Ivabradine Impurity 68 synthesis

8synthesis methods

Product Name:Ivabradine Impurity 68
CAS Number:1220993-44-1
Molecular formula:C11H12O4
Molecular Weight:208.21

4,5-Dimethoxybenzocyclobutene-1-carboxylic acid

41234-23-5
36 suppliers
inquiry

Bicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid, 3,4-dimethoxy-, (7R)-

1220993-48-5
2 suppliers
inquiry

1220993-44-1
21 suppliers
inquiry

Yield:1220993-44-1 76.8%

Reaction Conditions:

Stage #1: (R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acidwith (R)-1-phenyl-ethyl-amine in isopropyl alcohol; for 1 h;Reflux;Resolution of racemate;
Stage #2: with hydrogenchloride;waterReagent/catalyst;Solvent;Time;

Steps:

(S)-4,5-Dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylicAcid (11)

R-(α)-Phenylethanamine (28.8 g, 0.24 mol) was added dropwise in 30 min into solution of 10 (50.0 g, 0.24 mol) in isopropanol (500 mL). The mixture was refluxed for 1 h and allowed to crystallize at room temperature overnight. The white solid was collected and recrystallized from isopropanol three times, dissolved in water (125 mL), and acidified with 10% aqueous HCl to pH 2-3. The aqueous solution was extracted with ethyl acetate (125mLx3). The ethyl acetate extracts were combined, dried over anhydrous Na2SO4, and concentrated to afford 11 of 19.5 g (40 % yield) as a colorless solid, mp 136-137 C, [α]_D²⁰=61 (c 0.5, MeOH), ee 99.4%. The mother liquor from the crystallization was collected and concentrated. The residue was dissolved in water (125 mL) and acidified with 10% aqueous HCl to pH2-3. The aqueous solution was extracted with ethyl acetate (125mLx3). The ethylacetate layers were combined, dried over anhydrous Na2SO4, and concentrated to afford a solid (32.5 g). Sodium ethoxide (32.6 g, 0.48 mol) was added to an ethanol solution (250 mL) of the solid, and the mixture was stirred under refluxing for 8 h. After the reaction mixture was cooled to room temperature, water (250 mL) was added. The solvent was adjusted to pH 1-2 with 10% aqueous HCl. The aqueous solution was extracted with ethyl acetate (250mLx3), and the ethyl acetate layers were combined, dried over anhydrous Na2SO4, and concentrated to afford 32.5 g of the racemic acid 10. The racemic acid 10 obtained from stage II was resolved following the workup described previously to give 11.4 g of 11 as a colorless solid (yield 22.8%,mp 135-137 C, [α]_D²⁰60 (c 0.5, MeOH), ee 98.9%). Then the the motherliquor was also recycled as the procedure described previously and was resolved togive another 7.5 g of 11 as a colorless solid (yield 15.4%, mp 136-138 C, [α]_D²⁰=62 (c 0.5, MeOH), ee 98.8%). Finally an overall 38.4 g (76.8% yield) of 11 was obtained (ee 98.9%). Mp 136-138 C, retention time: 9.28 min, [α]_D²⁰= 60 (c 0.5, MeOH). 1H NMR (300MHz, CDCl3): d 3.40 (m, 2H), 3.85 (s, 6H),4.25 (t, 1H, J3.8 Hz), 6.71 (s, 1H), 6.77 (s, 1H). EI-MS m=z 208 (M). Anal. calcd.for C11H12O4: C, 63.45; H, 5.81. Found: C, 63.50; H, 6.08.

References:

Liu, Xin;Liu, Yu;He, Huili;Cai, Zhan;Yang, Yushe [Synthetic Communications,2014,vol. 44,# 4,p. 451 - 456]

35202-54-1 Synthesis