Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
  • C07D295/182—Radicals derived from carboxylic acids
  • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
  • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
  • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C235/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
  • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
  • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
  • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

• the "R" stereochemistry can be obtained utilizing (S)-ethyl lactate as the chiral auxiliary although diastereoselectivities are significantly lowered in comparison to pantolactone (60-75%).
• the instant invention relates to a highly stereoselective coupling reaction mediated with a pyrrohdine derived lactamide as a chiral auxiliary.
• This invention relates to a method for the stereoselective synthesis of a 2-aryloxycarboxylic acid using a chiral auxiliary, such as a compound of formula I to enhance the stereoselectivity of the alkylation of the ⁇ -halo acid with an aryloxy group.
• a chiral auxiliary such as a compound of formula I to enhance the stereoselectivity of the alkylation of the ⁇ -halo acid with an aryloxy group.
• the invention also relates to a novel compound of formula:
• R a is (Cl -C6)-alkyl, phenyl, or cyclohexyl, which is useful as a chiral auxiliary.
• R a is (Cl -C6)-alkyl, phenyl, or cyclohexyl, which is useful as a chiral auxiliary.
• X is Cl, Br, I, Omesylate, Otosylate, Otriflate
• R c is: a chiral auxiliary
• R is: (C ] -C6)-alkyl, or aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted as defined hereinbelow.
• R c is: a chiral auxiliary
• aryl wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with one, two or three substitutents defined as R ⁇ , R$ and R ⁇ ;
• R ! , R 2 , R3, R , R5 an d R6 are independently:
• R4 and R5 on adjacent carbon atoms can be joined together to form a ring structure:
• A represents:
• n 0, 1 or 2;
• n 2, 3 or 4;
• s 1 or 2;
• R7 is:
• R 8 and R 9 are independently: (a) H, fb) (Cl -C6)-alkyl or (C2-C6)-alkenyl each of which is unsubstituted or substituted with one or two substituents selected from the group consisting of:
• R7 and R ' 2 0 n the same nitrogen atom they can join together to form a ring selected from the group consisting of: morpholinyl, piperazinyl, or pyrrolyl, or
• X is Cl, Br, I, Omesylate, Otosylate or Otriflate
• M+ is Na+, K+, Li+, or NCR 1 6)4+; and R 1 ⁇ is H or (C j - C6)-alkyl;
• R c is: a chiral auxiliary
• aryl wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with one, two or three substitutents defined as R4, R5 and R6;
• R 1 , R2, R3, R4 5 R5 and R 6 are independently:
• R4 and R5 on adjacent carbon atoms can be joined together to form a ring structure:
• A represents:
• s 1 or 2;
• Y is-0-,-S(0) n -and-N(Rl2).
• R 8 and R 9 are independently: (a) H,
• aryl wherein aryl is defined as phenyl or naphthyl which is unsubstituted or substituted with one or two substituents selected from the group consisting of: i) (Cl-C4)-alkyl, ii) -0-(Cl-C4)-alkyl, iii) -CO[NR7]2, iv) F, Cl, Br or I, v) -COOR7, vi) -NH2, vii) -NH[(Cl -C4)-alkyl], viii) -N[(Cl -C4)-alkyI]2, or ix) -CONICH2CH2I2Q;
• R7 and R l 2 0 n the same nitrogen atom they can join together to form a ring selected from the group consisting of: morpholinyl, piperazinyl, or pyrrolyl, or
• Q is O, S or -NR 7 ;
• X is Cl. Br, 1, Omesylate, Otosylate or Otriflate;
• M+ is Na+, K+, Li+. or N(R l 6) 4 + ; an d R l 6 is H or (C ⁇ -C5)-alkyl; in an organic solvent at a temperature range of about -60 °C to about 30 °C for about 30 minutes to about 30 hours to give an alkylated derivative bearing the chiral auxiliary:
• M + is Na + , K + , or Li + ;
• the alkylation step can be carried out in organic solvents such as tetrahydrofuran, toluene, xylenes, or dimethylforamide.
• the alkylation step requires the addition of a solution of the salt of the phenoxide generally prepared by the addition of the salt of t-butoxide to a tetrahydrofuran solution of the phenol.
• N(R 1 6 )4 + , where R 1 6 is defined as H or (C ⁇ -C6)-alkyl] are useful in this alkylation step.
• the organic solvent is often a mixture of, for example, tetrahydrofuran and t-butanol.
• the preferred temperature range for the alkylation step is 60 °C to about room temperature (25 °C).
• the hydrolysis step can be carried out using an inorganic base, such as LiOH, KOH, NaOH, KOCH3, NaOCH3, OCH3, KOC2H5, NaOC2H5, LiOC2H5, etc.
• the hydrolysis step also requires the presence of a peroxide such as hydrogen peroxide.
• the aqueous solvent mixtures useful in the hydrolysis step are tetrahydrofuran- water, toluene-water, dimethylformamide-water or alternatively a polar organic solvent such as methanol, ethanol, or t-butanol.
• An acidic solution such as saturated ammonium chloride solution is useful in the neutralization step.
• a chiral auxilary is defined as an easily removable chiral group which is attached at a position near the site of alkylation and is capable of influencing the direction of nucleophilic attack.
• R a is (C l -C6)-alkyl, phenyl, or cyclohexyl
• R 13 is (C l -C6)-alkyl, phenyl or cyclohexyl
• R 14 and R l 5 are independently: (C i -C j ⁇ )-alkyl, or R l 4 and R l 5 can join together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of: piperadinyl or pyrrolidinyl.
• An aspect of this invention is a compound of formula:
• R a is (Cj -C6)-alkyl, phenyl or cyclohexyl
• Rl4 and R l 5 are independently: (C ⁇ -C ⁇ o)-alkyl or R l4 and R 1 ⁇ can join together to form a 5- or 6-membered heterocyclic ring
• 1 5 selected from the group consisting of piperadinyl or pyrrolidinyl.
• Another aspect of this invention is a compound of formula:
• X is Cl, Br, I, Omesylate, Otosylate, Otriflate
• R c is: a chiral auxiliary; R is:
• aryl wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with one, two or three substitutents defined as R , R5 a nd R6;
• R and R ⁇ on adjacent carbon atoms can be joined together to form a ring structure:
• A represents:
• n 0, 1 or 2;
• n 2, 3 or 4;
• s is I or 2;
• Y is-O-, -S(0)n-and-N(Rl2)_;
• R7 and R l 2 0 n the same nitrogen atom they can join together to form a ring selected from the group consisting of: morpholinyl, piperazinyl, or pyrrolyl; and
• Q is O, S or -NR7.
• An embodiment of this aspect of the invention is a compound of formula:
• R c is selected from the group consisting of:
• R a is (Ci-C6)-alkyl, phenyl or cyclohexyl
• Rl is (Cl-C6)-alkyl, phenyl or cyclohexyl
• Rl and Rl5 are independently: (C
• R is ethyl, phenyl or 3,4-methylenedioxyphenyl.
• alkyl substituents recited above denote straight and branched chain hydrocarbons of the length specified such as methyl, ethyl, isopropyl, isobutyl, neopentyl, isopentyl, etc.
• alkenyl-substituents denote alkyl groups as described above which are modified so that each contains a carbon to carbon double bond such as vinyl, allyl and 2-butenyl.
• Cycloalkyl denotes rings composed of 3 to 8 methylene groups, each of which may be substituted or unsubstituted with other hydrocarbon substituents, and include for example cyclopropyl, cyclopentyl, cyclohexyl and 4-methylcyclohexyl.
• the alkoxy substituent represents an alkyl group as described above attached through an oxygen bridge.
• the heteroaryl is defined as carbazolyl, furyl, thienyl, pyrrolyl, isothiazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridyl, pyrimidyl, purinyl or quinolinyl.
• the lactamide chiral auxiliary is synthesized from (R)- or
• lactamide esters of the racemic ⁇ -halo acids were prepared via DCC coupling with commercially available acids or upon reaction with commercially available acid halides according to literature procedure. [See (a) Durst, T.; Koh, K. Tetrahedron Lett. 1992, 33, 6799. (b) Harpp, D.N.; Bao, L.Q.; Black, C.J.; Gleason, J.G.; Smith. R.A.; J. Org. Chem. 1975, 40, 3420.]
• the coupling reaction was conducted by adding a preformed solution of aryloxide to a THF solution of halide, with or without tricaprylmethylammonium iodide, at the desired temperature (Table 1 ).
• the reactions were found to proceed at a much faster rate than with conventional ester auxiliaries.
• a reaction performed at -35 °C with sodium 4-methoxyphenoxide was completed in 0.5h with a diastereoselectivity of 92% (entry 1).
• a similar reaction utilizing ethyl lactate as the auxiliary required a reaction time of 24h at 0 °C.
• Product was also obtained with a diminished diastereoselectivity of 60%. This observation also holds true for the ethyl lactate auxiliary.
• the fact that coupling reactions involving pyrrohdine lactamide auxiliaries proceed at a more rapid rate than their ester counterparts allows for the use of alternative phenoxide salts.
• Lithium 4-methoxyphenoxide although unreactive at -35 °C, readily undergoes reaction with the ⁇ -bromoester at temperatures ranging from - 15 °C to ambient (entries 3-6). No temperature effect is observed, with diastereoselectivities obtained at room temperature rivaling those obtained with the sodium salt at -35 °C (entries 6-8). However, conducting the coupling reaction utilizing the ⁇ -iodoester leads to significant increases in diastereoselection (entries 9 & 10).
• the absolute configuration of the newly formed stereogenic center was determined by first hydrolyzing the coupled product to remove the chiral auxiliary, followed by converting the acid to the corresponding R- or S- methyl mandelate. [See Corey, E.J.; Link, J.O. Tetrahedron Lett. 1992, 53, 3431.]
• ketoester 3 182 g, 0.82 mole
• methanol 800 ml
• 5N sodium hydroxide 300 ml
• water 300 ml
• the batch was aged for 20 min. during which time a precipitate formed.
• Methylene chloride 500 ml was added and the mixture was acidified to pH 3.0 using concentrated HCl.
• the layers were separated and the organic phase was concentrated in vacuo to 100 ml.
• Toluene (300 ml) was added and concentration was continued to a final volume of 300 ml.
• the resulting slurry was aged for l h and filtered.
• the wet cake was washed with hexane and air dried to provide 120 g of ketoacid as a tan solid.
• ketoacid 80 g, 0.41 moles
• methylene chloride 800 ml
• DMF 3 ml
• the mixture was aged for lh. The batch was quenched into water (500 ml) and the layers separated. The organic layer was washed with water (500 ml) and then with sat'd sodium bicarbonate (2x300 ml). Concentration in vacuo provided 100 g of product as an oil. The material is used in the next step without purification.
• the mixture was poured into a mixture of brine (200 ml), water (200 ml), and ethyl acetate (400 ml). The layers were cut and the organic layer was concentrated // vacuo to yield 69.0 g of product as an oil.
• ketoester (44.4 g) in THF (300 ml) was added in water (30 ml).
• Diastereomeric ratio (DR) determined via HPLC utilizing either a Supelcosil LC CN column or a Chiracel OD column. Diastereoselectivities could also be obtained via 300MHz ] H NMR. Reaction conducted utilizing the ⁇ -iodoester.

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• Chemical & Material Sciences (AREA)
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• Hydrogenated Pyridines (AREA)
• Plural Heterocyclic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Surface Acoustic Wave Elements And Circuit Networks Thereof (AREA)

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• 1996
  • 1996-12-09 AU AU12878/97A patent/AU703380B2/en not_active Ceased
  • 1996-12-09 WO PCT/US1996/019782 patent/WO1997021693A1/en not_active Application Discontinuation
  • 1996-12-09 CA CA 2238960 patent/CA2238960A1/en not_active Abandoned
  • 1996-12-09 JP JP09522200A patent/JP2000501737A/ja active Pending
  • 1996-12-09 EP EP96943713A patent/EP0869950A1/en not_active Withdrawn

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