5-[Bis(2-hydroxyethyl)amino]-1-methyl-1H-benzimidazole-2-butanoic acid ethyl ester

Off-White to Light Tan Solid

To a solution of 81.3 g (650.6 mmol) 2-bromoethanol, 1 g potassium iodide and 100 g water was added 17.0g (65 mmol) compound (6). The reaction mixture was heated to 65-70 °C and held at this temperature for 8 h to 12 h.The pH value of the solution was held between 4.2-5.5 during this period by dropwise addition of a solution of 20.0 g(151.4 mmol) diammonium hydrogen phosphate in 35 g water. The control of pH over the duration of the reaction waseffected through use of a pH electrode. The conversion was followed by HPLC. The reaction was continued until thefraction of compound (7A) was ≤ 1.5 percent. Thereby ca. 8percent of compound (7B) had formed and the proportion of compound(7) was ca. 87percent. The reaction mixture was subsequently concentrated to dryness at ca. 55-60 °C under vacuum. Tothe residue was added 150 g water and, preferably with an alkali metal carbonate, the pH value adjusted to ca. 8.5. Thedesired product (7) was extracted with 200 g methylene chloride or 225 g chloroform, and the organic phase subsequentlywashed with 60 - 80 g water. The organic phase was then concentrated to dryness and the remaining oil or alreadycrystalline residue dissolved in 200 g ethyl acetate or alternatively in 60 g actetonitrile. Compound (7) crystallised at ca.5 °C and was filtered under suction, washed with 20 g cold ethyl acetate or alternatively with 15 g cold acetonitrile anddried at 60 -70 °C. The yield of compound (7) was 18.3 g (52.4 mmol) with a content of ≥ 98.2percent (80.5 percent of theory). Thecrude product contained ≤0.6percent compound (7A) and compound (7B) respectively as well as <0.15percent of compound (7C).0082] Analogous to Example 4 but with use of 9.0 g (65 mmol) potassium carbonate dissolved in 12 g water to holdthe pH value between 4.2 - 5.5. Identical results in terms of yield and quality.[0084] This example is a scaled-up analogue of Example 6 with use of 340 g (1.3 mol) compound (6), 2000 ml waterand 1625 g (13 mol) 2-bromoethanol. The reaction was performed without potassium iodide at 69 - 70°C.. The pH valuewas held between 4.2 - 5.5 using a solution of 138 g sodium carbonate (1.3 mol) in 500 g water. Until a content ofcompound (7A) of ≤1.5percent was reached, the duration of the reaction was 13.5 h. The yield of compound (7) was 365 gcrude and 343.5 g after recrystallisation from acetonitrile (75.6percent of theory).To a solution of 81.3 g (650.6 mmol) 2-bromoethanol, 1 g potassium iodide and 100 g water was added 17.0 g (65 mmol) compound (6). The reaction mixture was heated to 65-70° C. and held at this temperature for 8 h to 12 h. The pH value of the solution was held between 4.2-5.5 during this period by dropwise addition of a solution of 20.0 g (151.4 mmol) diammonium hydrogen phosphate in 35 g water. The control of pH over the duration of the reaction was effected through use of a pH electrode. The conversion was followed by HPLC. The reaction was continued until the fraction of compound (7A) was ≦1.5percent. Thereby ca. 8percent of compound (7B) had formed and the proportion of compound (7) was ca. 87percent. The reaction mixture was subsequently concentrated to dryness at ca. 55-60° C. under vacuum. To the residue was added 150 g water and, preferably with an alkali metal carbonate, the pH value adjusted to ca. 8.5. The desired product (7) was extracted with 200 g methylene chloride or 225 g chloroform, and the organic phase subsequently washed with 60-80 g water. The organic phase was then concentrated to dryness and the remaining oil or already crystalline residue dissolved in 200 g ethyl acetate or alternatively in 60 g acetonitrile. Compound (7) crystallised at ca. 5° C. and was filtered under suction, washed with 20 g cold ethyl acetate or alternatively with 15 g cold acetonitrile and dried at 60-70° C. The yield of compound (7) was 18.3 g (52.4 mmol) with a content of ≧98.2percent (80.5percent of theory). The crude contained ≦0.6percent compound ( 7A) and compound (7B) respectively as well as <0.15percent of compound (7C). The crude product obtained was recrystallized from ethyl acetate, or alternatively from acetonitrile, toluene, propan-2-ol, tetrahydrofuran, acetone, isopopyl acetate or water, prior to further conversion to compound ( 8). Thereby the yield of compound (7) was 17.2 g (94.0percent recrystallization yield) with a content of >99.2percent, wherein compound (7A) was removed below a content of 0.2percent and compound (7B) below 0.3percent. Through the course of the reaction, the content of compound (7C) was kept below 0.15percent, as this compound can only poorly be removed by recrystallization from the above described solvents. The overall yield of this step was 76.5percent of theory and was thus ca. 12.5percent higher than that described in the procedure using ethylene oxide as according to DD34727 and ca. 31percent higher in comparison to the favoured procedure of WO2011079193 involving addition of Hünig's base.Example-5 Preparation of Ethyl 4-{5-[bis(2-hydroxyethyI)amino]-l-methyl-lH-benzimidazol- 2-yl} butanoate (III) Ethyl 4-[5-amino-l -methyl- l H-benzimidazol-2-yl)butanoate (II, 200.0g, 0.763mol) was added to DM Water (1.1L). Aqueous sodium acetate.3HEXAMPLE-II

Molecular Weight:349.4
XLogP3:1
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:11
Exact Mass:349.20015635
Monoisotopic Mass:349.20015635
Topological Polar Surface Area:87.8
Heavy Atom Count:25
Complexity:404
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes