Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• the present invention relates to a process for the efficient preparation of chiral allylic alcohol intermediates which are useful in the asymmetric synthesis of 9-substituted-3-(optionally substituted-aryl)-nonanoic acids.
• the process comprises an enantioselective 1,2-reduction of prochiral ⁇ , ⁇ -unsaturated ketones with a chiral reducing agent to afford chiral allylic alcohols which can be further processed into the desired substituted nonanoic acid derivatives, which are useful as ⁇ v ⁇ 3 integrin receptor antagonists for the inhibition of bone resorption and treatment andor prevention of osteoporosis.
• the present invention provides an efficient process for the preparation of chiral allylic alcohols of structural formula (I)
• R2 is hydrogen, chloro, bromo, or iodo
• R3 is selected from the group consisting of hydrogen, Ci-8 alkyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl, C3-8 cycloalkyl-Ci-6 alkyl, and C3-8 cycloheteroalkyl-Ci-6 alkyl.
• the present invention provides a process for the preparation of (R)- allylic alcohols of structural formula (I) in an efficient enantioselective fashion via 1,2-reduction of prochiral ⁇ , ⁇ -unsaturated ketones (enones) of structural formula (H) with a chiral reducing agent,
• n, Y, Rl, R2, and R3 are as defined above.
• the present invention is concerned with a process for the preparation of chiral allylic alcohols of structural formula (I).
• the process utilizes an enantioselective chiral reducing agent under conditions that give rise to enhanced enantioselectivity in the reduction of prochiral ⁇ , ⁇ -unsaturated ketones (enones) of structural formula (II).
• the chiral allylic alcohols obtained in this fashion are key intermediates in the asymmetric synthesis of v ⁇ 3 integrin receptor antagonists, which are useful for inhibiting bone resorption and treating and/or preventing osteoporosis.
• the process of the present invention involves the preparation of chiral allylic alcohols of structural formula (I)
• n 0, 1, or 2;
• Y is CH or N;
• Rl is hydrogen, C ⁇ _6 alkyl, or C ⁇ _6 alkoxy;
• R2 is hydrogen, chloro, bromo, or iodo; and R3 is selected from the group consisting of hydrogen,
• the process of the present invention comprises the step of treating an enone of structural formula (II) with an enantioselective chiral reducing agent in a reaction solvent in the presence of an organic polyamine, polyether, or polyaminoether modifier.
• the reaction solvent for the enone reduction is selected from the group consisting of diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane (DME), methyl t-butyl ether (MTBE), diglyme, THF, toluene, dichloromethane, NMP, DMF, DMPU, and mixtures thereof.
• the solvent for the enone reduction is THF; a mixture of THF and toluene; a mixture of THF, toluene, and dichloromethane; or a mixture of THF and dichloromethane.
• the enantioselective chiral reducing agent is a chiral aluminum hydride reagent prepared by mixing lithium aluminum hydride and approximately equimolar amounts of optically pure (R)-binaphthol and a proton source in an organic solvent.
• the organic solvent used in the preparation of the chiral aluminum hydride reagent can be diethyl ether, 1,4-dioxane, DME, MTBE, THF, toluene, or a mixture thereof.
• the proton source is a compound of structural formula HXR4 wherein X is O, S, or NH and R4 is selected from the group consisting of Ci-10 alkyl, phenyl, naphthyl, pyridyl, phenyl-C ⁇ _3 alkyl, phenyl oxy-C 1-3 alkyl, COR5, SO2R 5 ,
• each R5 is independently selected from the group consisting of Ci-6 alkyl, phenyl, and phenyl-Ci-3 alkyl; in which phenyl and alkyl are unsubstituted or substituted with one to three groups independently selected from C1-4 alkoxy, amino, and (C ⁇ _4 alkyl) ⁇ _2 amino.
• the chiral aluminum hydride reagent is a (R)-binaphthol-lithium aluminum hydride reagent of structural formula HI.
• X is O, S, or NH;
• R is selected from the group consisting of C ⁇ _ ⁇ o alkyl, phenyl, naphthyl, pyridyl, phenyl-C ⁇ _3 alkyl, phenyloxy-Ci-3 alkyl, COR5, • SO 2 R5,
• each R is independently selected from the group consisting of C 1-6 alkyl, phenyl, and phenyl-Ci-3 alkyl; in which phenyl and alkyl are unsubstituted or substituted with one to three groups independently selected from Ci _4 alkoxy, amino, and (C1-4 alkyl) ⁇ _2 amino.
• XR4 is OCi-4 alkyl. In a subclass of this class, XR4 is OEt or OMe.
• BINAL-H reagents When XR4 represents an oxide residue, the chiral aluminum hydride reagents are known in the art as BINAL-H reagents [see R. Noyori et al., J. Am. Chem. Soc. 106: 6709-6716, 6717-6725 (1984); J. Am. Chem. Soc. 101: 3129-3131 (1979); and U.S. Patent No. 4,284,581 (Aug. 19, 1981), the contents of each of which are incorporated by reference herein in their entirety].
• the BINAL-H reagent is prepared in situ from lithium aluminum hydride, optically pure 2,2'-dihydroxy-l,r-binaphthyl, i.e., either (R)- or (S)-binaphthol (BTJSOL), and an alkanol.
• Preferred alkanols are methanol or ethanol.
• the "modified" BINAL-H reagent is prepared by mixing, for example, a lower alkanol, such as methanol or ethanol, and BINOL with a mixture of LAH in an organic solvent, such as toluene, THF, or a mixture thereof, which has been pre- treated with THF. After heating the mixture for a specified period of time, the organic polyamine, polyether, or polyaminoether modifier is added and aged for a specified period of time.
• a lower alkanol such as methanol or ethanol
• BINOL a mixture of LAH in an organic solvent, such as toluene, THF, or a mixture thereof, which has been pre- treated with THF.
• the modified (R)-BINAL-H reagent is produced by adding ethanol or methanol (approximately one molar equivalent) and (R)-BFNOL (slightly more than one molar equivalent) to a mixture of LAH in toluene or THF, which has been pre-treated with THF (>2 molar equivalents). After heating the mixture at 40-70°C for about 30-90 minutes, an organic polyamine, polyether, or polyaminoether modifier is added and the mixture aged for about 30-90 minutes.
• the resultant mixture constitutes the modified enantioselective chiral reducing agent ("modified" R-BINAL-H), which is then reacted with a solution of the enone of structural formula (II).
• modified R-BINAL-H modified enantioselective chiral reducing agent
• the molar ratio of organic polyamine, polyether, or polyaminoether modifier to BINAL-H reagent is about 0.1:1 to about 3:1.
• the organic polyamine, polyether, or polyaminoether modifier is selected from the group consisting of 12-crown-4; bis-(2- dimethylaminoethyl)ether; triethylamine; (S)-(+)-l-(2-pyrrolidinyl)-pyrrolidine; lJ,4JJ0J0-hexamethyltriethylenetetraamine (HMTTA); N,N,N',N'- tetramethylethylenediamine (TMEDA); N,N,N' ,N'-tetraethylethylenediamine (TEED A); and N,N,N',N' ,N"-pentamethyldiethylenetriamine (PMDTA).
• Preferred organic polyamines are TMEDA and PMDTA.
• the chiral reduction is carried out in a reaction solvent selected from the group consisting of diethyl ether, 1,4-dioxane, diglyme, DME, MTBE, THF, toluene, dichloromethane, DMF, NMP, DMPU, and mixtures thereof.
• the reaction solvent for the reduction is THF; a mixture of THF and toluene; a mixture of THF, toluene, and dichloromethane; or a mixture of THF and dichloromethane.
• the chiral reduction is carried out at a temperature in the range of about -100°C to 40°C. In a class of this embodiment, the reaction is carried out at a temperature range of about -60°C to 25°C.
• the molar ratio of BINAL-H reagent to enone substrate is in the range of about 5: 1 to about 1:1. In one class of this embodiment, the molar ratio of BINAL-H reagent to enone substrate is about 3:1.
• n, Y, Rl, R2, and R3 are as defined above.
• a second aspect of the present invention provides for the preparation of chiral allylic alcohols of structural formula (I) by enantioselective reduction of enones of structural formula (II) wherein the chiral reducing agent is an (S)- oxazaborolidine of structural formula (V) in admixture with a source of borane,
• R6 is hydrogen, methyl, or methoxy.
• Sources of borane include borane-dimethyl sulfide complex, catecholborane, dichloroborane-dimethyl sulfide complex, monochloroborane-dimethylsulfide complex, borane-THF complex, and 9- borabicyclo[3.3J]nonane (9-BBN):
• the reaction is carried out in an organic solvent, such as dichloromethane, THF, toluene, or a mixture thereof, in the presence of an amine base, such as triethylamine and diisopropylethylamine, at a temperature in the range of about -60 to 25°C.
• the compound of structural formula (I) is produced in an enantiomeric excess of about 80-90% over the enantiomer having the (S)-configuration at the stereogenic center. In one embodiment of this aspect of the present invention, the compound of structural formula (I) is produced in an enantiomeric excess of about 95% over the enantiomer having the (S)- configuration at the stereogenic center.
• the optical purity of the desired compound of structural formula (I) may be further increased by crystallization of residual amounts of the (R,S)-form from a suitable crystallization solvent system.
• the crystallization solvent system is selected from the group consisting of acetonitrile; n-butyl acetate; ethyl acetate; isopropyl acetate; toluene; a mixture of ethyl acetate and acetonitrile; a mixture of ethyl acetate and heptane; a mixture of ethyl acetate and ethanol; a mixture of ethyl acetate and toluene; and a mixture of Ci- alkanol (which includes, but is not limited to, methanol, ethanol, n- and isopropanol, and n-, sec-, t- butanol) and toluene.
• the crystallization solvent system is a mixture of 2% to 5% n-propanol in toluene (v/v).
• Yet another aspect of the process of the present invention comprises the following enantiomerically enriched compounds that are obtained from the process of the instant invention:
• the compound l-(2-methyl-pyrimidin-5-yl)-7-(5,6J,8-tetrahydro-[l,8]- naphthyridm-2-yl)-hept-l-en-3-ol comprising predominantly the (R)-enantiomer and a residual amount of the (S)-enantiomer, wherein the (R)-enantiomer is present in an enantiomeric excess of at least about 90% over the (S)-enantiomer.
• the (R)-enantiomer is present in an enantiomeric excess of at least about 98% over the (S)-enantiomer.
• the compound l-(pyrimidin-5-yl)-7-(5,6J,8-tetrahydro-[l,8]-naphthyridin-2- yl)-hept-l-en-3-ol comprising predominantly the (R)-enantiomer and a residual amount of the (S)-enantiomer, wherein the (R)-enantiomer is present in an enantiomeric excess of at least about 90% over the (S)-enantiomer.
• (R)-enantiomer is present in an enantiomeric excess of at least about 98% over the (S)-enantiomer.
• the chiral allylic alcohols of structural formula (I) of the present invention can be converted in the 3-step sequence of Claisen rearrangement, hydrogenation, and hydrolysis, as described in U.S. Patent No. 6,048,861, into the final products of structural formula (VI), which are useful as ⁇ v ⁇ 3 integrin receptor antagonists,
• n, Y, Rl , R2, and R are as defined above.
• % enantiomeric excess (abbreviated “ee) shall mean the % major enantiomer less the % minor enantiomer. Thus, an 80% enantiomeric excess corresponds to formation of 90% of one enantiomer and 10% of the other.
• enantiomeric excess is synonymous with the term “optical purity.”
• enantioselective shall mean a reaction in which one enantiomer is produced (or destroyed) more rapidly than the other, resulting in the predominance of the favored enantiomer in the mixture of products.
• alkyl shall mean straight or branched chain alkanes of one to six total carbon atoms, or any number within this range (i.e., methyl, ethyl, 1- propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, etc.).
• alkoxy refers to straight or branched-chain alkoxides of the number of carbon atoms specified (e.g., C1-.5 alkoxy) or any number within this range (i.e., methoxy, ethoxy, etc.).
• cycloalkyl shall mean cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl).
• cycloheteroalkyl shall mean a 3- to 8-membered fully saturated heterocyclic ring containing one or two heteroatoms selected from N, O, and S. Examples of cycloheteroalkyl groups include, but are not limited to, piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, and piperazinyl.
• BINOL is 2,2'-dihydroxy-l,rbinaphthyl (l,l'-bi-2- naphthol);
• DBU is l,8-diazabicyclo[5.4.0]undec-7-ene;
• DCM is dichloromethane (methylene chloride);
• DME is 1,2-dimethoxyethane;
• DMF is N,N- dimethylformamide;
• DMPU is l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone; ee is enantiomeric excess;
• ⁇ MTTA is lJ,4JJ0J0-hexamethyltriethylenetetramine;
• ⁇ PLC is high-performance liquid chromatography;
• JJPA is isopropanol;
• MTBE is methyl t-butyl ether;
• LA ⁇ is lithium aluminum hydride;
• NMP is l-methyl-2- pyr
• Step A l-(Pyrimidin-5-vn-7-(5.6J.8-tetrahvdro-ri.81naphthyridin-2-ylVhept- l-en-3-one (2)
• Step B Preparation of the "modified" (RVBINAL-H reagent
• Step C (R -l-(Pyrimidin-5-vn-7-(5.6J.8-tetrahvdro-ri.81-naphthyridin-2-yl)- hept-l-en-3-ol (3)
• reaction mixture was aged at -75°C to -70°C for 40 minutes and quenched with methanol (4 mL, 102 mmol) at -70°C and then allowed to warm to room temperature.
• the reaction mixture was filtered through a pad of solka flock and the pad rinsed with DCM (20 mL).
• the resulting filtrate was transferred to a separatory funnel and extracted twice with aqueous tartaric acid solution (2.0 M, 1X100 mL and 1X50 mL).
• the combined aqueous phase was washed with DCM (20 mL).
• the pH of the washed aqueous phase was adjusted to 7 to 8 with 23 wt.% aqueous ammonium hydroxide solution and extracted with DCM (3 X 60 mL).
• the combined DCM solution was washed with 0.5 M ammonium chloride solution (3 X 100 mL) and dried over sodium sulfate.
• the solution was filtered and concentrated under reduced pressure to an oil.
• the resulting residue was dissolved in acetonitrile (100 mL) and concentrated to 10% of the initial volume and treated with additional acetonitrile (90 mL) and concentrated back to an oily residue.
• the resulting residue (3.0 g) was charged into a 250-mL, 3 neck-round bottom flask, which was equipped with a temperature probe, a nitrogen inlet adapter, a magnetic stirrer, and a heating mantel, and treated with acetonitrile (60 mL) and then heated to 40°C and aged 15 min.
• the resulting solution was then allowed to cool to room temperature and stirred overnight at room temperature.
• the supernatant was checked by chiral HPLC assay at two wavelengths, 250 and 330 nm.
• the (R)-allylic alcohol in acetonitrile solution was assayed to be 95% ee for (R)-3.
• the slurry mixture was then cooled to 10°C and filtered to isolate the (R)-allylic alcohol 3 as an acetonitrile solution (60 mL; 28 g/L; 1.7 g; 52% recovery) in a HPLC area % purity of 70% and in a chiral HPLC purity of 98% ee.
• the resulting residue after work-up of the reduction step (3.0 g) was charged into a 200-mL, 3 neck-round bottom flask, which was equipped with a temperature probe, a nitrogen inlet adapter, a magnetic stirrer, and a heating mantel, and treated with 2% n-propanol in toluene (36 mL) and heated to 45°C and aged 15 min.
• the resulting solution was then allowed to cool to 34°C and seeded with racemate (several crystals) and aged at 34°C for 0.5 h and then cooled to room temperature and stirred overnight at room temperature.
• Alcohol 3 could be obtained as a crystalline solid. This was accomplished by first solvent switching to toluene and then concentrating to a volume of 14 mL (5 volume per gram of 3) and treating the resulting solution with heptane solvent (19 mL), which was added dropwise over 0.5 h, to crystallize 3. Filtration of the resulting slurry mixture afforded 3 (2.36 g) in 78% isolated yield and 98% ee chiral purity.
• the mixture was aged overnight at 23°C.
• the aqueous phase was separated from the organic phase.
• the organic phase was extracted with 3.3wt% citric acid (153 g).
• the combined aqueous phases were washed twice with toluene (1150 mL, 800 mL).
• the pH of the combined aqueous phases was adjusted to pH 7 with 50% NaOH (120 mL).
• the pH 7 aqueous phase was extracted twice with EtOAc (1 L, 400 mL), yielding a solution of allylic alcohols (38.5 g), with 3 present in 86% enantiomeric excess. Further enhancement of optical purity could be achieved as described in Example 1.
• Step B l-(2-Methylpyrimidin-5-yl)-7-(5.6J.8-tetrahvdro-ri.81naphthyridin-2- yl)-hept-l-en-3-one (4)
• Step C (R)-l-(2-Methyl-pyrimidin-5-yl)-7-(5.6J.8-tetrahvdro-ri,81- naphthyridin-2-yl -hept-l-en-3-ol (5)
• the slurry of modified BINAL-H reagent was transferred to a slurry of 4 (9.33 g, 27J mmol) in THF (49 mL) over 25 min while cooling at -60°C. The slurry was gradually warmed to -40°C over 90 min and aged 70 min thereafter. Acetic acid (6.4 mL, 112 mmol) was added to the slurry. The slurry was warmed to -15°C, whereupon n- heptane (134 mL) was added, followed by 40wt% citric acid. The mixture was allowed to warm to 20°C and aged overnight. To the biphasic mixture was added DCM (50 mL). The aqueous phase was separated from the organic phase.
• the aqueous phase was washed with EtOAc (2 x 200 mL). The pH of the aqueous phase was adjusted to pH 7 with 50% NaOH. The aqueous was extracted with EtOAc (2 x 200 mL), providing a solution of allylic alcohols (82% assay yield), with 5 present in 90% enantiomeric excess.
• the slurry mixture was filtered to isolate the (R)-allylic alcohol 5 as a wet ethyl acetate solution (268 mL; 68 mg/mL; 18.2g; 80% recovery) in a chiral HPLC purity of 99% ee.
• Alcohol 5 could be obtained as a crystalline solid. This was accomplished by first solvent switching to heptane and then concentrating to a volume of -127 mL (7 volumes per gram of 5). Filtration of the resulting slurry mixture afforded 5 (17.3 g) in 76% isolated yield in a chiral purity of 99% ee.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

Applications Claiming Priority (3)

Publications (2)

Family

ID=22897136

Family Applications (1)

Country Status (5)

Families Citing this family (5)

Citations (3)

Family Cites Families (1)

• 2001
  • 2001-10-01 AU AU2001296950A patent/AU2001296950A1/en not_active Abandoned
  • 2001-10-01 JP JP2002532426A patent/JP2004510766A/ja not_active Withdrawn
  • 2001-10-01 WO PCT/US2001/042411 patent/WO2002028840A1/fr not_active Ceased
  • 2001-10-01 EP EP01977866A patent/EP1326846A4/fr not_active Ceased
  • 2001-10-01 CA CA002424304A patent/CA2424304A1/fr not_active Abandoned

Patent Citations (3)

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events