Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention is concerned with a novel process for the preparation of (S)-2-methoxy-3- ⁇ 4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]- benzo[b]thiophen-7-yl ⁇ -propionic acid or a salt thereof.
• the invention relates in particular to a process for the preparation of a compound of formula (I)
• R 3 is alkyl, cycloalkyl or aryl;
• R 4 is cycloalkyl, aryl or heteroaryl;
• R 5 is cycloalkyl or aryl
• R 6 is cycloalkyl or aryl
• R 7 is cycloalkyl or aryl
• R 8 is cycloalkyl or aryl; and R 9 is cycloalkyl or aryl.
• the compound of formula (I) is known in the art and is described for example in international application WO 02/092084. It is especially useful for the prophylaxis and/or treatment of diabetes mellitus type I and II.
• the process according to the invention allows the synthesis of the compound of formula (I) with high enantiomeric excess. It can be performed in dichloromethane and the use of complex solvent mixtures can be avoided.
• the process with the catalyst comprising iridium gives particularly high yield and high enantiomeric excess of the compound of formula (I).
• optically pure compound of formula (I) is obtained without the use of multiple crystallization of diastereomeric salts.
• catalyst refers to a complex of ruthenium or iridium respectively with a chiral ligand.
• ruthenium is preferably characterised by the oxidation number II.
• iridium is preferably characterized by the oxidation number I.
• alkyl refers to a branched or straight chain monovalent alkyl radical of one to eight carbon atoms, preferably one to four carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, /so-propyl, /so-butyl, /7-butyl, ieri-butyl and the like with methyl, feri-butyl and /so-propyl being preferred.
• alkoxy refers to the group alkyl-O-.
• a preferred alkoxy group is methoxy.
• cycloalkyl refers to a monovalent carbocyclic radical of 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Cyclohexyl is a preferred cycloalkyl.
• aryl relates to the phenyl or naphthyl group, preferably the phenyl group, which can optionally be mono- or multiply-substituted, particularly mono-, di- or tri-substituted by halogen, hydroxy, CN, CF 3 , NO 2 , NH 2 , N(H, alkyl),
• N(alkyl) 2 carboxy, aminocarbonyl, alkyl, alkoxy, phenyl and/or phenyloxy.
• Preferred substituents are halogen, alkyl, CF 3 and alkoxy, particularly alkyl, CF 3 and alkoxy.
• heteroaryl refers to an aromatic 5- or 6-membered ring which can comprise 1 , 2 or 3 atoms selected from nitrogen, oxygen and/or sulphur such as fury I, pyridyl, 1 ,2-, 1 ,3- and 1 ,4-diazinyl, thienyl, isoxazolyl, oxazolyl, imidazolyl, or pyrrolyl.
• heteroaryl further refers to bicyclic aromatic groups
• heteroaryl group may have a substitution pattern as described earlier in connection with the term "aryl”.
• Preferred heteroaryl groups are 2-thienyl and 2- furyl. 2-Furyl is particularly preferred.
• halide refers to a halogen atom bearing a negative charge such as fluoride, chloride, bromide and iodide.
• pharmaceutically acceptable salts embraces salts of the compound of formula (I) with pharmaceutically acceptable bases such as alkali salts, e.g. Na- and K-salts, alkaline earth salts, e.g. Ca- and Mg-salts, and ammonium or alkyl-substituted ammonium salts, such as e.g. trimethylammonium salts.
• a preferred pharmaceutically acceptable salt of the compound of formula (I) is the sodium salt.
• ⁇ 5 means eta5 as used normaly in coordination chemistry. It indicates the number of electrons shared between a metal center and a ligand in a coordination compound or complex.
• a preferred process is process according to the invention wherein the catalyst comprises iridium and a compound of formula (III), (VIII) or (IX)
• R 1 is hydrogen, alkyl, aryl or arylalkyi;
• R 2 is aryl; and
• R 10 is aryl. Further preferred is a process according as defined above wherein the catalyst comprises iridium and a compound of formula (III)
• R 1 and R 2 are as defined above.
• the catalyst comprises iridium and a compound of formula (X)
• R 1 and R 2 are as defined above.
• R 1 is preferably hydrogen, alkyl, phenyl or benzyl, more preferably hydrogen, alkyl or benzyl.
• R is hydrogen, /so-propyl, phenyl or benzyl.
• R 1 is hydrogen, /so-propyl or benzyl.
• R 2 is phenyl or phenyl substituted with one or two alkyl.
• R 2 is phenyl, 3,5-di-methylphenyl or 3,5-di-terf-butyl-phenyl.
• R 0 is 3,5-di-methyl-phenyl is further preferred.
• the compound of formula (IX) is (S,R,R)-1 ,1 '-bis-[((1 -N,N-dimethylamino) ethylferrocenyl)(phenylphosphino)]ferrocene.
• a preferred compound of formula (VIII) is (S,S)-[1 ,3-dimethyl-1 ,3- propanediyl] bis[di-(3,5-dimethylphenyl)phosphine].
• L 1 is a compound of formula (III), (VIII) or (IX) as defined above;
• L 2 is cyclooctene, 1 ,5-cyclooctadiene, ethylene, 1 ,5-hexadiene or norbornadiene;
• Y is chloride, iodide, bromide, fluoride, trifluoroacetate, tetrafluoroborate, tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, tetraphenylborate, hexafluoroantimonate, hexafluorophosphate, triflate, mesylate, perchlorate, perbromate, periodate, nitrate, hydrogen sulfate or acetylacetonate; and n is 1 or 2.
• the catalyst is lr(L 1 ) (L 2 ) n Y wherein L 1 is a compound of formula (X) and wherein L 2 , Y and n are as defined above.
• L 1 is a compound of formula (III).
• Y is preferably chloride, tetrafluoroborate, hexafluorophosphate or tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, more preferably tetrafluoroborate or tetrakis[3,5-bis(trifluoromethyl)phenyl]borate.
• n is preferably 1.
• the catalyst comprises ruthenium and a compound of formula (IV), (V), (VI) or (VII)
• R 3 is preferably alkyl, cyciohexyl, phenyl, alkylphenyl or dialkylphenyl. In particular, preferred is a process as defined above wherein R 3 is terf-butyl, cyclohexyl, phenyl, 2-methyl-phenyl or 3,5-di-methyl-phenyl.
• R 4 is preferably alkyl, cyclohexyl, phenyl, naphtyl, fury I or phenyl substituted with one to three substituents independently selected from
• R 4 is tert-butyl, cyclohexyl, phenyl, 3,5-di-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 3,5-di-methyl-4- methoxy-phenyl, 1 -naphtyl or 2-furyl is also preferred.
• R 5 is preferably cyclohexyl, phenyl or phenyl substituted with one to three substituents independently selected from alkyl and alkoxy.
• R 5 is phenyl, cyclohexyl, 3,5-di-methyl-4-methoxy-phenyl or 3,5-di-methyl-phenyl is also preferred.
• R 6 is preferably cyclohexyl, norbornyl, phenyl or phenyl substituted with one to three substituents independently selected from alkyl and trifluoromethyl.
• R 6 is phenyl, cyclohexyl, 3,5-di-methyl-phenyl, 3,5-di-trifluoromethyl-phenyl or norbornyl.
• R 7 is preferybly cyclohexyl, phenyl or phenyl substituted with one to three substituents independently selected from alkyl, trifluoromethyl and alkoxy.
• R 7 is cyclohexyl, phenyl, 3,5-di-methyl-phenyl, 3,5-di-trifluoromethyl-phenyl, 3,5-di- methyl-4-methoxy-phenyl or 2-methyl-phenyl.
• R 8 is cyclohexyl or phenyl.
• R 9 is cyclohexyl or phenyl is further preferred.
• L 3 is a compound of formula (IV), (V), (VI) or (VII) as defined above;
• L 4 is r
• L 5 is halide, acetonitrile, diethyl ether, water, acetone, tetrahydrofuran,
• dioxane pyridine, imidazole or thiophene
• Y is tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, tetrafluoroborate,
• tetraphenylborate hexafluoroantimonate, hexafluorophosphate, triflate, mesylate, hydrogen sulfate or perchlorate; m is 0 or 1 ; and p is 0 or 1 .
• L 5 is preferably iodine.
• m is preferably 1.
• p is preferably 1 .
• the process is preferably carried out at a temperature of 10 to 120°C, more preferably 40 to 100°C, particularly preferably 60 to 80°C.
• a catalyst comprising iridium When a catalyst comprising iridium is used, the process is preferably carried out in a solvent selected from alcohols, fluorinated alcohols, tetrahydrofuran, methyl-tetrahydrofuran, dichloromethane, dialkyl ethers, aromatic solvents such as benzene, toluene, CF 3 -C 6 H 5 , mono- and poly-fluorinated aromatic solvents and mixtures thereof, more preferred in methanol, tetrahydrofuran, dichloromethane and mixtures thereof, most preferably in methanol/tetrahydrofuran 3:2.
• a solvent selected from alcohols, fluorinated alcohols, tetrahydrofuran, methyl-tetrahydrofuran, dichloromethane, dialkyl ethers, aromatic solvents such as benzene, toluene, CF 3 -C 6 H 5 , mono- and poly-fluorinated aromatic solvent
• the process is preferably carried out under a hydrogen pressure range of 1 to 200 bar, more preferably 10 to 100 bar, particularly preferably 40 to 60 bar.
• a hydrogen pressure range of 1 to 200 bar, more preferably 10 to 100 bar, particularly preferably 40 to 60 bar.
• a pressure of 10 bar preferred is a pressure of 10 bar.
• a pressure of 30 bar preferred is a pressure of 30 bar.
• (mol/mol) is preferably 0 to 50000, more preferably between 100 and 10000, particularly preferably between 1000 and 5000.
• the process is preferably carried out at a temperature of 10 to 120°C, more preferably 20 to 80°C, particularly preferably 30 to 50°C.
• a catalyst comprising ruthenium When a catalyst comprising ruthenium is used, the process is preferably carried out in a solvent selected from alcohols, tetrahydrofuran, dichloromethane, fluorinated alcohols, methyl-tetrahydrofuran, ethers and mixtures thereof, preferably methanol, tetrahydrofuran, dichloromethane and mixtures thereof, more preferably in a mixture dichloromethane/tetrahydrofuran 1 :1 or in a solvent selected from alcohols, tetrahydrofuran, dichloromethane, fluorinated alcohols, methyl-tetrahydrofuran, ethers and mixtures thereof, preferably methanol, tetrahydrofuran, dichloromethane and mixtures thereof, more preferably in a mixture dichloromethane/tetrahydrofuran 1 :1 or in
• dichloromethane and particularly preferably in dichloromethane.
• the process is preferably carried out under a hydrogen pressure of 1 to 200 bar, more preferably 10 to 100 bar, particularly preferably 40 to 60 bar.
• the s u bstrate-to-catalyst ratio is preferably 10 to 50000, more preferably 100 to 10000, particularly preferably 1000 to 5000.
• the invention also relates to a compound of formula (I) as defined above or a salt thereof obtained by a process according to the invention.
• the invention also relates to the use of a catalyst as defined above for the preparation of a compound of formula (I) as defined above.
• the catalysts for use in the process of the present invention may be prepared by reacting a compound of formula [lr(L)CI] 2 , [lr(L) 2 ] BARF or [lr(L) 2 ]BF 4 where L denotes a neutral ligand, e.g. COD with the desired ligand of formula (III), (VIII), (IX) or (X), e.g. (S,S)-3,5-Xyl-Skewphos or (S,R,R)-TRIFER, in an appropriate solvent, such as e.g. dichloromethane or methanol.
• an appropriate solvent such as e.g. dichloromethane or methanol.
• the catalyst may be used after isolation or as prepared in situ.
• the compounds [lr(COD)CI] 2 and [lr + (COD) 2 ]BF 4 are either commercially available, e.g. from Strem Chemicals Inc., Newburgport, Mass. USA or can be prepared according to to methods known per se, e.g. J. Herde et al., Inorg. Syn. 1974, 8-20 or M. Green et al., J. Chem. Soc. 1971 , 2334-2337.
• the term "neutral ligand” as used herein denotes a readily exchangeable ligand such as an olefin, e.g.
• a preferred neutral ligand is cyclooctadiene.
• i -2,4-DMP i -2,4-dimethylpentadienyl
• TFA trifluoroacetic acid
• BARF tetrakis[3,5-bis(trifluoromethyl)phenyl]borate
• Triflate trifluoromethanesulfonate
• All ferrocenyl-diphosphine ligands are commercially available from Solvias AG, CH-4002 Basel.
• the ruthenium complexes are commercially available from Umicore AG, D-63457 Hanau-Wolfgang or can be prepared according to O. Briel et al. in "Catalysis of Organic Reactions", 2009, 203, CRC Press, Boca Raton.
• the oxazoline-monophosphine ligands (SIPHOX ligands) and their corresponding iridium complexes are commercially available from Nankai University, Tianjin 300071 China or can be prepared according to Q.L. Zhou et al. J.
• Xyl-Skewphos and 3,5-tBu-MeOBIPHEP are commercially available from Solvias AG, CH-4002 Basel.
• TRIFER is commercially available from Phoenix Chemicals, 34 Thursby Rod., Bromborough, Wirral CH62, 3PW, United Kingdom (UK) or can be prepared according to P. McCormack et al.
• the (S a ,S) or (S a ,R) configuration of the SIPHOX ligand may also be noted (S,S) or (S,R) respectively.
• Example 2.1 In a glove box (0 2 content ⁇ 2 ppm ), a 185- ml stainless steel autoclave was charged with 2.00 g of (Z)-2-methoxy-3- ⁇ 4-[2-(5-methyl-2-phenyl-oxazol-4-yl)- ethoxy]-benzo[b]thiophen-7-yl ⁇ -acrylic acid (4.59 mmol), 35.9 mg of [lr((S,S)-DBT- Bn-SIPHOX)(COD)]BARF (0.018 mmol, S/C 250), 24 ml of methanol, 16 ml of tetrahydrofuran and 0.12 ml of (S)-1 -phenylethylamine (0.93 mmol).
• HPLC method for chemical purity (area-%, (S)-phenylethylamine not included): YMC-Pack Pro C18, 150 x 4.6 mm; mobile phase A: mobile phase A: water with 0.1 % TFA, B: NCMe with 0.1 % TFA, 22°C, 2 ml/min, isocratic A/B 51/49% during 10 min, gradient from 51/49% to 5/95% within 10 min and 5 min at 5/95%, 285 nm.
• Examples 5.1-5.2 In an analogous manner to Example 4 the following hydrogenations were performed at 60°C under 30 bar of hydrogen (reaction time: 16 h) using iridium complexes of general formula [lr(Phosphorus Ligand)(COD)]BARF as catalysts to afford crude 2-methoxy-3- ⁇ 4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]- benzo[b]thiophen-7-yl ⁇ -propionic acid (Acid I) as listed in Table 2.
• Table 2 Table 2
• the crude product was dissolved in 50 ml of ethyl acetate. 10 ml of water and 3 ml of 2M aqueous HCI were added and the biphasic mixture was stirred at 55°C for 15 min. The organic layer was separated, the aqueous layer extracted with 20 ml of ethyl acetate and the combined organic layers stirred over 0.5 g of carcoal (Darko KB) at r.t. for 30 min. After filtration over celite, the colorless solution was dried over 3 g of sodium sulfate and evaporated to dryness (40°C/10 mbar). The crude product was dissolved in 50 ml of isopropyl acetate at reflux (oil bath temp.
• Example 8.3 In a glove box (O 2 content ⁇ 2 ppm ), a 185-ml stainless steel autoclave was charged with 2.00 g of (Z)-2-methoxy-3- ⁇ 4-[2-(5-methyl-2-phenyl-oxazol-4-yl)- ethoxy]-benzo[b]thiophen-7-yl ⁇ -acrylic acid (4.59 mmol), 2.84 mg of [ir((Ra,S)- DBT-Bn-SIPHOX)(COD)]OTf (0.0023 mmol, S/C 2 ⁇ 00), 24 ml of methanol, 16 ml of tetrahydrofuran and 0.12 ml of (S)-1 -phenylethylamine (0.92 mmol).
• Example 8.5 In a glove box (0 2 content ⁇ 2 ppm ), a 185-ml stainless steel autoclave was charged with 0.77 mg of [lr(COD)CI] 2 (0.0012 mmol, S/C 2 ⁇ 00), 1.81 mg of (R a ,S)-DBT-Bn-SIPHOX ( 0.0023 mmol) and 10 ml of tetrahydrofuran. The formed yellow solution was stirred for 30 min at ambient temperature.
• Example 8.7 In a glove box (0 2 content ⁇ 2 ppm ), a 185-ml stainless steel autoclave was charged with 2.00 g of (Z)-2-methoxy-3- ⁇ 4-[2-(5-methyl-2-phenyl-oxazol-4-yl)- ethoxy]-benzo[b]thiophen-7-yl ⁇ -acrylic acid (4.59 mmol), 1.80 mg of [lr((S a ,R)- DBT-Bn-SIPHOX)(COD)]BF 4 (0.0015 mmol, S/C 3 ⁇ 00), 24 ml of methanol, 16 ml of tetrahydrofuran and 0.12 ml of (S)-1 -phenylethylamine (0.92 mmol).
• Example 9 In an analogous manner to Example 4 the following hydrogenation was performed at 40°C under 30 bar of hydrogen (reaction time: 16 h) using [lr((S,S)-Xyl- Skewphos)(COD)]BF 4 (S/C 1 ⁇ 00) as catalysts to afford crude (S)-2-methoxy-3- ⁇ 4- [2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl ⁇ -propionic acid (Acid I) as a white solid with a chemical purity of 98.8 % (99.4% conversion) and an enantiomeric purity of 85%.
• Example 11 In a glove box (0 2 content ⁇ 2 ppm ), a 50- ml stainless steel autoclave was charged with 1.00 g of (Z)-2-methoxy-3- ⁇ 4-[2-(5-methyl-2-phenyl-oxazol-4-yl)- ethoxy]-benzo[b]thiophen-7-yl ⁇ -acrylic acid (2.30 mmol),1 .99 mg of [Ru(r
• HPLC method for chemical purity (area-%, (S)-phenylethylamine not included): YMC-Pack Pro C18, 150 x 4.6 mm; mobile phase A: mobile phase A: water with 0.1 % TFA, B: NCMe with 0.1 % TFA, 22°C, 2 ml/min, isocratic A/B 51/49% during 10 min, gradient from 51/49% to 5/95% within 10 min and 5 min at 5/95%, 285 nm.
• Example 13 In an analogous manner to Example 11 the following hydrogenations were performed at 40°C under 30 bar of hydrogen (reaction time: 16 h) using ruthenium complexe [Rul(n 5 -2,4-DMP)((S)-(R)-PPPhCHNMe 2 F-PP)] as catalysts to afford crude (S)-2-methoxy-3- ⁇ 4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]- benzo[b]thiophen-7-yl ⁇ -propionic acid (Acid I) as a white solid with a chemical purity of 98.7 % (99.2% conversion) and an enantiomeric purity of 46%.
• Example 14 In an analogous manner to Example 14 the following hydrogenations were performed at 40°C under 30 bar of hydrogen (reaction time: 16 h) using ruthenium complexe [Ru(D5-2,4-DMP)((S)-(R)-2-Fur2PF-PtBu2)(NCMe)]BF4 as catalysts to afford crude (S)-2-methoxy-3- ⁇ 4-[2-(5-methyl-2-phenyl-oxazol-4-yl)- ethoxy]-benzo[b]thiophen-7-yl ⁇ -propionic acid (Acid I) as a white solid with a chemical purity of 99.3 % (>99.9% conversion) and an enantiomeric purity of 73%.
• ruthenium complexe [Ru(D5-2,4-DMP)((S)-(R)-2-Fur2PF-PtBu2)(NCMe)]BF4 as catalysts to afford crude (S)-2-methoxy-3- ⁇ 4-[2-(5-
• Example 16 In a glove box (0 2 content ⁇ 2 ppm ), a 50-ml stainless steel autoclave was charged with 1.99 mg of [Ru(n 5 -2,4-DMP)((R)-(S)-PPF-PtBu 2 )(NCMe)]BF 4 (0.0023 mmol, S/C 1 ⁇ 00) and 5 ml of dichloromethane. The resulting violet solution was stirred for 2 h at r.t.
• Example 19 In a glove box (0 2 content ⁇ 2 ppm ), a 50-ml stainless steel autoclave was charged with 0.66 mg of [Rufa 5 -2,4-DMP)((R)-(S)-PPF-PtBu 2 )(NC e)]BF 4

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