| Title of Invention | METHOD FOR PRODUCING DIBENZOXEPIN COMPOUND |
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| Abstract | Olopatadine which is useful as a mdicanaent can be efficiently and industrially advantageously produced by heating a dibenzoxepin derivative represented by Formula [I]: (wherein Me represents a methyl group; and each of R1, R2 and R3 independently represents an alkyl group having 1 to 4 carbon atoms) or a salt thereof in a solvent in the presence of an acid. |
| Full Text | DESCRIPTION METHOD FOR PRODUCING DIBENZOXEPIN COMPOUND Technical Field The present invention relates to a method for producing olopatadine which is useful as a medicament. Background Art Olopatadine ((Z)-11-(3-dimethylaminopropylidene)- 6,11-dihydrodibenz[b,e]oxepin-2-acetic acid) is a compound represented by Formula (II) : and it is a pharmaceutical compound useful as an antiallergic agent to be applied to allergic rhinitis, urticaria or the like. When (Z)-11-(3-dimethylaminopropylidene)-6,11- dihydrodibenz[b,e]oxepin-2-acetic acid is produced by a chemical synthetic method, its E-isomer is simultaneously generated in general. Therefore, in order to obtain the objective Z-isomer more, it is necessary to isomerize the E-isomer to the Z-isomer. JP-B-5-86925 and JP-B-7-116174 describe that when the objective substance is obtained as an E/Z mixture, the isomers can be separated through column chromatography, recrystallization or the like, and if necessary, the cis-isomer (Z-isomer) can be isomerized to the trans-isomer (E-isomer) through a reflux treatment in acetic acid in the presence of an appropriate acid catalyst such as p-toluenesulfonic acid for 1 to 24 hours. However, these documents do not describe isomerization from the E- to the Z-isomer. Further, J. Med. Chem., 35, 2074-2084 (1992) describes that methyl 11-(3'-dimethylaminopropylidene)-6,11- dihydrodibenz[b,e]oxepin-2-acetate is saponified to obtain a corresponding carboxylic acid as a mixture of E/Z isomers (E:Z = 1:2), and the E-isomer is isolated from the mixture through a column, and then, an acetic acid solution of the E-isomer is heated at 100°C in the presence of p-toluenesulfonic acid for 21 hours to cause isomerization, whereby a mixture of E/Z isomers (E:Z = 65:35) is obtained. However, a method capable of more efficiently obtaining the objective Z-isomer has not been found yet. Disclosure of the Invention The present invention provides a method for efficiently and industrially advantageously producing olopatadine which is useful as a medicament. According to the invention, a Z-isomer represented by the following Formula [II] can be efficiently obtained by heating an ester compound represented by the following Formula [I] in a solvent in the presence of an acid. That is, the invention relates to: [1] a method for producing (Z)-ll-(3- dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2- acetic acid represented by Formula [II]: (wherein Me represents a methyl group) or an acid addition salt thereof (hereinafter referred to as Compound [II]), comprising heating a tertiary alkyl 11-(3-dimethylaminopropyl)-11- hydroxydibenzoxepinacetate represented by Formula [I]: (wherein Me has the same meaning as above; and each of R1, R2 and R3 independently represents an alkyl group having 1 to 4 carbon atoms) or an acid addition salt thereof (hereinafter referred to as Compound [I]) in a solvent in the presence of an acid; [2] a method for producing (Z)-ll-(3- dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2- acetic acid represented by Formula [II]: (wherein Me represents a methyl group) or an acid addition salt thereof, characterized by a reaction of a tertiary alkyl 11-oxodibenzoxepinacetate (hereinafter referred to as Compound [III]) represented by Formula [III]: (wherein each of R1, R2 and R3 independently represents an alkyl group having 1 to 4 carbon atoms) with a Grignard reagent (hereinafter referred to as Compound [IV]) represented by Formula [IV]: (wherein Me has the same meaning as above; and X represents a chlorine or bromine atom); and heating a resulting tertiary alkyl 11-(3-dimethylaminopropyl)-11- hydroxydibenzoxepinacetate represented by Formula [I]: (wherein R1, R2, R3 and Me have the same meanings as above) or an acid addition salt thereof in a solvent in the presence of an acid; [3] the production method according to the above [1] or [2], wherein the acid is hydrogen chloride; [4] the production method according to any one of the above [1] to [3], wherein the solvent is an organic solvent; [5] the production method according to any one of the above [1] to [3], wherein the solvent is a mixed solvent of an organic solvent and water; [6] the production method according to the above [4] or [5], wherein the organic solvent is toluene; [7] the production method according to any one of the above [1] to [6], wherein R1, R2 and R3 are a methyl group; and [8] the production method according to any one of the above [1] to [7] , wherein the heating is performed at 50 to 150°C. Hereinafter, the invention will be described in detail. (Step 1) Compound [III] + Compound [IV] → Compound [I] Compound [I] can be produced by a reaction of Compound [III] with Compound [IV]. Examples of a solvent used in the reaction include ethers (such as tetrahydrofuran, diethyl ether and diisopropyl ether) , aromatic hydrocarbons (such as toluene and xylene) and the like, and mixed solvents thereof, and a reaction temperature is generally from 0 to 50°C. The Compound [IV] (that is, a 3-dimethylaminopropylmagnesium halide) used here can be produced from, for example, a 3-dimethylaminopropylhalide (3-dimethylaminopropyl chloride or bromide) and magnesium. The Compound [IV] is used in an amount of generally from 1 to 2 mol, preferably from 1.1 to 1.7 mol per mol of the Compound [III] . It is preferred that the reaction is performed by dissolving the Compound [IV] in an appropriate solvent (such as tetrahydrofuran or a toluene/tetrahydrofuran mixed solvent) at a concentration of about 10 to 40% and gradually adding dropwise the obtained solution to a solution of the Compound [III] in a solvent (such as tetrahydrofuran). The temperature of the liquid at the time of dropwise addition is generally from 0 to 50°C, preferably from 10 to 30°C. The dropwise addition time is generally from 1 to 10 hours, preferably from 1 to 3 hours. Further, it is preferred that stirring is performed for about 0.5 to 5 hours after completion of the dropwise addition for allowing the reaction to sufficiently proceed. After it is confirmed that the reaction has sufficiently proceeded according to the above procedure, by performing a common post-treatment method, for example, a procedure such as extraction, liquid layer separation, washing, drying (dehydration) , concentration and the like, the Compound [I] can be isolated. (Step 2) Compound [I] → Compound [II] Compound [II] can be produced by heating the Compound [I] in a solvent in the presence of an acid. Examples of the acid include hydrogen chloride and sulfuric acid, and hydrogen chloride is preferred. Hydrogen chloride may be used in a gaseous form or as hydrochloric acid. A used amount of the acid is preferably from about 1 to 5 mol per mol of the Compound [I]. With regard to the solvent, an organic solvent or a mixture of an organic solvent and water is preferred. A mixing ratio of the organic solvent to water is generally from 10:1 to 10:3 by volume. Examples of the organic solvent include esters (such as ethyl acetate, propyl acetate, butyl acetate, ethyl propionate, propyl propionate and butyl propionate), ethers (such as diethyl ether, tert-butyl methyl ether, diethylene glycol dimethyl ether, diethylene glycol dibutyl ether, diethylene glycol diethyl ether, 1,2-dimethoxyethane and tetrahydrofuran), amides (such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and 1,3-dimethyl-2-imidazolidinone), ketones (such as methyl isobutyl ketone, methyl ethyl ketone, cyclohexanone and cyclopentanone) , nitriles (such as acetonitrile and propionitrile), alcohols (such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol and 2-butanol), halogenated hydrocarbons (such as methylene chloride, chloroform and chlorobenzene) , aromatic hydrocarbons (such as toluene and xylene) and nitrobenzene, and toluene is preferred. A used amount of the solvent is not particularly limited as long as it is an amount capable of completely dissolving the Compound [I], and, it is generally from 1 L to 5 L, preferably from 1.5 L to 2.5 L based on 1 kg of the Compound [I]. A heating temperature is generally from 50°C to 150°C, preferably from 80°C to 110°C. A reaction time depends on the temperature, used amount of the raw material or the like, and, it is generally from 0.5 hour to 20 hours, preferably from 2 hours to 10 hours. This reaction is preferably performed under stirring. In this manner, the dehydration reaction and deesterif ication reaction of the Compound [I] and isomerization from the E- to the Z-isomer of the produced compound proceed. In the case where hydrogen chloride gas is used as the acid, it is preferred that the reaction is performed in an autoclave. Further, in the case where hydrochloric acid or sulfuric acid is used as the acid, it is preferred that water is azeotropically distilled off for the purpose of accelerating the isomerization reaction after heating. The azeotropic distillation of water can be performed by using a known distillation method, for example, with a Dean-Stark apparatus. In the reaction solution from which water has been azeotropically distilled off, the Compound [II] rich in the Z-isomer is present; however, by distilling off the solvent from the reaction solution, the Compound [II] can be obtained as an acid addition salt corresponding to the acid used. Purification can also be performed by recrystallization from an appropriate solvent (for example, a mixed solvent of acetone and water). Further, the acid addition salt of the Compound [II] can be converted into the acid-free Compound [II] by an alkali treatment using a common procedure. The Compound [III] which is the raw material compound of the invention can be produced by a reaction of (11-oxo-6,11- dihydrodibenz[b,e]oxepin-2-yl)acetic acid produced according to a method described in J. Med. Chem. 19, 941 (1976), J. Med. Chem. 20, 1499 (1977) or JP-A-58-21679 with a compound represented by: (wherein R1, R2 and R3 have the same meanings as above) in the presence of a dehydrating agent such as trifluoroacetic anhydride or an acid catalyst according to a known tertiary esterification method. Examples Hereinafter, the present invention will be described with reference to Examples; however, the invention is not limited to these. A ratio of E- to Z-isomers of the produced compound was determined based on a value measured by high performance liquid chromatography (HPLC). In the following Examples, % other than an area percent indicating a purity determined by HPLC refers to % by weight. Example 1 Production of t-butyl 11-hydroxy-ll-(3-dimethylaminopropyl)- 6,11-dihydrodibenz[b,e]oxepin-2-acetate To 121.4 g (0.5 mol) of a 65.1% aqueous solution of 3-dimethylaminopropyl chloride hydrochloride, 143 g of water, 110 ml of toluene and 146. 4 g of a 25% aqueous solution of sodium hydroxide were added, and the mixture was stirred at about 25°C for 30 minutes. To the separated organic layer, 16.8 g of potassium carbonate was added to dehydrate the organic layer, which was then filtered. The residue was washed with 60 ml of toluene, and the filtrate and the washings were combined, whereby a toluene solution of 3-dimethylaminopropyl chloride was prepared. • Ten milliliters (10 ml) of tetrahydrofuran (THF) and 0.73 g of magnesium were mixed, and 0.1 g of 1, 2-dibromethane was added to activate magnesium. Then, 11.6 g of the obtained toluene solution of 3-dimethylaminopropyl chloride was added dropwise thereto at 37 to 39°C over 30 minutes. The mixture was stirred at 50°C for 1 hour, whereby a Grignard reagent was prepared. To a solution of 6.4 g (0.02 mol) of t-butyl (11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-yl)acetate dissolved in 35 ml of tetrahydrofuran, the thus obtained Grignard reagent was added dropwise at 15 to 20°C over about 1 hour. The mixture was stirred at the same temperature for 30 minutes, and the resulting reaction mixture was poured into a mixed liquid of 30 ml of water and 5.4 g of acetic acid. Then, 28% aqueous ammonia was added thereto to adjust the pH of the mixture to 9.6, and the mixture was subjected to liquid layer separation. The separated organic layer was washed with 50 ml of a 15% saline solution and then concentrated, whereby 8.04 g of t-butyl 11—hydroxy-11-(3-dimethylaminopropyl)-6,11- dihydrodibenz[b,e]oxepin-2-acetate was obtained. The apparent yield was 97.7%. 1H NMR (400 MHz, CDCl3) δ 1.41 (s, 9H) , 1.43-1.45 (m, 2H), 1.96 (q, J =8.4 Hz, 1H), 2.19-2.26 (m, 2H), 2.26(s, 6H), 3.20 (q, J = 8.0 Hz, 1H), 3.4 8 (s, 1H), 5.02 (d, J = 15.6 Hz, 1H), 5.45 (d, J = 15.6 Hz, 1H), 6.87 (d, J = 6.8 Hz, 1H), 7.03 (d, J = 7.6, 1H), 7.13-7.16 (m, 2H) , 7.23 (t, J=8.0 Hz, 2H) , 7.67 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 9.6, 1H) Example 2 Production of (Z)-11-(3-dimethylaminopropylidene)-6,11- dihydrodibenz[b,e]oxepin-2-acetic acid hydrochloride (olopatadine hydrochloride) Into a flask, 10.0 g (0.0243 mol) of t-butyl 11-hydroxy-ll-(3-dimethylaminopropyl)-6,11-dihydrodibenz[b, e] oxepin-2-acetate and 20 ml of toluene were charged, and 3.8 g (0.03645 mol) of 35% hydrochloric acid was added thereto. A ratio of E- to Z-isomers in the resulting reaction mixture was 85:15. This reaction mixture was stirred on a bath at a temperature between 100 and 105°C for 14 hours (reflux was initiated when the interior temperature reached 88°C and the temperature rose to 95°C) . A ratio of E- to Z-isomers at this time was 66:33. Further, a Dean-Stark apparatus was attached thereto and water was azeotropically distilled off (distilled amount: about 10 ml of toluene and about 1 ml of water) . The resulting reaction mixture was cooled to room temperature and the solvent was removed. To the residue, 100 ml of acetone and 1 ml of water were added, and the mixture was stirred for 4 hours . Then, the mixture was cooled to 5°C followed by filtration, and the resulting crystals were washed with 10 ml of cold acetone. The washed crystals were dried at 50°C, whereby 4.6 g of olopatadine hydrochloride was obtained. The purity measured by HPLC was determined to be 91.8% for the Z-isomer and 5.8% for the E-isomer. (Conditions for HPLC) Column: Inertsil ODS-2, 5 µm (4.6 mm ID x 15 cm) Mobile phase A: 5 mmol of an aqueous solution of sodium dodecyl sulfate (pH = 3.0, H3PO4) Mobile phase B: acetonitrile A/B = 5/5 → 3/7 (20 min) Flow rate: 1.0 ml/min Column temperature: 30°C Detection wavelength: UV 254 nm Example 3 (Z)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b, c] oxepin-2-acetic acid hydrochloride (olopatadine hydrochloride) Into a 100-ml Teflon-coated autoclave, 5.0 g (0.0122 mol) of t-butyl 11-hydroxy-ll-(3-dimethylaminopropyl)-6,11- dihydrodibenz[b,c]oxepin-2-acetate and 10 ml of toluene were charged, and 0.63 g (0.0173 mol) of hydrogen chloride gas was added thereto at 20°C by bubbling. Then, the autoclave was hermetically sealed and the mixture was stirred at a temperature between 90°C and 97°C for 8 hours, and then, the resulting reaction mixture was cooled to 25°C. A ratio of E- to Z-isomers at this time was 3.5 : 96.5. The reaction mixture was diluted by adding 10 ml of toluene thereto followed by filtration, and the resulting crystals were washed with 20 ml of toluene and then with 10 ml of acetone. The washed crystals were dried at 50°C, whereby 3.8 g (0.0101 mol) of olopatadine hydrochloride was obtained. The apparent yield was 83%. The purity measured by HPLC was determined to be 97.5% for the Z-isomer and 1.1% for the E-isomer. lH NMR (400 MHz, DMSO-d6) δ 2.73 (s, 6H), 2.77(t d, J = 7.6, 7.2 Hz, 2H), 3.25 (t, J=7.6Hz, 2H) , 3.55 (s, 2H) , 5.21 (brs, 1H), 5.65 (t, J = 7.2 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 7.10 (dd, J =8.0, 2.0 Hz, 1H) , 7.28-7.40 (m, 4H), 10.28 (brs, 1H), 12.31 (brs, 1H) Reference example Production of t-butyl (ll-oxo-6,11-dihydrodibenz[b,e]oxepin- 2-yl)acetate Into a 1-L four-necked flask, 60.4 g (0.225 mol) of (ll-oxo-6,11-dihydrodibenz[b,e]oxepin-2-yl)acetic acid and 300 ml of toluene were charged and 49.6 g (0.236 mol) of trifluoroacetic anhydride was added thereto, and the mixture was stirred at about 20°C for 1 hour. One hundred milliliters (100 ml) of t-butanol was added thereto, and the mixture was stirred at about 20°C for 2 hours, and was further stirred at 80°C for 2 hours. Then, the mixture was cooled to about 20°C, and 600 ml of water was added thereto, and the mixture was stirred for 20 minutes and then subjected to liquid layer separation. The separated organic layer was sequentially washed with 400 ml of water and a solution obtained by dissolving 6.2 g (0.045 mol) of potassium carbonate in 100 ml of water. To the washed organic layer, 3.0 g of activated carbon was added, and the mixture was stirred and then filtered through a Buechner funnel to separate the activated carbon. Further, the activated carbon was washed with 50 ml of toluene on the Buechner funnel. The original filtrate and the washings were combined, and the mixture was concentrated under reduced pressure, whereby 58.3 g of the title compound was obtained. The apparent yield was 7 9.9%, and the purity measured by HPLC was determined to be 99.1%. (Conditions for HPLC) Column: Inertsil ODS-2, 5 urn (4.6 mm ID X 15 cm) Mobile phase: a 0 . 02% aqueous solution of trif luoroacetic acid/ acetonitrile = 5/5 → 3/7 (30 min) Flow rate: 1.0 ml/min Column temperature: 30°C Detection wavelength: UV 254 nm (Physical data) 1H NMR (400 MHz, CDCl3) δ 1.45 (s, 9H), 3.55 (s, 2H), 5.17 (s, 2H), 7.02 (d, J=8.4, 1H), 7.40-7.48 (m, 3H) , 7.54 (t, J=6.4 Hz, 1H), 7.89 (d, J = 6.4 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H) Industrial Applicability According to the present invention, olopatadine which is useful as a medicament can be efficiently and industrially advantageously produced. CLAIMS 1. A method for producing (Z)-ll-(3- dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2- acetic acid represented by Formula [II]: (wherein Me represents a methyl group) or an acid addition salt thereof, characterized by heating a tertiary alkyl 11-(3- dimethylaminopropyl)-11-hydroxydibenzoxepinacetate represented by Formula [I]: (wherein Me has the same meaning as above; and each of R1, R2 and R3 independently represents an alkyl group having 1 to 4 carbon atoms) or a salt thereof in a solvent in the presence of an acid. 2. A method for producing (Z)-ll-(3- dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2- acetic acid represented by Formula [II]: (wherein Me represents a methyl group) or an acid addition salt thereof, characterized by comprising a reaction of a tertiary alkyl 11-oxodibenzoxepinacetate represented by Formula [III]: (wherein each of R1, R2 and R3 independently represents an alkyl group having 1 to 4 carbon atoms) with a Grignard reagent represented by Formula [IV]: (wherein Me has the same meaning as above; and X represents a chlorine or bromine atom); and heating a resulting tertiary alkyl 11-(3-dimethylaminopropyl)-11- hydroxydibenzoxepinacetate represented by Formula [I]: (wherein R1, R2, R3 and Me have the same meanings as above) or a salt thereof in a solvent in the presence of an acid. 3. The production method according to claim 1 or 2, wherein the acid is hydrogen chloride. 4. The production method according to claim 1 or 2, wherein the solvent is an organic solvent. 5. The production method according to claim 1 or 2, wherein the solvent is a mixed solvent of an organic solvent and water. 6. The production method according to claim 4, wherein the organic solvent is toluene. 7. The production method according to claim 5, wherein the organic solvent is toluene. 8. The production method according to claim 1, wherein R1, R2 and R3 are a methyl group. 9. The production method according to claim 1, wherein the heating is performed at 50 to 150°C. Olopatadine which is useful as a mdicanaent can be efficiently and industrially advantageously produced by heating a dibenzoxepin derivative represented by Formula [I]: (wherein Me represents a methyl group; and each of R1, R2 and R3 independently represents an alkyl group having 1 to 4 carbon atoms) or a salt thereof in a solvent in the presence of an acid. |
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| Patent Number | 270230 | |||||||||||||||
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| Indian Patent Application Number | 2721/KOLNP/2009 | |||||||||||||||
| PG Journal Number | 49/2015 | |||||||||||||||
| Publication Date | 04-Dec-2015 | |||||||||||||||
| Grant Date | 03-Dec-2015 | |||||||||||||||
| Date of Filing | 27-Jul-2009 | |||||||||||||||
| Name of Patentee | SUMITOMO CHEMICAL COMPANY, LIMITED | |||||||||||||||
| Applicant Address | 27-1, SHINKAWA 2-CHOME, CHUO-KU, TOKYO 104-8260 | |||||||||||||||
Inventors:
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| PCT International Classification Number | C07D 313/12 | |||||||||||||||
| PCT International Application Number | PCT/JP2008/052473 | |||||||||||||||
| PCT International Filing date | 2008-02-07 | |||||||||||||||
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