US 12,227,527 B2
Process for the preparation of 2,2′,2″-(10-((2R,3S)-1,3,4-trihydroxy butan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid and its complexes
Manik Reddy Pullagurla, Hyderabad (IN); Jagadeesh Babu Rangisetty, Hyderabad (IN); and Bhaskar Reddy Pitta, Hyderabad (IN)
Assigned to BIOPHORE INDIA PHARMACEUTICALS PVT. LTD, Hyderabad (IN)
Appl. No. 17/258,890
Filed by BIOPHORE INDIA PHARMACEUTICALS PVT. LTD, Hyderabad (IN)
PCT Filed Jul. 10, 2019, PCT No. PCT/IB2019/055868
§ 371(c)(1), (2) Date Jan. 8, 2021,
PCT Pub. No. WO2020/012372, PCT Pub. Date Jan. 16, 2020.
Claims priority of application No. 201841025736 (IN), filed on Jul. 10, 2018; and application No. 201841026063 (IN), filed on Jul. 12, 2018.
Prior Publication US 2021/0284662 A1, Sep. 16, 2021
Int. Cl. C07F 5/00 (2006.01); C07B 63/04 (2006.01); C07F 3/00 (2006.01)
CPC C07F 5/003 (2013.01) [C07B 63/04 (2013.01); C07F 3/003 (2013.01); C07B 2200/13 (2013.01)] 5 Claims
 
1. An improved process for the preparation of Gadobutrol of formula (1) with purity greater than 99.0%,

OG Complex Work Unit Chemistry
the process consisting essentially of the steps:
a) reacting 1,4,7,10-tetraazacyclododecane of formula (6)

OG Complex Work Unit Chemistry
with 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] octane of formula (5)

OG Complex Work Unit Chemistry
In presence of metal salt to obtain 2,2-dimethyl-6-(1,4,7,10-tetraazacyclododecan-1-yl)-1,3-dioxepan-5-ol of formula (4);

OG Complex Work Unit Chemistry
b) reacting 2,2-dimethyl-6-(1,4,7,10-tetraazacyclododecan-1-yl)-1,3-dioxepan-5-ol of the formula (4) with chloroacetic acid or its salts of formula (3)

OG Complex Work Unit Chemistry
 Wherein X═H or Sodium, potassium or Lithium
and a base and purifying by adding an acidic or a basic resin and adding ammonia thereby obtaining 2,2′,2″-(10-((2R,3S)-1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid, triammonia salt of formula (2);

OG Complex Work Unit Chemistry
c) reacting 2,2′,2″-(10-((2R,3S)-1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraaza cyclododecane-1,4,7-triyl) triacetic acid, triammonia salt of formula (2) with gadolinium (III) oxide to yield the Gadobutrol of the formula (1); and
d) purifying the Gadobutrol of the formula (1) by treating with acidic resin and basic resins.