromatography columns, together with the use of dangerous reagents such as lithium aluminium hydride, n-butyl lithium or Jones reagent, make the process unfeasible on an industrial scale.
- Application US2007/0232814 describes obtaining Olopatadine hydrochloride by means of a process which includes a Wittig reaction between Isoxepac (3) and the corresponding Wittig reagent [(3-dimethylaminopropyl)-triphenylphosphonium halides or salts thereof], using as base sodium hydride (NaH), whereby obtaining Olopatadine base which, after subsequent formation of an addition salt (essential for the production and isolation of the product of interest) and purification, yields Olopatadine hydrochloride (1), as shown in reaction scheme 3.
- In the process shown in scheme 3, the amounts of Wittig reagent and of base used are very high since when the Wittig reagent is used in the form of salt 2.7 equivalents and 8.1 equivalents of base (NaH) are used, whereas if the free Wittig reagent is used 2.7 equivalents and 4.0 equivalents of base (NaH) are used. In these conditions, the reaction is very long (it can last more than one day) and the obtained Z/E isomer ratio is only 2.3:1, which results in a relatively low final yield and makes subsequent purification necessary. This process is, in addition, slow and tedious, therefore it is not very attractive from the industrial point of view.
- 21.49 g (0.050 moles) of (3-dimethylaminopropyl)-triphenylphosphine bromide were suspended in 80 ml of tetrahydrofuran (THF) in a reaction flask under a N2 stream. 1.86 g (0.046 moles) of 60% NaH were carefully added, maintaining the obtained suspension at 20-25°C. Then, 10 ml of dimethylacetamide were slowly added to the previous suspension. The resulting mixture was heated at 35-40°C for 1 hour. At the end of this time period, 10 g (0.031 moles) of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-ethyl acetate dissolved in 30 ml of THF were added dropwise to the previous solution. The reaction mixture obtained was maintained at 35-40°C for 2 hours. After this time period, the reaction mixture was left to cool to a temperature lower than 10°C, then adding 150 ml of water on the reaction mixture. The solvent was eliminated by means of distillation under reduced pressure until obtaining an aqueous residue on which 100 ml of toluene were added. Subsequently, the organic and aqueous phases were decanted and separated. The organic phase was washed with concentrated HCl (2×50 ml). Then, the organic and aqueous phases were decanted and separated. The obtained aqueous phases were pooled and 100 ml of toluene and 2×10 ml of a solution of 20% Na2CO3 were added to them. The organic and aqueous phases were decanted and separated and the organic phase was concentrated under reduced pressure until obtaining a residue which was used without purifying in Part B.
- The obtained product can be identified, after being purified by means of silica gel column chromatography. The compound of the title is eluted with a dichloromethane/methanol/ammonia (95/5/1) mixture, the spectroscopic properties of which compound are:
- 1H-NMR (CDCl3, 400 MHz), δ: 1.24 (t, 3H), 2.80 (s, 6H), 2.89 (m, 2H), 3.20 (m, 2H), 3.51 (s, 2H), 4.11 (m, 2H), 5.15 (bs, 2H), 5.63 (t, 1H), 6.82 (d, 1H), 7.04 (m, 2H), 7.25 (m, 4H) ppm.
- 13C-NMR (CDCl3, 400 MHz), δ: 14.41; 25.03; 40.12; 43.14; 57.33; 61.16; 70.93; 120.34; 123.95: 125.44; 126.34; 126.63; 127.72; 128.27; 129.33; 130.85; 131.64; 133.66; 143.74; 144.12; 154.96; 163.34; 172.27 ppm.
- MS, M++1: 366.06.
- The compound (Z)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid ethyl ester (residue obtained in Part A) was dissolved in 100 ml of acetone in a reaction flask. 3.4 ml (0.040 moles) of HCl were added to this solution. The reaction was heated under reflux for 10 hours, in which time the reaction passed from being a solution to being a suspension. After this time, the reaction was cooled until reaching 20-25°C. The solid was filtered, washed and the resulting product was dried in an oven with air circulation at 50-55°C, obtaining 5.2 g (0.015 moles, 50%) of a white solid identified as (Z)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e] oxepin-2-acetic acid, isolated as hydrochloride, the spectroscopic properties of which are the following:
- 1H-NMR (DMSO, 400MHz), δ: 2.69 (s, 6H); 2.77 (m, 2H); 3.24 (m, 2H): 3.56 (s, 2H); 5.15 (bs, 2H); 5.62 (t, 1H); 6.76 (d, 1H); 7.06 (m, 2H); 7.30 (m, 4H) ppm.
- 13C-NMR (DMSO, 400MHz), δ: 25.12; 40.13; 42.44(2); 56.02; 70.26; 119.95; 123.43; 126.62; 127.64; 128.03; 128.47(2); 129.85; 131.34; 132.57; 134.12; 141.63; 145.25; 154.52; 173.67 ppm.
- MS, M’+1: 338.17
- Drugs.com, Alcon’s Patanase Nasal Spray Approved by FDA for Treatment of Nasal Allergy Symptoms
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