Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

• the present invention relates to an improved process for preparing (2R,3aR, 10Z, l laS, 12aR, 14aR)-cyclopenta[c]cyclopropa[g][l ,6]diazacyclotetradecine-12a(lH)-carboxylic acid, 2,3,3a,4,5,6,7,8,9,l la,12, 13,14,14a-tetradecahydro-2-[[7-methoxy-8-methyl-2-[4- (l-methylethyl)-2-thiazolyl]-4-quinolinyl]oxy]-5-methyl-4, 14-dioxo-, ethyl ester (or compound (2) as referred to hereinafter).
• This compound is an intermediate in the overall synthesis route of the macrocyclic compound TMC 435.
• TMC 435 is an inhibitor of NS3/4A protease which plays an important role in the replication of the hepatitis C virus.
• HCV hepatitis C virus
• liver transplantations hepatocellular carcinoma
• NQ 5,12-naphthoquinone
• IS internal standard
• reaction mixture was refluxed for 3 hours 20 minutes (total cyclization reaction time 4 hours), then cooled to room temperature, 0.5 mL of ethanolamine was added and stirred for 1 hour.
• a sample analyzed by LC-MS showed the formation of a 2: 1 mixture of the undesired macrocycle cleavage product, and the desired product.
• Example 4 The reaction mixture of Example 4 was allowed to cool to 30°C, and 0.24 g of 2-mercaptonicotinic acid (MNA) was added, followed by the addition of 25 mL of 1-butanol, and 0.2 mL of triethylamine. Analysis of this mixture after 10 minutes showed no detectable amounts of compound (2). Further 13.5 mL of triethylamine was added, and the mixture stirred overnight. Analysis of this reaction mixture showed a 12: 15 mixture of the desired compound (2) and monomeric macrocycle compound (Ill-a), wherein R 2 is CF 3 .
• MNA 2-mercaptonicotinic acid
• N-methyl ethanolamine corresponding to 182 ⁇
• one of the resulting solutions was stirred vigorously at room temperature and the other one was heated to 40°C in an easy-max.
• the reactions were monitored regularly by LC-analysis over time.
• Example 10 reaction of diethyldiallylmalonate : ring closing metathesis reaction rate improvement by a addition of an iodide compound i.e. tetrabutyl- ammoniumiodide
• a 0.2 M solution of 700 ⁇ CD 2 C1 2 and 34 ⁇ diethyldiallylmalonate (DEDAM) (0.994 g/ml) was made.
• Stock solutions of M2 catalyst in DCM (665 mg in 10 ml) and tetrabutylammonium iodide (TBAI) (518 mg in 10 ml) were made and 20 of each stock solution (containing 1 mol% M2 and 2 mol% TBAI respectively) were added to the NMR tube.
• Example 11a reaction of compound (1) with (ClCF z CO z O and M2 (path '3 ⁇ 4").
• Example lib reaction of compound (I) with (C1CF CC Q and M2 (path '3 ⁇ 4").
• Example 12a reaction of compound (1) with 1.2 equivalent (ClCF z CO) z O and M2 (tricyclohexylphosphine)ruthenium (M2 catalyst) was added. Next, of 15.1 mL of DCM solution containing 3.51 g (5 mmoles) of compound (1) and 1.05 mL (6 mmoles) of chlorodifluoroacetic anhydride was added and the mixture was stirred at reflux for 13 hours. After cooling to room temperature, the reaction mixture was treated with a solution of 2-mercaptonicotinic acid (116.38 mg) in 40 % aqueous dimethylamine solution (3.17 mL) and 5 mL water, and stirred at room temperature for 1 hour. The phases were separated, and the organic phase was submitted to quantitative HPLC analysis. Yield: 76.3 %.
• Example 12b reaction of compound (1) with 1.2 equivalent (CICF ⁇ CO ⁇ O and M2
• a catalyst stock solution was prepared by dissolving 113 mg of [l,3-bis(2,4,6- trimethylphenyl)-2-imidazo lidinylidene] dichloro(3-phenyl- 1 H-inden- 1 -ylidene)- (tricyclohexylphosphine)ruthenium (M2 catalyst) in 8 mL DCM at room temperature.
• An EasyMax reactor was charged with 85 mL DCM and heated to reflux with stirring. 1.67 mL of the above catalyst stock solution was added to the reactor and the mixture stirred at reflux for 5 minutes.
• Example 13b reaction of compound (1) with 1.2 equivalent (CICF ⁇ CO ⁇ O and M2
• a catalyst stock solution was prepared by dissolving 114 mg of [l,3-bis(2,4,6- trimethylphenyl)-2-imidazolidinylidene]dichloro(3-phenyl-lH-inden-l-ylidene)- (tricyclohexylphosphine)ruthenium (M2 catalyst) and 297 mg tetrabutylammonium iodide in 8 mL DCM at room temperature.
• a catalyst stock solution was prepared by mixing 124 mg of [l,3-bis(2,4,6- trimethylphenyl)-2-imidazo lidinylidene] dichloro(3-phenyl- 1 H-inden- 1 -ylidene)- (tricyclohexylphosphine)ruthenium (M2 catalyst) and 173 mg tetraethylammonium iodide in 6.7 mL DCM at room temperature The tetraethylammonium iodide did not completely dissolve - the supernatant, i.e. the solution phase of this mixture was used.
• An EasyMax reactor was charged with 85 mL DCM and heated to reflux with stirring.
• a catalyst stock solution was prepared by mixing 1.03 g of [ 1 ,3-bis(2,4,6- trimethylphenyl)-2-imidazo lidinylidene] dichloro(3-phenyl- 1 H-inden- 1 -ylidene)- (tricyclohexylphosphine)ruthenium (M2 catalyst) and 100.82 mL DCM at room temperature under nitrogen in an EasyMax reactor.
• a stock solution of the acylated diene was prepared in a 250 mL 4-neck round bottom flask by mixing 148.85 mL of DCM solution containing 72.014 mmoles of compound (1), 57.61 mL DCM and 25.12 mL of chlorodifluoroacetic anhydride. The mixture was stirred at room temperature for 30 minutes, and diluted to an end volume of 200 mL. In a 5 L round bottom flask equipped with mechanical stirring, reflux condenser, thermometer and inlet for the addition cannulae, 2.78 g of tetraethylammonium iodide were mixed with 3.36 L of DCM. The mixture was then heated to reflux with stirring.
• TBAI tetrabutylammonium iodide

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
• Plural Heterocyclic Compounds (AREA)
• Catalysts (AREA)
• Peptides Or Proteins (AREA)

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• 2012
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