Process for the synthesis of olopatadine

Abstract

The present invention provides a process for the synthesis of olopatadine. Further, the invention discloses a process that results in improved yield of the desired Z isomer.

Claims

1. An improved process for synthesis of olopatadine comprising the steps of: a. treating Isoxepac (5), 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetic acid with thionyl chloride in the ratio ranging between 2 to 4 in the presence of an alcohol at room temperature in the range of 15 to 30 C. for period in the range of 12 to 24 hours to yield the corresponding ester; ##STR00009## b. treating the ester of step (a) with allyl bromide using Zn in a solvent conducting Barbier reaction to obtain the allylic alcohol 4; ##STR00010## c. Hydroborating the allyl alcohol (4) as obtained in step (b) using 9-BBN (9-Borabicyclo(3.3.1)nonane)/diborane quenched by sodium hydroxide and hydrogen peroxide to obtain diol 6; ##STR00011## d. treating diol 6 as obtained in step (c) with catalytic p-toluenesulfonic acid to form a spiro tetrahydrofuran ring 3 in almost quantitative yield; ##STR00012## e. treating compound 3 as obtained in step (d) with AlCl.sub.3 as Lewis acid in dichloromethane to yield olefin 2 and satisfactory E/Z ratio of 1 to 1.5; ##STR00013## f. subjecting compound 2 of step (e) to mesylation and dimethyl amination to result in compound 7 ##STR00014## in the range of 55 to 60%; g. treating compound 7 as obtained in step (f) with aqueous NaOH to yield the corresponding carboxylic acid, treating the acid with p-toluenesulfonic acid to yield the corresponding p-toluenesulfonate, crystallizing the p-toluenesulfonate to isolate the Z-isomer of the p-toluenesulfonate, treating the Z-isomer of the p-toluenesulfonate with NaHCO.sub.3 to yield the free base 8 ##STR00015## and treating free base 8 with aqueous HCl to give 1 with E:Z ratio of 1:1.5 ##STR00016##

2. The process according to claim 1, wherein the alcohol used in step (a) is methanol.

3. The process according to claim 1, wherein the solvent used in step (b) is dimethyl formamide (DMF).

Description

BRIEF DESCRIPTION OF THE DRAWING

(1) FIG. 1 is a scheme of the process steps for synthesis of olopatadine, wherein: i) SOCl.sub.2, MeOH, 24 hours, RT, 98%; ii) Zn, Allyl bromide, DMF, 2 hours, 91%. iii) 9-BBN, NaOH, H.sub.2O.sub.2, THF, 24 h, 84%. iv) p-TSA, DCM, 10 minutes, RT, 99%; v) AlCl.sub.3, DCM, 0 C.-RT, 7 hours, 95%; vi) MsCl, Pyridine, 2 hours; vii) 50% Me.sub.2NH, MeOH, reflux, 3 hours, 84% over two steps; viii) Ref. Ohshima, E; Otaki, S; Sato, H; Kumazawa, T; Obase, H; Ishii, A; Ishii, H; Ohmori, K; and Hirayama, N J. J. Med Chem. 1992, 35, 2074.

SUMMARY OF THE INVENTION

(2) Accordingly, present invention relates to an improved process for synthesis of olopatadine comprising the steps of: a. treating Isoxepac (5), 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetic acid with thionyl chloride in the ratio ranging between 2 to 4 in the presence of alcohol at room temperature in the range of 15 to 30 C. for period in the range of 12 to 24 hours to yield corresponding ester;

(3) ##STR00002## b. treating ester of step (a) with allyl bromide using Zn in a solvent conducting Barbier reaction to obtain allylic alcohol 4;

(4) ##STR00003## c. Hydroborating the allyl alcohol (4) as obtained in step (b) using 9-BBN (9-Borabicyclo(3.3.1)nonane)/diborane quenched by sodium hydroxide and hydrogen peroxide to obtain diol 6;

(5) ##STR00004## d. treating diol 6 as obtained in step (c) with catalytic p-TSA instantly form a spiro tetrahydrofuran ring 3 in almost quantitative yield;

(6) ##STR00005## e. treating compound 3 as obtained in step (d) with AlCl.sub.3 as Lewis acid in DCM to yield olefin 2 and satisfactory E/Z ratio of 1 to 1.5;

(7) ##STR00006## f. subjecting compound 2 of step (e) to mesylation and dimethyl amination resulted in compound 7 in the range of 55 to 60%; g. converting compound 7 as obtained in step (f) to compound 1 by known techniques with E:Z ratio of 1:1.5.

(8) ##STR00007##

(9) In another embodiment of the present invention, alcohol used in step (a) is methanol.

(10) In yet another embodiment of the present invention, solvent used in step (b) is dimethyl formamide (DMF).

DETAILED DESCRIPTION OF THE INVENTION

(11) Present invention provides a process for synthesis of olopatadine resulting in yields of greater than 50%, with the E:Z of 1:1.5.

(12) In accordance to FIG. 1, the process for the synthesis of olopatadine comprises: a. treating Isoxepac (5), 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetic acid with thionyl chloride in the presence of methanol at room temperature in the range of 15 to 30 C. for 24 hours to yield corresponding ester; b. conducting Barbier reaction on the ester of step (a) with allyl bromide using Zn in a solvent, to form allylic alcohol 4; c. conducting Hydroboration of 4 using 9-BBN/diborane which was quenched by sodium hydroxide and hydrogen peroxide, affording diol 6. d. treating the diol 6 with catalytic p-TSA instantly form a spiro tetrahydrofuran ring 3 in almost quantitative yield. e. treating compound 3 with AlCl.sub.3 as Lewis acid in DCM to yield olefin 2 in excellent yield and satisfactory E/Z ratio (1/1.5); f. subjecting compound 2 of step (e) to mesylation and dimethyl amination resulted in compound 7, which was converted to compound 1 by known techniques.

EXAMPLES

(13) Following examples are given by way of illustration and therefore should not be construed to limit the scope of the invention.

Example 1

(14) 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetic acid (5 g, 18.65 mmol) was dissolved in methanol (100 mL) and cooled at 0 C. Thionyl chloride (2.06 mL, 27.98 mmol) was added dropwise during a half hour period and the solution was stirred at room temperature (25 C.) for 24 h. The solvent was evaporated almost to dryness and the residue was partitioned between dichloromethane (50 mL) and saturated sodium bicarbonate solution (50 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure, giving ketoester, which was used without further purification.

Example 2

(15) To a stirred mixture of Isoxepac ester (5 g, 17.66 mmol) and zinc (3.44 g, 53 mmol) in DMF (50 mL), allyl bromide (1.66 mL, 19.43 mmol) was added at 0 C. After 2 hours the reaction mixture was filtered to remove the remaining zinc, 10% hydrochloric acid (20 mL) was added and organic layer was separated. The aqueous layer extracted with small portions of EtOAc, the combined organic extracts were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The resulting liquid was purified by column chromatography (pet ether-ethyl acetate, 8:2) to give compound 4 (5.2 g, 91%) as thick colorless oil.

(16) Colorless liquid; .sup.1H NMR (200 MHz, CDCl.sub.3+CCl.sub.4): 2.86-2.97 (m, 1H), 3.34-3.44 (m, 1H), 3.60 (s, 2H), 3.68 (s, 3H), 5.04 (d, J=15.5 Hz, 1H), 5.09-5.18 (m, 2H), 5.47 (d, J=15.5 Hz, 1H), 5.35-5.56 (m, 1H), 6.90-7.00 (m, 1H), 7.06 (d, J=8.09 Hz, 1H), 7.15-7.31 (m, 3H), 7.56 (d, J=2.15 Hz, 1H), 7.94-7.84 (m, 1H); .sup.13C NMR (50 MHz, CDCl.sub.3+CCl.sub.4): 40.5, 48.7, 51.8, 73.6, 75.7, 119.4, 121.3, 125.8, 125.9, 126.8, 127.0, 127.5, 129.5 (2C), 133.5, 134.5, 139.0, 142.1, 154.7, 171.9; HRMS m/z: Calculated for C.sub.20H.sub.21O.sub.4-325.1434. observed-325.1433.

Example 3

(17) At first, 9-BBN (1.80 g, 14.81 mmol) was added to a well stirred solution of olefin 4 (4 g, 12.34 mmol) in anhydrous THF (40 mL) at room temperature (25 C.) and the reaction mixture was stirred for 24 h at 70 C. Then the reaction mixture was quenched with 3 M NaOH (0.54 g, 13.50 mmol) at 0 C., followed by the dropwise addition of 30% H.sub.2O.sub.2 (3.5 mL, 37.03 mmol) and the resulting solution was stirred for 6 h at room temperature (25 C.). The organic phase was separated and the aqueous layer extracted with ethyl acetate (320 mL). The combined organic phase was washed with brine (130 mL), dried over anhydrous Na.sub.2SO.sub.4, and the solvent was evaporated under reduced pressure. The crude product was subjected to flash column chromatography (pet ether-ethyl acetate, 7:3) to obtain diol 6 (3.54 g, 84%).

(18) Colorless liquid; .sup.1H NMR (200 MHz, CDCl.sub.3+CCl.sub.4): 1.20-1.56 (m, 2H), 2.08-2.28 (m, 1H), 2.64-2.89 (m, 1H), 3.36-3.64 (m, 4H), 3.67 (s, 3H), 4.84 (brs, 1H), 5.01 (d, J=15.4 Hz, 1H), 5.43 (d, J=15.4 Hz, 1H), 6.93 (d, J=7.2 Hz, 1H), 6.98-7.32 (m, 4H), 7.62 (d, J=2.15 Hz, 1H), 7.97 (d, J=7.5 Hz, 1H); .sup.13C NMR (50 MHz, CDCl.sub.3+CCl.sub.4): 27.3, 40.4, 41.8, 52.0, 62.7, 73.6, 76.6, 121.2, 125.8, 126.2, 126.9 (2C), 128.2, 129.3 (2C), 134.4, 139.6, 143.3, 154.8, 172.6; HRMS m/z: Calculated for C.sub.20H.sub.22O.sub.5Na-365.1359. observed-365.1360.

Example 4

(19) The diol 6 (3 g, 2.5 mmol) was dissolved in dry DCM (30 mL) in an oven-dried flask under a nitrogen atmosphere and p-TSA (83 mg, 0.43 mmol) was added at room temperature (25 C.). The solution was stirred for additional 10 min. and then the reaction was quenched by the addition of water (20 mL). Resulting organic mass was extracted with DCM (320 mL), washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and column purified over silica gel (pet ether:ethyl acetate, 9:1) to furnish spiro ether 3 (2.81 g, 99%) as oil.

(20) Colorless liquid; .sup.1H NMR (400 MHz, CDCl.sub.3+CCl.sub.4): 1.87-1.99 (m, 2H), 2.56-2.72 (m, 2H), 3.59 (s, 2H), 3.69 (s, 3H), 4.20 (q, J=7.1 and 7.1 Hz, 1H), 4.31 (q, J=7.1 and 7.1 Hz, 1H), 5.02 (d, J=15.3 Hz, 1H), 5.56 (d, J=15.3 Hz, 1H), 6.97 (d, J=7.2 Hz, 1H), 7.03 (d, J=8.03 Hz, 1H), 7.10-7.26 (m, 3H), 7.51 (s, 1H), 7.74 (d, 0.5 Hz, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3+CCl.sub.4): 25.9, 40.7, 42.6, 51.9, 68.9, 72.9, 85.1, 121.4, 124.5, 126.2 (2C), 126.9, 127.0, 129.21, 129.27, 133.6, 140.2, 143.4, 153.9, 172.0; HRMS m/z: Calculated for C.sub.20H.sub.21O.sub.4-325.1434. observed-325.1437.

Example 5

(21) To a cold (0 C.), magnetically stirred solution of Spiro ether 3 (2 g, 6.12 mmol) in anhydrous DCM, was added anhydrous crystalline aluminium chloride (2.05 g, 15.43 mmol) in one portion under nitrogen. The resulting mixture was warmed to room temperature (25 C.) and the red-orange reaction mixture was stirred at room temperature (25 C.) until the completion of reaction (7 h). The reaction mixture was then poured into an ice cooled 10% aqueous HCl and the aqueous layer was extracted with DCM. The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude reaction mixture was purified by flash silica gel column chromatography (pet ether:ethyl acetate, 7:3) resulted in allylic alcohol 2 (1.9 g, 95%).

(22) White solid; .sup.1H NMR (200 MHz, CDCl.sub.3+CCl.sub.4): 2.38-2.49 (m, 0.8H, E-Form), 2.63-2.73 (m, 1.2H, Z-Form), 3.53 (s, 2H), 3.68 (s, 3H), 3.75 (m, 0.8H, E-Form), 3.81 (t, J=6.3 Hz, 1.2H), 5.19 (brs, 2H), 5.73 (t, J=7.8 Hz, 0.6H, Z-Form), 6.06 (t, J=7.8 Hz, 0.4H, E-Form), 6.70 (d, J=8.2 Hz, 0.4H, E-Form), 6.79 (d, J=8.2 Hz, 0.6H, Z-Form), 7.00-7.34 (m, 6H), HRMS m/z: Calculated for C.sub.20H.sub.21O.sub.4-325.1434. observed-325.1437.

Example 6

(23) To allyl alcohol 2 (1 g, 3.08 mmol) in pyridine (16 mL) was added methanesulfonyl chloride (0.95 mL, 11.72 mmol) gradually at 0 C. The reaction mixture was heated to room temperature (25 C.) and stirred for 2 h. The mixture was quenched with water (5 mL) and then extracted with ethyl acetate (202). The organic layer was washed with saturated aqueous NaCl (10 mL) and concentrated. To a solution of obtained oil in MeOH (20 mL) was add 50% aqueous dimethylamine (5.2 mL, 18.0 equiv) and the mixture was stirred under reflux for 3 h. The solvent was evaporated and extracted with ethyl acetate (202). The organic layer was washed with saturated aqueous NaCl (10 mL) and dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by flash silica gel column chromatography (MeOH) resulted in 7 (0.91 g, 84%). Overall yield: 59% pale yellow liquid; .sup.1H NMR (200 MHz, CDCl.sub.3+CCl.sub.4): 2.15 (s, 2H), 2.24 (s, 4H), 2.31-2.62 (m, 4H), 3.51 (s, 2H), 3.67 (s, 3H), 4.73 (brs, 1H), 5.45 (brs, 1H), 5.69 (t, J=7.1 Hz, 0.6H, Z-Form), 6.02 (t, J=6.9 Hz, 0.4H, E-Form), 6.69 (d, J=8.3 Hz, 0.4H, E-Form), 6.78 (d, J=8.3 Hz, 0.6H, Z-Form), 6.98-7.37 (m, 6H).

Example 7

(24) A mixture of 7 (2.87 g, 8.2 mmol, E/Z=1/1.5), MeOH (100 mL), 10 N NaOH (3.0 mL, 30 mmol), and water (20 mL) was refluxed for 1 h and then concentrated under reduced pressure. The residue (E/Z=1/1.5) was diluted with H.sub.2O and the solution was neutralized with 4 N HCl. The crude mixture (2.6 g, 7.7 mmol, E/Z 1/1.5) on subsequent desalination with HP-10 (H.sub.2O and then MeOH as eluent) was dissolved in 2-propanol (40 mL) containing p-TsOH.H.sub.2O (1.47 g, 7.7 mmol). The solution was stirred at room temperature (27 C.) and the resultant precipitate was collected by filtration. The crude product was recrystallized from 2-propanol to give 2.16 g (55%) of (Z)-2-(11-(3-(dimethylamino)propylidene)-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetic acid p-toluenesulfonate mp 185-187 C. The salt was added portionwise to aqueous NaHCO.sub.3, with ice cooling and the resultant solution was neutralized with 4 N HCl. The crude product was desalinated with HP-10 and recrystallized successively from 2-propanol and water to give 1.14 g (66%) of the free base 8 mp 188-189.5C; .sup.1H NMR (DMSO-d.sub.6): 2.15 (s, 6H), 2.40-2.60 (m, 4H), 3.45 (8, 2H), 5.00-5.55 (br, 2H), 5.66 (t, J=6.7 Hz, 1H), 6.75 (d, J=8.1 Hz, 1H), 7.0-7.1 (m, 2H), 7.2-7.4 (m, 4H); MS m/z 337 (M+). The free base 8 (1.14 g, 35 mmol) was added to a 8 N solution of HCl in 2-propanol (0.8 mL, 64 mmol) and the mixture was stirred at room temperature (27 C.). After being concentrated, the residue was recrystallized from acetone-water (2/1) to give 0.93 g (80%) of 8 as hydrochloride salt: mp 248 C. dec. (Compound 1). The E/Z ratio was determined by analyzing the .sup.1H NMR spectrum of compound 7, by integration of characteristic protons at 5.69 (Z) and 6.02 (E) which appear as triplets.

(25) ##STR00008##

ADVANTAGES OF THE INVENTION

(26) 1. Avoids expensive metal catalysts.

(27) 2. Avoids hazardous reagents and reaction conditions.

(28) 3. Improved yield of preferred diastereomer.