WO2017093889A1 - An improved process for the preparation of indocyanine green - Google Patents

An improved process for the preparation of indocyanine green Download PDF

Info

Publication number
WO2017093889A1
WO2017093889A1 PCT/IB2016/057178 IB2016057178W WO2017093889A1 WO 2017093889 A1 WO2017093889 A1 WO 2017093889A1 IB 2016057178 W IB2016057178 W IB 2016057178W WO 2017093889 A1 WO2017093889 A1 WO 2017093889A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
process according
solvent
indocyanine green
benzo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2016/057178
Other languages
French (fr)
Inventor
Janmejay Rajnikant VYAS
Himani Dhotre
Narasimha SARMA
Babulal R. PATEL
Dinesh Kumar Sharma
Dilip N. PATEL
Ashish A. SONI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dishman Carbogen Amcis Ltd
Original Assignee
Dishman Pharmaceuticals and Chemicals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dishman Pharmaceuticals and Chemicals Ltd filed Critical Dishman Pharmaceuticals and Chemicals Ltd
Priority to US15/780,555 priority Critical patent/US10287436B2/en
Priority to EP16870081.3A priority patent/EP3383436B1/en
Priority to AU2016362673A priority patent/AU2016362673A1/en
Priority to DK16870081.3T priority patent/DK3383436T3/en
Priority to KR1020187018918A priority patent/KR102786409B1/en
Priority to CA3007062A priority patent/CA3007062A1/en
Priority to JP2018548295A priority patent/JP2018538428A/en
Publication of WO2017093889A1 publication Critical patent/WO2017093889A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
    • C09B23/02—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups
    • C09B23/08—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines
    • C09B23/086—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines more than five >CH- groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0032—Methine dyes, e.g. cyanine dyes
    • A61K49/0034—Indocyanine green, i.e. ICG, cardiogreen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/60—Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B67/00—Influencing the physical, e.g. the dyeing or printing properties of dyestuffs without chemical reactions, e.g. by treating with solvents grinding or grinding assistants, coating of pigments or dyes; Process features in the making of dyestuff preparations; Dyestuff preparations of a special physical nature, e.g. tablets, films
    • C09B67/0071—Process features in the making of dyestuff preparations; Dehydrating agents; Dispersing agents; Dustfree compositions
    • C09B67/0092—Dyes in solid form
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B67/00—Influencing the physical, e.g. the dyeing or printing properties of dyestuffs without chemical reactions, e.g. by treating with solvents grinding or grinding assistants, coating of pigments or dyes; Process features in the making of dyestuff preparations; Dyestuff preparations of a special physical nature, e.g. tablets, films
    • C09B67/0096—Purification; Precipitation; Filtration

Definitions

  • the present invention provides a novel process for the preparation of stable amorphous form of Indocyanine green.
  • Indocyanine green chemically known as sodium 4-[2-[(lZ?,3Z?,5Z?,7Z)-7-[l ,l-dimethyl-3- (4- sulf onatobutyl)benzo [e] indol-2-ylidene] hepta- 1 , 3 ,5 -trienyl] -1,1 -dimethylbenzo [e] indol-3-ium-3-yl]butane-l-sulfonate, used in medical diagnostics. It is used for determining cardiac output, hepatic function, and liver blood flow, and for ophthalmic angiography. Indocyanine green is a fluorescent dye which is used in medicine as an indicator substance (e.g.
  • Indocyanine green sodium salt is normally available in powder form and can be dissolved in various solvents; 5% ( ⁇ 5% depending on batch) sodium iodide is usually added to ensure better solubility.
  • the sterile lyophilisate of a water-Indocyanine green solution is approved many European countries and the United States under the names Indocyanine green-Pulsion and Indocyanine green as a diagnostic for intravenous use.
  • Indocyanine green as its pharmaceutical acceptable salts[iodide disodium salt].
  • Indocyanine green can prepared by reacting l,l,2-trimethyl-lH-benzo[e]indole with 1 ,4-butane sultone in without solvent to produce 4-(l,l,2-trimethyl-lH-benzo[e]indolium-3-yl)butane-l-sulfonate, followed by treatment with N-phenyl-N-((lE,3E,5E)-5-(phenylimino)penta-l,3-dienyl)acetamide triethyl amine in ethanol and extraction in ether, and making sodium iodide salt in alcoholic solvent.
  • US5750722 disclosed a process for preparing Indocyanine green acetone as purification solvent.
  • US20090069573 patent purification solvent is methylene dichloride.
  • Hydrocyanines a class of fluorescent sensors that can image reactive oxygen species in cell culture, tissue, and in vivo.
  • the main objective of the present invention is to provide an improved process for the preparation of Indocyanine green
  • Yet another objective of the present invention is to provide an improved process for preparing ahigh purity NLT (Not Less Than) 98.0 % of intermediate compound formula(IV).
  • Yet another objective of the present invention is to provide a simple and environmentally friendly process for the preparation of Indocyanine green, which avoids use of hazardous and expensive reagents.
  • Yet another objective of the present invention is to provide a process with a good yield and high purity NLT(Not Less Than) 99.0%
  • Yet another objective of the present invention is to provide an improved process for Indocyanine green, which is simple and industrially applicable.
  • the present invention provides a novel and improved one -pot process for the preparati 99.0%
  • said process comprises the steps of: a) reacting l,l,2-trimethyl-lH-benzo[e] indole Formula (II) with 1 ,4-butane sultone of Formula III) in boiling solvent to give 4-(l,l,2-trimethyl-lH-benzo[e]indolium-3-yl)butane-l- sulfonate of Formula (IV);
  • the present invention provides a process for preparation of the compound of formula(V)
  • Figure-I X-Ray Powder Diffraction (XRPD) pattern of Indocyanine green Formula (I) as a stable Amorphous form
  • the condensation reaction is carried out in presence of alkali metal acetate salt, such as sodium, potassium, lithium salt of acetate, preferably sodium acetate.
  • alkali metal acetate salt such as sodium, potassium, lithium salt of acetate, preferably sodium acetate.
  • alcohol solvent define as methanol, ethanol, isopropanol, n-butanol but preferably solvent is methanol.
  • ester solvents such as ethyl acetate, isopropyl acetate, methyl acetate, preferably ethyl acetate.
  • the crude compound purification reaction is usually run in a suitable ketonic solvent such as water or a mixture of water and a ketonic solvent such as acetone, methyl ethyl ketone, preferably solvent is acetone and water.
  • a suitable ketonic solvent such as water or a mixture of water and a ketonic solvent such as acetone, methyl ethyl ketone, preferably solvent is acetone and water.
  • solvents used in the reaction between compound of formula II and compound of formula III is selected from toluene, xylene, hexane, sulfolene, silicone oil but preferably solvent is sulfolene.
  • the reaction for preparing compound formula(IV) reaction is carried out at temperature range from about 110°C to about 180°C, preferably in the temperature range from 120°C to 140°C.
  • the present invention also provides a process for the preparation of the compound formula(V)
  • the preparation of compound of formula(V) reaction is carried out in an organic base such as primary amine, secondary, tertiary amine, methyl amine, ethyl amine, dimethyl amine, triethyl amine, preferably triethyl amine.
  • organic base such as primary amine, secondary, tertiary amine, methyl amine, ethyl amine, dimethyl amine, triethyl amine, preferably triethyl amine.
  • the solvent can also be selected from chlorinated solvent such as methylene dichloride, ethylene dichloride, preferably solvent is methylene dichloride.
  • the temperature range for carrying out the preparation of compound of formula V is from about 0°C to about 30°C, preferably a temperature range from 0°C to 5°C.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Indole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention involves an improved process for the preparation of Indocyanine green of Formula (I) having high purity of about 99%, wherein the process comprises steps of reacting 1,1,2-trimethyl-1H-benzo[e]indole with 1,4-butane sulfone in boiling solvent to give 4-(1,1,2-trimethyl-1H-benzo[e]indolium-3-yl)butane-1-sulfonate. Followed by reacting 4-(1,1,2-trimethyl-1H-benzo[e]indolium-3-yl)butane-1-sulfonate of Formula (IV) and N-phenyl-N-((1E,3E,5E)-5-(phenylimino)penta-1,3-dienyl)acetamide of formula (V) in presence of sodium acetate and alcohol; and extracting the title compound formula (I) with an ester solvent.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF INDOCYANINE
GREEN
FIELD OF INVENTION
The present invention provides a novel process for the preparation of stable amorphous form of Indocyanine green.
BACKGROUND OF THE INVENTION
Indocyanine green, chemically known as sodium 4-[2-[(lZ?,3Z?,5Z?,7Z)-7-[l ,l-dimethyl-3- (4- sulf onatobutyl)benzo [e] indol-2-ylidene] hepta- 1 , 3 ,5 -trienyl] -1,1 -dimethylbenzo [e] indol-3-ium-3-yl]butane-l-sulfonate, used in medical diagnostics. It is used for determining cardiac output, hepatic function, and liver blood flow, and for ophthalmic angiography. Indocyanine green is a fluorescent dye which is used in medicine as an indicator substance (e.g. for photometric hepatic function diagnostics and fluorescence angiography) in cardiac, circulatory, hepatic and ophthalmic conditions. It is administered intravenously and, depending on liver performance, is eliminated from the body with a half life of approx. 3-4 minutes. Indocyanine green sodium salt is normally available in powder form and can be dissolved in various solvents; 5% (<5% depending on batch) sodium iodide is usually added to ensure better solubility. The sterile lyophilisate of a water-Indocyanine green solution is approved many European countries and the United States under the names Indocyanine green-Pulsion and Indocyanine green as a diagnostic for intravenous use.
US2895955 describes a structure including Indocyanine green and its pharmaceutically acceptable salts. Indocyanine green as its pharmaceutical acceptable salts[iodide disodium salt]. In accordance with the US'955 patent, Indocyanine green can prepared by reacting l,l,2-trimethyl-lH-benzo[e]indole with 1 ,4-butane sultone in without solvent to produce 4-(l,l,2-trimethyl-lH-benzo[e]indolium-3-yl)butane-l-sulfonate, followed by treatment with N-phenyl-N-((lE,3E,5E)-5-(phenylimino)penta-l,3-dienyl)acetamide triethyl amine in ethanol and extraction in ether, and making sodium iodide salt in alcoholic solvent. In this process 4-(l ,l,2-trimethyl-lH-benzo[e]indolium-3-yl)butane-l-sulfonate compound is not isolating or not easy filtration, also Indocyanine green not getting purity 99.0%.
According to PCT application WO2014/165216 patent, intermediate of N-((lE,3E,5E)-5- (phenylimino)penta-l,3-dien- 1-yl) benzenaminium chloride treated with acetic anhydride in presence of triethylamine at -20°C to give N-phenyl-N-((lE,3E,5E)-5- (phenylimino)penta-l,3-dienyl)acetamide, reaction carried out concentrated under high vacuum. According to PCT application WO 2014192972 patent, intermediate of N-((lE,3E,5E)-5- (phenylimino)penta-l,3-dien- 1-yl) benzenaminium chloride treated with acetic anhydride in presence of sodium acetate at 100°C to give N-phenyl-N-((lE,3E,5E)-5- (phenylimino)penta- 1 ,3-dienyl)acetamide,reaction4-(l , 1 ,2-trimethyl- lH-benzo[e] indolium-3-yl)butane-l -sulfonate in water.
US5750722 disclosed a process for preparing Indocyanine green acetone as purification solvent. And also US20090069573 patent purification solvent is methylene dichloride.
Wang, Dun; Jin, Wenshu; Qin, Enwei;Wang, Shuobing; Li, Peng Zhongguo Yiyao Gongye Zazhi Volume 37, Issue 9, Pages 584-585(2006) process for making indocyanine green.
Kundu, Kousik; Knight, Sarah F.; Willett, Nick; Lee, Sungmun; Taylor, W. Robert; Murthy, Niren Angewandte Chemie, International Edition Volume 48, Issue 2,Pages 299- 303(2009) disclosed process for making Hydrocyanines: a class of fluorescent sensors that can image reactive oxygen species in cell culture, tissue, and in vivo.
According to PCT application WO2007/120579 patent describe process for making Indocyanine green as sodium iodide salt. OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide an improved process for the preparation of Indocyanine green Yet another objective of the present invention is to provide an improved process for preparing ahigh purity NLT (Not Less Than) 98.0 % of intermediate compound formula(IV).
Yet another objective of the present invention is to provide a simple and environmentally friendly process for the preparation of Indocyanine green, which avoids use of hazardous and expensive reagents.
Yet another objective of the present invention is to provide a process with a good yield and high purity NLT(Not Less Than) 99.0%
Yet another objective of the present invention is to provide an improved process for Indocyanine green, which is simple and industrially applicable.
SUMMARY OF INVENTION
In one aspect the present invention provides a novel and improved one -pot process for the preparati 99.0%
Figure imgf000005_0001
said process comprises the steps of: a) reacting l,l,2-trimethyl-lH-benzo[e] indole Formula (II)
Figure imgf000006_0001
with 1 ,4-butane sultone of Formula III)
Figure imgf000006_0002
in boiling solvent to give 4-(l,l,2-trimethyl-lH-benzo[e]indolium-3-yl)butane-l- sulfonate of Formula (IV);
Figure imgf000006_0003
b) reacting 4-(l,l,2-trimethyl-lH-benzo[e]indolium-3-yl)butane-l-sulfonate of Formula (IV)
Figure imgf000006_0004
and N-phenyl-N-((lE,3E,5E)-5-(phenylimino)penta-l,3-dienyl)acetamide compound formula(V)
Figure imgf000006_0005
presence of sodium acetate and alcohol as solvent to give title compound formula(I). In another aspect the present invention provides a process for preparation of the compound of formula(V)
Figure imgf000007_0001
wherein the process comprises reacting (E)-N,N'-((lE,3E)-penta-l,3-diene-l-yl-5- ylidene)dianiline or hydrochloride of compound formula (VI)
Figure imgf000007_0002
with acetic an-hydride in presence of organic base.
BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS:
Figure-I: X-Ray Powder Diffraction (XRPD) pattern of Indocyanine green Formula (I) as a stable Amorphous form
DETAILED DESCRIPTION OF THE INVENTION
An improved process for the preparation of Indocyanine green of Formula (I) having >99.0% and without using sodium iodide.
Figure imgf000007_0003
condensation of the 4-(l,l,2-trimethyl-lH-benzo[e]indolium-3-yl)butane-l-sulfonate of Formula (IV)
Figure imgf000008_0001
and N-phenyl-N-((lE,3E,5E)-5-(phenylimino)penta-l,3-dienyl)acetamide compound formula(V)
Figure imgf000008_0002
in presence of sodium acetate and alcohol as solvent followed by extraction using an extraction solvent to give title compound formula(I).
The condensation reaction is carried out in presence of alkali metal acetate salt, such as sodium, potassium, lithium salt of acetate, preferably sodium acetate.
The present invention is carried out in alcohol as solvent, alcohol solvent define as methanol, ethanol, isopropanol, n-butanol but preferably solvent is methanol.
It is is carried out at temperature range about 50°C to 90°C, but preferably temperature is 60°C to 70°C. The extraction is carried out in ester solvents such as ethyl acetate, isopropyl acetate, methyl acetate, preferably ethyl acetate.
The crude compound purification reaction is usually run in a suitable ketonic solvent such as water or a mixture of water and a ketonic solvent such as acetone, methyl ethyl ketone, preferably solvent is acetone and water.
According to the present invention compound of formula(IV) is prepared
Figure imgf000009_0001
θ using the l,l,2-trimethyl-lH-benzo[e]indole compound formula(II) and 1,4-butane sultone compound formula(III)
Figure imgf000009_0002
in high boiling solvent to give 4-(l,l,2-trimethyl-lH-benzo[e]indolium-3-yl)butane-l- sulfonate of Formula (IV) The solvents used in the reaction between compound of formula II and compound of formula III is selected from toluene, xylene, hexane, sulfolene, silicone oil but preferably solvent is sulfolene.
The reaction for preparing compound formula(IV) reaction is carried out at temperature range from about 110°C to about 180°C, preferably in the temperature range from 120°C to 140°C.
The present invention also provides a process for the preparation of the compound formula(V)
Figure imgf000010_0001
Wherein the process comprises reacting (E)-N,N'-((lE,3E)-penta-l,3-diene-l-yl-5- ylidene)dianiline or hydrochloride of compound formula (VI)
Figure imgf000010_0002
with acetic an-hydride in presence of organic base.
The preparation of compound of formula(V) reaction is carried out in an organic base such as primary amine, secondary, tertiary amine, methyl amine, ethyl amine, dimethyl amine, triethyl amine, preferably triethyl amine.
The solvent can also be selected from chlorinated solvent such as methylene dichloride, ethylene dichloride, preferably solvent is methylene dichloride.
The temperature range for carrying out the preparation of compound of formula V is from about 0°C to about 30°C, preferably a temperature range from 0°C to 5°C.
Throughout the description and claims the word "comprise" and variations of the word are not intended to exclude other technical features, additives, components, or steps. The content of the abstract of the present application is incorporated herein as reference. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples are provided by way of illustration, and is not intended to be limiting of the present invention.
Example - 1
Preparation of 4-(l,l,2-trimethyl-lH-benzo[e]indolium-3-yl)butane-l-sulfonate l,l,2-trimethyl-lH-benzo[e]indole (100 gm, 1.0 equivalent) was suspended in sulfolane (100 ml, 1.0 vol) and 1,4-Buane sultone was added and mixture was heated to 120-130°C for 3-4hrs, upon cooling to RT (Room temperature) add dichloromethane and stir for 4- 5hrs at 25-30°C. The mixture was filtered and the resulting solid was washed with dichloromethane. dried under vacuum and analyzed by HPLC (High performance liquid chromatography) (153g, 92.0 percent). Having HPLC more than 98.0%
Yield: 153 gm
Chromatographic Purity (by HPLC): >98 (% area), Example - 2
Preparation of N-phenyl-N-((lE,3E,5E)-5-(phenylimino)penta-l,3-dienyl)acetamide
A solution of acetic anhydride (32.4g, 3.6 equivalent) was added to a cooled (0-5 °C), stirred suspension of N-((l£,3£',5Z)-5-(phenylimino)penta-l,3-dien-l-yl)benzen aminium chloride ( 25g, 1.0 equivalent) and triethylamine (28.3g, 4.47 equivalent) in CH2CI2 (500 mL). The resulting clear solution was stirred for another 3h at RT (Room temperature). Add water and stir for 5min, separated dichloromethane and concentrated under high vacuum. The residue containing N-phenyl-N-((l£,3£',5Z)-5-(phenylimino)penta-l,3-dien- l-yl)acetamide to yield the title compound as an oily residue.
Yield: 25-26 gm (Oily liquid)
Chromatographic Purity (by TLC): >95 (% area),
Example - 3
Preparation of Indocyanine Green
Charge methanol to the assembly at 25-30°C and then charge 4-(l,l,2-trimethyl-lH- benzo[e]indolium-3-yl)butane-l-sulfonate(56.17g 1.95equivalennt) and anhydrous sodium acetate(35.1g, 2.6 Equivalent) stir solution for 5min, then heat to reflux (65- 70°C) and maintain for 15-30min. Then added solution of N-phenyl-N-((lE,3E,5E)-5- (phenylimino)penta-l,3-dienyl)acetamide (25gm) in methanol (25ml) at reflux temperature(65-70°C). Reaction progress monitored by TLC (Thin layer chromatography) or HPLC .4-(l,l,2-trimethyl-lH-benzo[e]indolium-3-yl)butane-l- sulfonate NMT (Not More Than) -1.0%. After completion of reaction cool to 25-30°C and Charge 1000ml ethyl acetate and stir for 6 hrs at 25-30°C. Filter and wash with 50ml ethyl acetate. The desired product was obtained as a green colour crystaline powder (46- 50.5gm, 80%). Having HPLC purity more than >98.0%.
Purification of Indocyanine Green
Example :1
Add DM 315ml water to the assembly at 25-30°C and then add 45g Indocyanine green (1.0 equivalent), heat to 55-60°C. And add 900ml acetone and reflux for lhr.gradually cool to RT (Room temperature)and stir for 12hrs at 25-30°C. Filter and wash with acetone. The desired product was obtained as a green colour crystaline powder (25 to 35gm). Having HPLC purity more than >99.0%. XRPD pattern of powder diffractogram of Indocyanine green (FIG. I).
Example:2
Add DM (DE-mineralization water) 315ml water to the assembly at 25-30°C and then add 45g Indocyanine green (1.0 equivalent) and sodium iodide(0.9g,2.0%w/w), heat to 55-60°C.and add 900ml acetone and reflux for lhr.gradually cool to RT (Room temperature) and stir for 12hrs at 25-30°C. Filter and wash with acetone The desired product was obtained as a green color crystalline powder (25 to 35gm). Having HPLC purity more than >99.0%.
Example:3
Add acetonitrile to the assembly at 25-30°C and then add 45g Indocyanine green (1.0 equivalent), heat to 55-60°C. And reflux for lhr.gradually cool to RT (Room temperature) and stir for 2-3hrs at 25-30°C. Filter and wash with acetone. The desired product was obtained as a green colour crystaline powder (25 to 35gm). Having HPLC purity more than >99.0%.

Claims

1. An improved process for preparation of Indocyanine green of Formula (I) having high purity,
Figure imgf000013_0001
wherein the process comprises steps of:
a) reacting l,l,2-trimethy -lH-benzo[e] indole of Formula (II)
Figure imgf000013_0002
with 1,4-butane sultone of Formula III)
Figure imgf000013_0003
in boiling solvent to give 4-(l,l,2-trimethyl-lH-benzo[e]indolium-3-yl)butane-l- sulfonate of Formula (IV);
Figure imgf000013_0004
b) condensing 4-(l,l,2-trimethyl-lH-benzo[e]indolium-3-yl)butane-l-sulfonate of Formula(IV)
Figure imgf000014_0001
and N-phenyl-N- -5-(phenylimino)penta-l,3-dienyl)acetamide of formula(V)
Figure imgf000014_0002
in presence of sodium acetate and an alcohol; and
c) extracting the title compound formula(I) with an ester solvent.
2) The process according to claim 1, wherein preparation of compound of formula V comprises
Figure imgf000014_0003
reacting (E)-N,N'-((lE,3E)-penta-l,3-diene-l-yl-5-ylidene)dianiline or hydrochloride of compound of formula (VI) with an acetic an-hydride in presence of an organic base.
Figure imgf000014_0004
3) The process according to claim 1, wherein the solvent in step-(a) is sulfolene, toluene, xylene or silicone oil. 4) The process according to claim 1, wherein the reaction in step-(a) is performed at a temperature range from about 110°C to about 150°C, preferably a temperature range from about 120°C to aboutl40°C.
5) The process according to claim 1, where the reaction in step-(b) is performed at a temperature range from about 50°C to about 90°C, preferably a temperature range from about 60°C to about70°C. 6) The process according to claim 1, wherein the alcohol in step-(b) is selected from methanol, ethanol, and isopropanol, preferably methanol
7) The process according to claim 1, wherein the ester solvent in step-(c) is methyl acetate or ethyl acetate, preferably ethyl acetate.
8) The process according to claim 1, wherein the process comprises a further step of purification.
9) The process according to claim 8, wherein the purification is carried out in a solvent selected from Q to C5 alcohols.
10) The process according to claim 8, wherein the purification is carried out in ketonic solvents like acetone and acetonitrile with water. 11) The process according to claim 2, wherein the solvent is a chlorinated solvent.
12) The process according to claim 11, wherein the chlorinated solvent is methylene dichloride or ethylene dichloride, preferably methylene dichloride. 13) The process according to claim 2, wherein the wherein the reaction is performed at a temperature range from about 50°C to about 90°C, preferably temperature range from about 60°C to about70°C. 14) The process according to claim 2, wherein the organic base is methyl amine, dimethyl amine, triethyl amine, preferably triethyl amine 15) A stable Amorphous form of Indocyanine green of Formula(I) characterized by X-ray powder diffraction (XRPD) pattern.
16) A process for the preparation of Indocyanine green substantially as herein described with reference to the examples.
PCT/IB2016/057178 2015-12-01 2016-11-29 An improved process for the preparation of indocyanine green Ceased WO2017093889A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
US15/780,555 US10287436B2 (en) 2015-12-01 2016-11-29 Process for the preparation of indocyanine green
EP16870081.3A EP3383436B1 (en) 2015-12-01 2016-11-29 An improved process for the preparation of indocyanine green
AU2016362673A AU2016362673A1 (en) 2015-12-01 2016-11-29 An improved process for the preparation of indocyanine green
DK16870081.3T DK3383436T3 (en) 2015-12-01 2016-11-29 Improved process for the preparation of indocyanine green
KR1020187018918A KR102786409B1 (en) 2015-12-01 2016-11-29 Method for producing improved indocyanine green
CA3007062A CA3007062A1 (en) 2015-12-01 2016-11-29 An improved process for the preparation of indocyanine green
JP2018548295A JP2018538428A (en) 2015-12-01 2016-11-29 Improved process for producing indocyanine green

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN4536MU2015 2015-12-01
IN4536/MUM/2015 2015-12-01

Publications (1)

Publication Number Publication Date
WO2017093889A1 true WO2017093889A1 (en) 2017-06-08

Family

ID=58796411

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2016/057178 Ceased WO2017093889A1 (en) 2015-12-01 2016-11-29 An improved process for the preparation of indocyanine green

Country Status (8)

Country Link
US (1) US10287436B2 (en)
EP (1) EP3383436B1 (en)
JP (1) JP2018538428A (en)
KR (1) KR102786409B1 (en)
AU (1) AU2016362673A1 (en)
CA (1) CA3007062A1 (en)
DK (1) DK3383436T3 (en)
WO (1) WO2017093889A1 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190337896A1 (en) * 2018-05-02 2019-11-07 Biophore India Pharmaceuticals Pvt. Ltd. PROCESS FOR THE PREPARATION OF SODIUM 4-(2-((1E,3E,5E,7Z)-7-(1,1-DIMETHYL-3-(4-SULFONATOBUTYL)-1H-BENZO[e]INDOL-2(3H)-YLIDENE) HEPTA-1,3,5-TRIENYL)-1,1-DIMETHYL-1H-BENZO[e]INDOLIUM-3-YL) BUTANE-1-SULFONATE (INDOCYANINE GREEN)
CN113332428A (en) * 2021-05-31 2021-09-03 南京诺源医疗器械有限公司 Application of small molecule based on indole tricarbocyanine structure in preparation of tumor photothermal treatment medicine
WO2022194734A1 (en) 2021-03-17 2022-09-22 Provepharm Life Solutions Stable formulations of indocyanine green
WO2022194733A2 (en) 2021-03-17 2022-09-22 Provepharm Life Solutions Stable formulations of indocyanine green
WO2022194731A1 (en) 2021-03-17 2022-09-22 Provepharm Life Solutions Stable formulations of indocyanine green
WO2023213805A1 (en) 2022-05-06 2023-11-09 Provepharm Life Solutions Crystalline indocyanine green and method for the production thereof

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10738192B2 (en) * 2015-12-01 2020-08-11 Dishman Carbogen Amcis Limited Process for the preparation of indigo carmine
CN110885570B (en) * 2019-12-16 2021-05-25 常州工程职业技术学院 Preparation method of near-infrared dye
CN112469698B (en) * 2020-07-28 2023-05-02 北京数字精准医疗科技有限公司 Preparation method of indocyanine green triethylamine salt
WO2022115980A1 (en) * 2020-12-01 2022-06-09 珠海市迪谱医疗科技有限公司 Method for refining indocyanine green
IT202100006794A1 (en) * 2021-03-22 2022-09-22 Icrom Srl PROCESS FOR PREPARING INDOCYANINE GREEN
CA3208002A1 (en) * 2021-03-22 2022-09-29 Pierfrancesco Morosini Solid composition of indocyanine green and sodium fluorescein
KR102635160B1 (en) 2021-06-14 2024-02-13 농심태경 주식회사 Plant cheese-alternatives, and a process for preparing plant cheese-alternatives containing fermented almond protein and enzyme reacton product of legume protein as main components
EP4543990A1 (en) * 2022-06-23 2025-04-30 The Children's Medical Center Corporation Indocyanine green (icg) modification for treatment of liver cancer

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2895955A (en) 1957-06-05 1959-07-21 Eastman Kodak Co Tricarbocyanine infrared absorbing dyes
US5750722A (en) 1993-09-17 1998-05-12 Societe D'etudes Et De Recherches Biologiques Method for the preparation of high purity substituted benz E! indoles and the alkaline salts thereof
WO2007120579A2 (en) 2006-04-10 2007-10-25 Carestream Health, Inc. Loaded latex optical molecular imaging probes
US20090069573A1 (en) 2005-06-01 2009-03-12 Pulsion Medical Systems Ag Method for the purification of betaines
WO2014165216A1 (en) 2013-03-12 2014-10-09 The Trustees Of The University Of Pennsylvania Diagnosing and treating cancer
CN104130178A (en) * 2014-06-30 2014-11-05 辽宁天医生物制药股份有限公司 Industrialized synthesis method of medicinal indocyanine green
WO2014192972A1 (en) 2013-05-30 2014-12-04 Canon Kabushiki Kaisha Macrophage identification agent, and identification method, sorting method, evaluation method, screening method and kit using the macrophage identifier agent

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000095758A (en) * 1998-09-18 2000-04-04 Schering Ag Near-infrared fluorescent contrast agent and fluorescent contrast method
ATE435262T1 (en) * 1999-07-02 2009-07-15 Visen Medical Inc FLUORESCENT CYANINE LABELS WITH A SULPHAMIDO BRIDGE
FR2889700B1 (en) * 2005-08-11 2012-11-23 Synthinnove Lab MARKERS, METHOD FOR PRODUCING THE SAME, AND APPLICATIONS THEREOF
US9329185B2 (en) * 2013-03-15 2016-05-03 University Of Massachusetts Sulfonate compounds

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2895955A (en) 1957-06-05 1959-07-21 Eastman Kodak Co Tricarbocyanine infrared absorbing dyes
US5750722A (en) 1993-09-17 1998-05-12 Societe D'etudes Et De Recherches Biologiques Method for the preparation of high purity substituted benz E! indoles and the alkaline salts thereof
US20090069573A1 (en) 2005-06-01 2009-03-12 Pulsion Medical Systems Ag Method for the purification of betaines
WO2007120579A2 (en) 2006-04-10 2007-10-25 Carestream Health, Inc. Loaded latex optical molecular imaging probes
WO2014165216A1 (en) 2013-03-12 2014-10-09 The Trustees Of The University Of Pennsylvania Diagnosing and treating cancer
WO2014192972A1 (en) 2013-05-30 2014-12-04 Canon Kabushiki Kaisha Macrophage identification agent, and identification method, sorting method, evaluation method, screening method and kit using the macrophage identifier agent
CN104130178A (en) * 2014-06-30 2014-11-05 辽宁天医生物制药股份有限公司 Industrialized synthesis method of medicinal indocyanine green

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM [o] 27 March 2005 (2005-03-27), "Substance Record for SID", XP055544619, retrieved from Pubchem Compound Database accession no. 967. *
KUNDU, KOUSIKKNIGHT, SARAH FWILLETT, NICKLEE, SUNGMUNTAYLOR, W. ROBERTMURTHY, NIREN, ANGEWANDTE CHEMIE, INTERNATIONAL EDITION, vol. 48, 2009, pages 299 - 303
WANG, DUNJIN, WENSHUQIN, ENWEIWANG, SHUOBING, LI, PENG ZHONGGUO YIYAO GONGYE ZAZHI, vol. 37, 2006, pages 584 - 585

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190337896A1 (en) * 2018-05-02 2019-11-07 Biophore India Pharmaceuticals Pvt. Ltd. PROCESS FOR THE PREPARATION OF SODIUM 4-(2-((1E,3E,5E,7Z)-7-(1,1-DIMETHYL-3-(4-SULFONATOBUTYL)-1H-BENZO[e]INDOL-2(3H)-YLIDENE) HEPTA-1,3,5-TRIENYL)-1,1-DIMETHYL-1H-BENZO[e]INDOLIUM-3-YL) BUTANE-1-SULFONATE (INDOCYANINE GREEN)
WO2022194734A1 (en) 2021-03-17 2022-09-22 Provepharm Life Solutions Stable formulations of indocyanine green
WO2022194733A2 (en) 2021-03-17 2022-09-22 Provepharm Life Solutions Stable formulations of indocyanine green
WO2022194731A1 (en) 2021-03-17 2022-09-22 Provepharm Life Solutions Stable formulations of indocyanine green
CN113332428A (en) * 2021-05-31 2021-09-03 南京诺源医疗器械有限公司 Application of small molecule based on indole tricarbocyanine structure in preparation of tumor photothermal treatment medicine
WO2022252599A1 (en) * 2021-05-31 2022-12-08 南京诺源医疗器械有限公司 Use of small molecule based on indole tricarbocyanine structure in preparation of tumor photothermal therapy drug
WO2023213805A1 (en) 2022-05-06 2023-11-09 Provepharm Life Solutions Crystalline indocyanine green and method for the production thereof
EP4523709A2 (en) 2022-05-06 2025-03-19 Provepharm Life Solutions Crystalline indocyanine green and method for the production thereof

Also Published As

Publication number Publication date
EP3383436B1 (en) 2023-08-30
EP3383436A4 (en) 2019-07-03
US10287436B2 (en) 2019-05-14
AU2016362673A1 (en) 2018-06-28
US20180346728A1 (en) 2018-12-06
KR102786409B1 (en) 2025-03-24
KR20180087413A (en) 2018-08-01
EP3383436A1 (en) 2018-10-10
JP2018538428A (en) 2018-12-27
CA3007062A1 (en) 2017-06-08
DK3383436T3 (en) 2023-11-20

Similar Documents

Publication Publication Date Title
EP3383436B1 (en) An improved process for the preparation of indocyanine green
JP7532371B2 (en) THRβ receptor agonist compounds, and methods for producing and using same
US9382240B2 (en) Crystalline salts of a potent HCV inhibitor
US10538507B2 (en) Preparation process for high-purity dabigatran etexilate
US10196400B2 (en) Process for the preparation of lurasidone and its intermediate
EP2363395A2 (en) Process for preparation of celecoxib crystalline form
CN1064809A (en) Medicament
US6071916A (en) HIV protease inhibitor
JP7784434B2 (en) Preparation process of indocyanine green
US20230365535A1 (en) Compounds and method for preparing the same
JP2004528380A (en) Method for producing zolpidem
US8039621B2 (en) Process for preparing anhydrous Aripirazole type I
JPH0353314B2 (en)
EP0545170A1 (en) Quinolylmethoxyphenylacetamides
JP2020105506A (en) Fluorescent labeling agent and phosphorus phthalocyanine
ES3029434T3 (en) A fxr small molecule agonist, the preparation and use thereof
JP6471123B2 (en) Triarylmethane composition, staining composition for ophthalmic staining
CN109776521A (en) A kind of quinine class compound and preparation method thereof containing quaternary ammonium group
US20240083884A1 (en) Compounds and method for preparing the same
AU730245B2 (en) Sulfate salt of an HIV protease inhibitor having an improved oral absorption and bioavailability
JPS5984870A (en) Benzyl ether of phenolmannich base and manufacture
WO2024074080A1 (en) Anti-influenza virus derivative and use thereof
CN120271493A (en) Indocyanine green medicine impurity and preparation method and application thereof
US20230295141A1 (en) Fxr small molecule agonist, the preparation and use thereof
JPH05247015A (en) New piperazine derivative

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16870081

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3007062

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2018548295

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2016362673

Country of ref document: AU

Date of ref document: 20161129

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 20187018918

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 1020187018918

Country of ref document: KR

Ref document number: 2016870081

Country of ref document: EP