WO2016079697A1 - Process for the preparation of an intermediate of daclatasvir dihydrochloride - Google Patents
Process for the preparation of an intermediate of daclatasvir dihydrochloride Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- the present invention provides an improved process for the preparation of 5,5'- biphenyl-4,4'-diylbis ⁇ 2-[(2S)-pyrrolidin-2-yl]-lH-imidazole ⁇ of Formula II and its use the preparation of daclatasvir dih drochloride.
- Daclatasvir dihydrochloride is chemically designated as methyl ((lS)-l-(((2S)-2 (5-(4'-(2-((2S)-l-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)- lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl)-l-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate dihydrochloride having the structure depicted by Formula I.
- Daclatasvir dihydrochloride is indicated for the treatment of hepatitis C in adults.
- U.S. Patent No. 8,329,159 discloses a process for the preparation of daclatasvir by reacting N-(methoxycarbonyl)-L-valine, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 5,5'-(4,4'-biphenyldiyl)bis(2-((2S)-2-pyrrolidinyl)-lH-imidazole).
- 7,728,027 discloses a process for the preparation of 5,5'-biphenyl- 4,4'-diylbis ⁇ 2-[(2S)-pyrrolidin-2-yl]-lH-imidazole ⁇ of Formula II by reacting 1, 1'- (biphenyl-4,4'-diyl)diethanone with bromine, followed by condensation with l-(tert- butoxycarbonyl)-L-proline.
- This process makes use of 6 different solvents and requires the isolation of intermediates.
- U.S. Patent No. 8,629,171 discloses a crystalline and substantially pure form N-2 of daclatasvir dihydrochloride salt.
- the present invention provides a process for the preparation of 1, ⁇ -biphenyl-4,4 '- diylbis(2-bromoethanone) of Formula III,
- the compound of formula III is further converted into 5,5'-biphenyl-4,4'- diylbis ⁇ 2-[(2S)-pyrrolidin-2-yl]-lH-imidazole ⁇ of Formula II with or without isolating intermediate compounds thereof.
- the present invention also provides a process for the preparation of 5,5'-biphenyl- 4,4'-diylbis ⁇ 2-[(2S)-pyrrolidin-2-yl]-lH-imidazole ⁇ of Formula II, a useful synthetic intermediate for the preparation of daclatasvir dihydrochloride, comprising the steps of: i) treating 1,1 ' -biphenyl -4,4 ' -diyldiethanone of Formula IV with N- bromosuccinimide in the presence of an alcoholic solvent to obtain 1, 1 '- biphenyl-4,4'-diylbis(2-bromoethanone) of Formula III;
- step iii) treating the reaction mixture obtained in step ii) with ammonium acetate; iv) treating the reaction mixture obtained in step iii), with or without isolation, with concentrated hydrochloric acid;
- treating includes adding, dissolving, slurrying, stirring, and combinations thereof.
- the term "isolating” includes precipitation, cooling, filtration, concentration, centrifugation, and combinations thereof, followed by drying. Drying may be carried out under reduced pressure, vacuum tray drying, or air drying.
- alcoholic solvent includes primary, secondary, and tertiary alcohols having from one to six carbon atoms. Examples of alcoholic solvents include methanol, ethanol, n-propanol, isopropanol, and butanol.
- l-(Tert-butoxycarbonyl)-L-proline is also known as N-boc-L-proline.
- organic base includes hydroxides, carbonates, and bicarbonates of alkali or alkaline earth metals and the like.
- hydroxides, carbonates, and bicarbonates of alkali or alkaline earth metals include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate.
- a first aspect of the present invention provides a process for the preparation of l,r-biphenyl-4,4'-diylbis(2-bromoethanone) of Formula III,
- the compound of formula III is further converted into 5,5'-biphenyl-4,4'- diylbis ⁇ 2-[(2S)-pyrrolidin-2-yl]-lH-imidazole ⁇ of Formula II with or without isolating intermediate compounds thereof.
- N-bromosuccinimide is added repeatedly after an interval of time for better yield.
- N-bromosuccinimide is added hourly in 3 to 4 portions.
- the alcoholic solvent is selected from methanol, ethanol, n-propanol, isopropanol, and butanol.
- l,r-biphenyl-4,4'-diylbis(2-bromoethanone) of Formula III is converted into 5,5'-biphenyl-4,4'-diylbis ⁇ 2-[(2S)-pyrrolidin-2-yl]-lH-imidazole ⁇ of Formula II with or without isolating the in-between prepared 2,2'-[biphenyl-4,4'-diylbis(2- oxoethane-2, l-diyl)] ⁇ , ⁇ -di-tert-butyl (2S, S)di -pyrrolidine- 1,2-dicarboxylate of Formula V:
- l,r-biphenyl-4,4'-diyldiethanone of Formula IV is added into methanol and treated with N-bromosuccinimide.
- the temperature of the reaction mixture is raised to about 50°C to about 55°C and the reaction mixture is stirred for about one hour. This process is repeated 3 to 4 times.
- the reaction mixture is stirred until completion of the reaction.
- the reaction mixture is filtered, washed, and dried to obtain 1, r-biphenyl-4,4'-diylbis(2-bromoethanone) of Formula III.
- the compound of Formula III is treated with N-boc-L-proline in the presence of potassium carbonate to obtain 2,2'- [biphenyl-4,4'-diylbis(2-oxoethane-2, 1 -diyl)] 1 , 1 '-di-fert-butyl (2,S',2' 1 S)di-pyrrolidine- 1 ,2- dicarboxylate of Formula V, which is treated with ammonium acetate to convert into di- fert-butyl (25 , ,2 , 5)-2,2 , -[biphenyl-4,4 , -diylbis( lH-imidazole-5,2-diyl)]dipyrrolidine- 1- carboxylate of Formula VI.
- the compound of Formula VI is treated with concentrated hydrochloric acid to obtain 5,5'-biphenyl-4,4'-diylbis ⁇ 2-[(2S)-pyrrolidin-2-yl]-lH- imidazole ⁇ of Formula II, which is finally isolated.
- a second aspect of the present invention provides a process for the preparation of 5,5'-biphenyl-4,4'-diylbis ⁇ 2-[(2S)-pyrrolidin-2-yl]-lH-imidazole ⁇ of Formula II, a useful synthetic intermediate for the preparation of daclatasvir dihydrochloride, comprising the steps of:
- 5,5'-biphenyl-4,4'-diylbis ⁇ 2-[(2S)- pyrrolidin-2-yl]-lH-imidazole ⁇ of Formula II can be used as an intermediate for the preparation of daclatasvir dihydrochloride.
- N-bromosuccinimide is added repeatedly after a regular interval of time for better yield.
- N-bromosuccinimide is added hourly while stirring the reaction mixture in 3 to 4 portions.
- the alcoholic solvent is selected from methanol, ethanol, n-propanol, isopropanol, and butanol.
- the inorganic base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate.
- reaction mixture obtained in step iii), with or without isolation is treated with concentrated hydrochloric acid.
- isolation of 5,5'-biphenyl-4,4'-diylbis ⁇ 2-[(2S)-pyrrolidin- 2-yl]-lH-imidazole ⁇ of Formula II may be carried out by purification, precipitation, filtration, or concentration.
- purification is carried out by treating the reaction mixture with carbon.
- the precipitation is carried out by treating the reaction mixture with a basic reagent, for example, an ammonia solution.
- the filtration can be carried out by using filter media and can be associated with washing with water.
- the concentration can be performed by drying under vacuum.
- l,r-biphenyl-4,4'-diyldiethanone of Formula IV is added into methanol and treated with N-bromosuccinimide.
- the temperature of reaction mixture is raised to about 50°C to about 55°C and the reaction mixture is stirred for one hour. This process is repeated 3 to 4 times.
- the reaction mixture is stirred until completion.
- the reaction mixture is filtered, washed, and dried to obtain l, l'-biphenyl-4,4'-diylbis(2- bromoethanone) of Formula III.
- the compound of Formula III is treated with N-boc-L- proline in the presence of potassium carbonate to obtain 2,2'-[biphenyl-4,4'-diylbis(2- oxoethane-2, l-diyl)] l,l'-di-fert-butyl (2S,2'S)di -pyrrolidine- 1,2-dicarboxylate of Formula V, which is treated with ammonium acetate to convert into di-fert-butyl ⁇ 2S,TS)-2, - [biphenyl-4,4'-diylbis(lH-imidazole-5,2-diyl)]dipyrrolidine-l-carboxylate of Formula VI.
- the compound of Formula VI is treated with concentrated hydrochloric acid to obtain 5,5'-biphenyl-4,4'-diylbis ⁇ 2-[(2S)-pyrrolidin-2-yl]-lH-imidazole ⁇ of Formula II, which is finally isolated.
- Example 1 Preparation of 1 J '-biphenyl-4.4'-diylbis(2-bromoethanone) of Formula III l,r-Biphenyl-4,4'-diyldiethanone (50 g, Formula IV) was added into methanol (500 mL) and stirred for 15 minutes at 25 °C, followed by the addition of N- bromosuccinimide (50 g). The temperature of the reaction mixture was raised to 50°C to 55°C, and the mixture was stirred for one hour. N-bromosuccinimide (20 g) was added to the reaction mixture at 50°C to 55°C, and the mixture was stirred for another one hour.
- N- bromosuccinimide (20 g) was again added to the reaction mixture at 50°C to 55°C, and the mixture was stirred for one hour.
- N-bromosuccinimide (20 g) was further added to the reaction mixture at 50°C to 55°C, and the mixture was stirred for 4 hours to 6 hours.
- the reaction mixture was cooled to 25 °C.
- the reaction mixture was filtered, then washed with methanol (150 mL), and then dried.
- the wet cake obtained was mixed with aqueous sodium thiosulphate solution (10% w/v, 400 mL) and then stirred for 30 minutes to 60 minutes at 25°C.
- the resultant mixture was filtered, then washed with water (200 mL) and methanol (150 mL), and then dried under vacuum (5 mmHg - 20 mmHg) at 50°C to 55°C for 18 hours to obtain the title product.
- Step 1 Preparation of 2,2'-[biphenyl-4,4'-diylbis(2-oxoethane-2,l-diyl)]
- Step 2 Preparation of di-teri-butyl (2S,2'S)-2,2'- [biphenyl-4,4'-diylbis(lH-imidazole- 5,2-diyl)]dipyrrolidine-l-carboxylate:
- Step 3 Preparation of 5,5'-biphenyl-4,4'-diylbis ⁇ 2-[(2S)-pyrrolidin-2-yl]-lH- imidazole ⁇ :
- step 2 The reaction mixture obtained in step 2 was cooled to 60°C to 65 °C and concentrated hydrochloric acid (400 mL) was added slowly over a period of 2.5 hours. The reaction mixture was stirred for 3 hours to 4 hours at 60°C to 65°C. On completion of reaction, the reaction mixture was cooled to 25°C and de-ionized water (200 mL) was added. The organic layer was discarded, and carbon (5 g) was added to the aqueous layer. The mixture was stirred for an hour at 25°C, then filtered through a Hyflo ® bed, and then washed with water (2 ⁇ 150 mL).
- the aqueous filtrate was added slowly over a period of 60 minutes to an aqueous ammonia solution (25%, 800 mL) at 10°C to 30°C.
- the reaction mixture was stirred for 3 hours at 25 °C, then filtered, and then washed with water (3 x 500 mL) to obtain a solid residue.
- the solid residue was dried under vacuum (5 mmHg - 20 mmHg) at 25 °C for 2 hours to 3 hours, followed by drying under vacuum (5 mmHg - 20 mmHg) at 45°C to 50°C for about 15 hours to about 20 hours to obtain the title product. Dry weight: 104.5g
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Abstract
The present invention provides an improved process for the preparation of 5,5'- biphenyl-4,4'-diylbis{2-[(2S)-pyrrolidin-2-yl]-1H-imidazole}of Formula II and its use for the preparation of daclatasvir dihydrochloride.
Description
PROCESS FOR THE PREPARATION OF AN INTERMEDIATE OF DACLATASVIR DIHYDROCHLORIDE
Field of the Invention
The present invention provides an improved process for the preparation of 5,5'- biphenyl-4,4'-diylbis{2-[(2S)-pyrrolidin-2-yl]-lH-imidazole}of Formula II and its use the preparation of daclatasvir dih drochloride.
Formula II
Background of the Invention
Daclatasvir dihydrochloride is chemically designated as methyl ((lS)-l-(((2S)-2 (5-(4'-(2-((2S)-l-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)- lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl)-l-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate dihydrochloride having the structure depicted by Formula I.
Formula I
Daclatasvir dihydrochloride is indicated for the treatment of hepatitis C in adults.
U.S. Patent No. 8,329,159 discloses a process for the preparation of daclatasvir by reacting N-(methoxycarbonyl)-L-valine, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 5,5'-(4,4'-biphenyldiyl)bis(2-((2S)-2-pyrrolidinyl)-lH-imidazole). This patent also describes the preparation of 5,5'-biphenyl-4,4'-diylbis{2-[(2S)-pyrrolidin-2- yl]-lH-imidazole} of Formula II comprising a step of treating l, l '-(biphenyl-4,4'- diyl)diethanone with bromine.
U.S. Patent No. 7,728,027 discloses a process for the preparation of 5,5'-biphenyl- 4,4'-diylbis{2-[(2S)-pyrrolidin-2-yl]-lH-imidazole} of Formula II by reacting 1, 1'- (biphenyl-4,4'-diyl)diethanone with bromine, followed by condensation with l-(tert- butoxycarbonyl)-L-proline. This process makes use of 6 different solvents and requires the isolation of intermediates.
U.S. Patent No. 8,629,171 discloses a crystalline and substantially pure form N-2 of daclatasvir dihydrochloride salt.
There is still a need for an improved and simple process for the preparation of 5,5'- biphenyl-4,4'-diylbis{2-[(2S)-pyrrolidin-2-yl]-lH-imidazole} of Formula II which can reduce the burden of isolation, crystallization, and purification of intermediates. The present invention provides a safe, cost-effective, efficient, and industrially feasible process which avoids the use of hazardous reagents and a tedious work up procedure for the preparation of 5,5'-biphenyl-4,4'-diylbis{2-[(2S)-pyrrolidin-2-yl]-lH-imidazole} of Formula II, an intermediate of daclatasvir dihydrochloride.
Summary of the Invention
The present invention provides a process for the preparation of 1, Γ -biphenyl-4,4 '- diylbis(2-bromoethanone) of Formula III,
Formula III
comprising treating 1, 1 ' -biphenyl-4,4 '-diyldiethanone of Formula IV with N- bromosuccinimide in the presence of an alcoholic solvent.
Formula IV
The compound of formula III is further converted into 5,5'-biphenyl-4,4'- diylbis{2-[(2S)-pyrrolidin-2-yl]-lH-imidazole} of Formula II with or without isolating intermediate compounds thereof.
Formula II
The present invention also provides a process for the preparation of 5,5'-biphenyl- 4,4'-diylbis{2-[(2S)-pyrrolidin-2-yl]-lH-imidazole} of Formula II, a useful synthetic intermediate for the preparation of daclatasvir dihydrochloride, comprising the steps of: i) treating 1,1 ' -biphenyl -4,4 ' -diyldiethanone of Formula IV with N- bromosuccinimide in the presence of an alcoholic solvent to obtain 1, 1 '- biphenyl-4,4'-diylbis(2-bromoethanone) of Formula III;
ii) condensing 1,1 ' -biphenyl-4,4 ' -diylbis(2-bromoethanone) of Formula III with l-(tert-butoxycarbonyl)-L-proline in the presence of an inorganic base and toluene;
iii) treating the reaction mixture obtained in step ii) with ammonium acetate; iv) treating the reaction mixture obtained in step iii), with or without isolation, with concentrated hydrochloric acid;
v) isolating 5,5'-biphenyl-4,4'-diylbis{2-[(2S)-pyrrolidin-2-yl]-lH-imidazole} of Formula II.
Detailed Description of the Invention
Various embodiments and variants of the present invention are described hereinafter.
The term "about," as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value.
The term "treating" includes adding, dissolving, slurrying, stirring, and combinations thereof.
The term "isolating" includes precipitation, cooling, filtration, concentration, centrifugation, and combinations thereof, followed by drying. Drying may be carried out under reduced pressure, vacuum tray drying, or air drying.
The term "alcoholic solvent" includes primary, secondary, and tertiary alcohols having from one to six carbon atoms. Examples of alcoholic solvents include methanol, ethanol, n-propanol, isopropanol, and butanol.
l-(Tert-butoxycarbonyl)-L-proline is also known as N-boc-L-proline.
The term "inorganic base" includes hydroxides, carbonates, and bicarbonates of alkali or alkaline earth metals and the like. Examples of hydroxides, carbonates, and bicarbonates of alkali or alkaline earth metals include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate.
A first aspect of the present invention provides a process for the preparation of l,r-biphenyl-4,4'-diylbis(2-bromoethanone) of Formula III,
Formula III
comprising treating l,r-biphenyl-4,4'-diyldiethanone of Formula IV with N- bromosuccinimide in the presence of an alcoholic solvent.
Formula IV
The compound of formula III is further converted into 5,5'-biphenyl-4,4'- diylbis{2-[(2S)-pyrrolidin-2-yl]-lH-imidazole} of Formula II with or without isolating intermediate compounds thereof.
According to one embodiment of this aspect, N-bromosuccinimide is added repeatedly after an interval of time for better yield.
In another embodiment, N-bromosuccinimide is added hourly in 3 to 4 portions.
In another embodiment, the alcoholic solvent is selected from methanol, ethanol, n-propanol, isopropanol, and butanol.
In another embodiment, l,r-biphenyl-4,4'-diylbis(2-bromoethanone) of Formula III is converted into 5,5'-biphenyl-4,4'-diylbis{2-[(2S)-pyrrolidin-2-yl]-lH-imidazole} of Formula II with or without isolating the in-between prepared 2,2'-[biphenyl-4,4'-diylbis(2-
oxoethane-2, l-diyl)] Ι,Γ-di-tert-butyl (2S, S)di -pyrrolidine- 1,2-dicarboxylate of Formula V:
Formula V
and di-fert-butyl (25',2'5)-2,2'-[biphenyl-4,4'-diylbis(lH-imidazole-5,2-diyl)]dipyrrolidine- 1-carboxylate of Formula VI:
Formula VI
Accordingly, l,r-biphenyl-4,4'-diyldiethanone of Formula IV is added into methanol and treated with N-bromosuccinimide. The temperature of the reaction mixture is raised to about 50°C to about 55°C and the reaction mixture is stirred for about one hour. This process is repeated 3 to 4 times. The reaction mixture is stirred until completion of the reaction. The reaction mixture is filtered, washed, and dried to obtain 1, r-biphenyl-4,4'-diylbis(2-bromoethanone) of Formula III. The compound of Formula III is treated with N-boc-L-proline in the presence of potassium carbonate to obtain 2,2'- [biphenyl-4,4'-diylbis(2-oxoethane-2, 1 -diyl)] 1 , 1 '-di-fert-butyl (2,S',2'1S)di-pyrrolidine- 1 ,2- dicarboxylate of Formula V, which is treated with ammonium acetate to convert into di-
fert-butyl (25,,2,5)-2,2,-[biphenyl-4,4,-diylbis( lH-imidazole-5,2-diyl)]dipyrrolidine- 1- carboxylate of Formula VI. The compound of Formula VI is treated with concentrated hydrochloric acid to obtain 5,5'-biphenyl-4,4'-diylbis{2-[(2S)-pyrrolidin-2-yl]-lH- imidazole} of Formula II, which is finally isolated.
A second aspect of the present invention provides a process for the preparation of 5,5'-biphenyl-4,4'-diylbis{2-[(2S)-pyrrolidin-2-yl]-lH-imidazole} of Formula II, a useful synthetic intermediate for the preparation of daclatasvir dihydrochloride, comprising the steps of:
i) treating 1,1 ' -biphenyl-4,4 ' -diyldiethanone of Formula IV with N- bromosuccinimide in the presence of an alcoholic solvent to obtain 1, 1 '- biphenyl-4,4'-diylbis(2-bromoethanone) of Formula III;
ii) condensing 1,1 ' -biphenyl-4,4 ' -diylbis(2-bromoethanone) of Formula III with l-(tert-butoxycarbonyl)-L-proline in the presence of an inorganic base and toluene;
iii) treating the reaction mixture obtained in step ii) with ammonium acetate; iv) treating the reaction mixture obtained in step iii), with or without isolation, with concentrated hydrochloric acid; and
v) isolating 5,5'-biphenyl-4,4'-diylbis{2-[(2S)-pyrrolidin-2-yl]-lH-imidazole} of Formula II.
According to one embodiment of this aspect, 5,5'-biphenyl-4,4'-diylbis{2-[(2S)- pyrrolidin-2-yl]-lH-imidazole} of Formula II can be used as an intermediate for the preparation of daclatasvir dihydrochloride.
5,5' -Biphenyl-4,4 ' -diylbis {2-[(2S)-pyrrolidin-2-yl] - lH-imidazole } of Formula II can be converted to daclatasvir dihydrochloride by following the method disclosed in U.S. Patent No. 7,728,027.
In another embodiment, N-bromosuccinimide is added repeatedly after a regular interval of time for better yield.
In another embodiment, N-bromosuccinimide is added hourly while stirring the reaction mixture in 3 to 4 portions.
In another embodiment, the alcoholic solvent is selected from methanol, ethanol, n-propanol, isopropanol, and butanol.
In another embodiment, the inorganic base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate.
In another embodiment, the reaction mixture obtained in step iii), with or without isolation, is treated with concentrated hydrochloric acid.
In another embodiment, isolation of 5,5'-biphenyl-4,4'-diylbis{2-[(2S)-pyrrolidin- 2-yl]-lH-imidazole} of Formula II may be carried out by purification, precipitation, filtration, or concentration.
In general, purification is carried out by treating the reaction mixture with carbon. The precipitation is carried out by treating the reaction mixture with a basic reagent, for example, an ammonia solution. The filtration can be carried out by using filter media and can be associated with washing with water. The concentration can be performed by drying under vacuum.
Accordingly, l,r-biphenyl-4,4'-diyldiethanone of Formula IV is added into methanol and treated with N-bromosuccinimide. The temperature of reaction mixture is raised to about 50°C to about 55°C and the reaction mixture is stirred for one hour. This process is repeated 3 to 4 times. The reaction mixture is stirred until completion. The reaction mixture is filtered, washed, and dried to obtain l, l'-biphenyl-4,4'-diylbis(2- bromoethanone) of Formula III. The compound of Formula III is treated with N-boc-L- proline in the presence of potassium carbonate to obtain 2,2'-[biphenyl-4,4'-diylbis(2- oxoethane-2, l-diyl)] l,l'-di-fert-butyl (2S,2'S)di -pyrrolidine- 1,2-dicarboxylate of Formula V, which is treated with ammonium acetate to convert into di-fert-butyl {2S,TS)-2, - [biphenyl-4,4'-diylbis(lH-imidazole-5,2-diyl)]dipyrrolidine-l-carboxylate of Formula VI. The compound of Formula VI is treated with concentrated hydrochloric acid to obtain 5,5'-biphenyl-4,4'-diylbis{2-[(2S)-pyrrolidin-2-yl]-lH-imidazole} of Formula II, which is finally isolated.
The starting materials, l, -biphenyl-4,4'-diyldiethanone of Formula IV and N- boc-L-proline, are obtained from commercial sources.
While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be within the scope of the present invention.
The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.
EXAMPLES
Example 1 : Preparation of 1 J '-biphenyl-4.4'-diylbis(2-bromoethanone) of Formula III l,r-Biphenyl-4,4'-diyldiethanone (50 g, Formula IV) was added into methanol (500 mL) and stirred for 15 minutes at 25 °C, followed by the addition of N- bromosuccinimide (50 g). The temperature of the reaction mixture was raised to 50°C to 55°C, and the mixture was stirred for one hour. N-bromosuccinimide (20 g) was added to the reaction mixture at 50°C to 55°C, and the mixture was stirred for another one hour. N- bromosuccinimide (20 g) was again added to the reaction mixture at 50°C to 55°C, and the mixture was stirred for one hour. N-bromosuccinimide (20 g) was further added to the reaction mixture at 50°C to 55°C, and the mixture was stirred for 4 hours to 6 hours. On completion of the reaction, the reaction mixture was cooled to 25 °C. The reaction mixture was filtered, then washed with methanol (150 mL), and then dried. The wet cake obtained was mixed with aqueous sodium thiosulphate solution (10% w/v, 400 mL) and then stirred for 30 minutes to 60 minutes at 25°C. The resultant mixture was filtered, then washed with water (200 mL) and methanol (150 mL), and then dried under vacuum (5 mmHg - 20 mmHg) at 50°C to 55°C for 18 hours to obtain the title product.
Dry weight: 75.13 g
Yield (w/w): 90.36%
Example 2: Preparation of 5.5,-biphenyl-4.4,-diylbis{2-r(2S)-pyrrolidin-2-yll-lH- imidazole} of Formula II
butyl (2 ,2 )di-pyrrolidine-l,2-dicarboxylate:
l,r-Biphenyl-4,4'-diylbis(2-bromoethanone) (100 g, Formula III) was added into toluene (1.5 L) at 25°C. N-boc-L-proline (110 g) was added to the reaction mixture followed by the addition of potassium carbonate (70 g) at 25 °C. The temperature of the reaction mixture was raised to 90°C to 95 °C, and the mixture was stirred for 3 hours to 4
hours. On completion of reaction, the reaction mixture was cooled to 45 °C to 50°C and then filtered. The solid obtained was washed with toluene. The reaction mixture comprised of 2,2'-[biphenyl-4,4'-diylbis(2-oxoethane-2,l-diyl)] l,l'-di-fert-butyl
(2S,2'S)di -pyrrolidine- 1,2-dicarboxylate was used as such for further reaction.
Step 2: Preparation of di-teri-butyl (2S,2'S)-2,2'- [biphenyl-4,4'-diylbis(lH-imidazole- 5,2-diyl)]dipyrrolidine-l-carboxylate:
Ammonium acetate (250 g) was added to the reaction mixture obtained in Step 1 at 25°C. The temperature of the reaction mixture was raised to 90°C to 95°C, and the mixture was stirred for 18 hours. On completion of reaction, the reaction mixture was used as such for further reaction.
Step 3: Preparation of 5,5'-biphenyl-4,4'-diylbis{2-[(2S)-pyrrolidin-2-yl]-lH- imidazole}:
The reaction mixture obtained in step 2 was cooled to 60°C to 65 °C and concentrated hydrochloric acid (400 mL) was added slowly over a period of 2.5 hours. The reaction mixture was stirred for 3 hours to 4 hours at 60°C to 65°C. On completion of reaction, the reaction mixture was cooled to 25°C and de-ionized water (200 mL) was added. The organic layer was discarded, and carbon (5 g) was added to the aqueous layer. The mixture was stirred for an hour at 25°C, then filtered through a Hyflo® bed, and then washed with water (2 χ 150 mL). The aqueous filtrate was added slowly over a period of 60 minutes to an aqueous ammonia solution (25%, 800 mL) at 10°C to 30°C. The reaction mixture was stirred for 3 hours at 25 °C, then filtered, and then washed with water (3 x 500 mL) to obtain a solid residue. The solid residue was dried under vacuum (5 mmHg - 20 mmHg) at 25 °C for 2 hours to 3 hours, followed by drying under vacuum (5 mmHg - 20 mmHg) at 45°C to 50°C for about 15 hours to about 20 hours to obtain the title product. Dry weight: 104.5g
Yield (w/w): 97.2%
Claims
Formula III
comprising treating 1, 1 ' -biphenyl-4,4 ' -diyldiethanone of Formula IV with N- bromosuccinimide in the presence of an alcoholic solvent.
Formula IV
2. The process according to claim 1, wherein N-bromosuccinimide is added hourly in 3 to 4 portions.
3. The process according to claim 1, wherein the alcoholic solvent is selected from methanol, ethanol, n-propanol, isopropanol, and butanol.
4. The process according to claim 1, wherein 1, 1 ' -biphenyl-4,4 '-diy Ibis (2- bromoethanone) of Formula4 III is converted into 5,5'-biphenyl-4,4'-diylbis{2-[(2S)- pyrrolidin-2-yl]-lH-imidazole} of Formula II, with or without isolating 2,2'-[biphenyl- 4,4'-diylbis(2-oxoethane-2,l-diyl)] l, l'-di-fert-butyl (2S,2'5)(u-pyrrolidine-l,2- dicarboxylate of Formula V and di-fert-butyl (2<S',2'<S)-2,2'-[biphenyl-4,4'-diylbis(lH- imidazole-5,2-diyl)]dipyrrolidine-l-carboxylate of Formula VI.
5. A process for the preparation of 5,5'-biphenyl-4,4'-diylbis{2-[(2S)-pyrrolidin-2- yl]-lH-imidazole} of Formula II, comprising the steps of:
i) treating 1,1 ' -biphenyl-4,4 ' -diyldiethanone of Formula IV with N- bromosuccinimide in the presence of an alcoholic solvent to obtain 1,1 '- biphenyl-4,4'-diylbis(2-bromoethanone) of Formula III;
ii) condensing 1, Γ -biphenyl-4,4' -diy lbis(2-bromoethanone) of Formula III with l-(tert-butoxycarbonyl)-L-proline in the presence of an inorganic base and toluene;
iii) treating the reaction mixture obtained in step ii) with ammonium acetate;
iv) treating the reaction mixture obtained in step iii), with or without isolation, with concentrated hydrochloric acid; and
v) isolating 5,5 '-biphenyl-4,4'-diylbis{2-[(2S)-pyrrolidin-2-yl]-lH-imidazole} of Formula II.
6. The process according to claim 5, wherein N-bromosuccinimide is added hourly while stirring the reaction mixture in 3 to 4 portions.
7. The process according to claim 5, wherein the alcoholic solvent is selected from methanol, ethanol, n-propanol, isopropanol, and butanol.
8. The process according to claim 5, wherein the inorganic base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate.
9. The process according to claim 5, wherein the reaction mixture obtained in step iii) with isolation is treated with concentrated hydrochloric acid.
10. The process according to claim 5, wherein the reaction mixture obtained in step iii) without isolation is treated with concentrated hydrochloric acid.
11. The process according to claim 5, wherein the isolation of 5,5'-biphenyl-4,4'- diylbis{2-[(2S)-pyrrolidin-2-yl]-lH-imidazole} of Formula II is carried out by purification, precipitation, filtration, or concentration.
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BUCKLES ET AL.: "Comparison of N-Bromoacetamide and N-Bromosuccinimide as Brominating Agents", JOURNAL OF ORGANIC CHEMISTRY, vol. 22, 1957, pages 55 - 59 * |
RAGHAVAN ET AL.: "Allosteric Modulation of the Dopamine D2 Receptor by Pro-Leu-Gly-NH2 Peptidomimetics Constrained in Either a Polyproline II Helix or a Type II betaTurn Conformation", JOURNAL OF MEDICINAL CHEMISTRY, vol. 52, 2009, pages 2043 - 2051, XP009156256, DOI: doi:10.1021/jm801575w * |
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CN108794454A (en) * | 2017-04-27 | 2018-11-13 | 广东东阳光药业有限公司 | A kind of preparation method of imidazo ring compounds |
CN108794454B (en) * | 2017-04-27 | 2023-08-15 | 广东东阳光药业股份有限公司 | Preparation method of imidazole ring compound |
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