Classifications

• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
  • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
  • C12P17/10—Nitrogen as only ring hetero atom
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
  • C12P13/00—Preparation of nitrogen-containing organic compounds
  • C12P13/04—Alpha- or beta- amino acids
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
  • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
  • C12P41/006—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the present disclosure relates to methods for generating stereospecific products from a racemic mixture of N-protected ⁇ -lactams that can be used for chiral syntheses.
• the method can be used to synthesize stereoisomerically pure ⁇ -lactam and ⁇ - amino carboxylic acid compounds that can be used as starting materials to synthesize a wide variety of stereoisomerically pure compounds.
• the stereoisomerically pure ⁇ -lactam can be used as a starting material to synthesize diastereomerically pure antiproliferative (lR,2R,3S,4S)-N4-(3-aminocarbonylbicyclo[2.2.1]hept-5-ene-2-yl)-5- fluoro-N2-[3-methyl-4-(4-methylpiperazin-l-yl)phenyl]-2 s 4-pyrimidinediamine, and the various compounds described in copending application Serial No. 11/133,419 filed May 18, 2005, international application no. PCT/US05/17470 and application Serial No. , entitled "Stereoisomerically Enriched 3-Aminocarbonyl Bicycloheptene
• A represents a saturated or unsaturated, monocyclic, polycyclic or bridged polycyclic ring and R represents a protecting group, with a lipase from Candida antarctica to yield stereoisomerically pure products according to structural formulae 1 and 4:
• Typical alkyl groups include, but are not limited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl, cyclopro ⁇ an-1-yl, prop-1-en-l-yl, prop-l-en-2-yl, ⁇ rop-2-en-l-yl, cycloprop-1-en-l-yl; cycloprop-2-en-l-yl, prop-1-yn-l-yl, prop-2-yn-l-yl, etc.; butyls such as butan-1-yl, butan-2-yl, 2-methyl- propan-1-yl, 2-methyl propan-2-yl, cyclobutan-1-yl, but-1-en-l-yl, but-l-en-2-yl, 2- methyl prop-1-en-l-yl, but-2-en-yl-yl ,
• Alkanyl by itself or as part of another substituent refers to a saturated branched, straight chain or cyclic alkyl derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane.
• Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl (isopropyl), cyclopropan- 1-yl, etc.; butanyls such as butan-1-yl, butan-2-yl ⁇ sec butyl), 2-methyl propan-1-yl (isobutyl), 2-methyl propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like.
• alkenyl by itself or as part of another substituent refers to an unsaturated branched, straight chain or cyclic alkyl having at least one carbon carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene.
• the group may be in either the cis or trans conformation about the double bond(s).
• Alkynyl by itself or as part of another substituent refers to an unsaturated branched, straight chain or cyclic alkyl having at least one carbon carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne.
• Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1-yn-l-yl, prop-2-yn-l-yl, etc.; butynyls such as but-1-yn-l-yl, but-l-yn-3-yl, but 3- yn-l-yl, etc.; and the like.
• Alkyldiyl by itself or as part of another substituent refers to a saturated or unsaturated, branched, straight chain or cyclic divalent hydrocarbon group having the stated number of carbon atoms (i.e., Cl C6 means from one to six carbon atoms) derived by the removal of one hydrogen atom from each of two different carbon atoms of a parent alkane, alkene or alkyne, or by the removal of two hydrogen atoms from a single carbon atom of a parent alkane, alkene or alkyne.
• the two monovalent radical centers or each valency of the divalent radical center can form bonds with the same or different atoms.
• alkanyldiyl alkenyldiyl and/or alkynyldiyl
• alkylidene alkylidene
• the alkyldiyl groups are saturated acyclic alkanyldiyl groups in which the radical centers are at the terminal carbons, e.g., methandiyl (methano); ethan-l,2-diyl, (ethano); propan-l,3-diyl (propano); butan-l,4-diyl (butano); and the like (also referred to as alkylenes, defined infra).
• Typical alkylene groups include, but are not limited to, methylene (methano); ethylenes such as ethano, etheno, ethyno; propylenes such as propano, prop[l]eno, propa[l,2]dieno, prop[l]yno, etc.; butylenes such as butano, but[l]eno, but[2]eno, buta[l,3]dieno, but[l]yno, but[2]yno, buta[l,3]diyno, etc.; and the like. Where specific levels of saturation are intended, the nomenclature alkano, alkeno and/or alkyno is used.
• the alkylene group is (C1-C6) or (C1-C3) alkylene.
• the alkylene group is a straight chain saturated alkano group, e.g., methano, ethano, propano, butano, and the like.
• Cycloalkyl by itself or as part of another substituent refers to a cyclic version of an "alkyl” group.
• Typical cycloalkyl groups include, but are not limited to, cyclopropyl; cyclobutyls such as cyclobutanyl and cyclobutenyl; cycloheptyls such as cycloheptanyl and cycloheptenyl; cyclohexyls such as cyclohexanyl and cyclohexenyl; cycloheptyls such as cycloheptanyl and cycloheptenyl; and the like.
• Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as indacene, s indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like, as well as the various hydro isomers thereof.
• the aryl group is (C6 ClO). Specific examples are phenyl and naphthyl. i [0023] "Halogen” or “Halo” by themselves or as part of another substituent, unless otherwise stated, refer to fiuoro, chloro, bromo and iodo.
• Haloalkyl by itself or as part of another substituent refers to an alkyl group in which one or more of the hydrogen atoms are replaced with a halogen.
• haloalkyl is meant to include monohaloalkyls, dihaloalkyls, trihaloalkyls, etc. up to perhaloalkyls.
• Hydroalkyl by itself or as part of another substituent refers to an alkyl group in which one or more of the hydrogen atoms are replaced with a hydroxyl substituent.
• hydroxyalkyl is meant to include monohydroxyalkyls, dihydroxyalkyls, trihydroxyalkyls, etc.
• alkyloxy or “alkoxy” refers to a group of the formula -OR'
• alkylamine refers to a group of the formula -NHR'
• dialkylamine refers to a group of the formula -NR'R', where each R' is independently an alkyl.
• haloalkoxy or “haloalkyloxy” refers to a group of the formula -OR", where R" is a haloalkyl.
• a method for resolving mixtures of ⁇ -lactam diastereomers and/or enantiomers, such as racemic mixtures of (2-exo, 3-exo) cis ⁇ - lactams, into stereoisomerically pure products using a lipase enzyme from Candida antarctica.
• the method comprises contacting a (2-exo, 3-exo) cis N-protected ⁇ -lactam comprising a mixture of enantiomers according to structural formulae 1 and 2:
• A represents a saturated or unsaturated, monocyclic, polycyclic or bridged polycyclic ring and R represents a protecting group.
• a rings include, but are not limited to, bicycloheptenyl, bicycloheptyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, cyclopropyl, and the like.
• Suitable protecting groups R have the formula -C(X)YR 1 , where, X is O or S; Y is O or S; and R 1 is selected from unsubstituted or substituted lower alkyl, unsubstituted or substituted lower alkanyl, unsubstituted or substituted (C6-C14) aryl and unsubstituted or substituted (C7-C20) arylalkyl.
• protecting group R taken together with the ⁇ - lactam nitrogen to which it is bonded, forms a carbamate or a carbamate equivalent, such as a thiocarbamate.
• R 1 is selected from t-butyl, benzyl and fluoren-9-yl.
• N-Benzoyl protected ⁇ -lactams have been enzymatically resolved using various enzymes, but not Candida antarctica (see Brieva et al., 1993, J. Org. Chem. 58(5): 1068- 1075).
• the benzoyl protected ⁇ -lactams were found to be unstable in aqueous media, undergoing hydrolysis without enzyme participation, presumably due to over-activation by the benzoyl group. Even so, when using organic media for the resolutions, good enantiomeric excess was achieved, however with poor yields.
• Suitable carbamates include, but are not limited to, those described above, including Boc, benzyloxycarbonyl and 9-fluorenylmethoxycarbonyl.
• Other useful carbamates can be found in Greene & Wuts., Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, Inc., New York (1999) and the references cited therein (see, e.g., the myriad carbamates at pp.
• the method for generating stereoisomerically pure compounds comprises contacting an N-protected ⁇ -lactam comprising a mixture of enantiomers according to structural formulae 1 and 2 (for example, a racemic mixture) with a lipase enzyme from Candida antarctica in a reaction solvent.
• the enzyme hydrolyzes one stereoisomer, but leaves the other stereoisomer intact.
• the amount of enzyme used is not critical and can be varied. Usually, a catalytic amount of enzyme is sufficient. In other situations, at least one molecule of enzyme per 500 molecules of substrate is desirous to achieve adequate resolution of N-protected ⁇ -lactams.
• reaction solvent can be varied, depending, in part, on the solubility of the starting materials and products.
• examples of common solvents useful for the methods described herein include diisopropyl ether, tetrahydrofuran, butanol, hexanes, toluene and acetonitrile. Mixtures of these solvents may also be used.
• organic solvents for enzymatic resolutions, rather than aqueous systems is particularly useful. Since some water may be necessary to adequately hydrate the enzyme,' a catalytic amount of water, for example, in the range of about 0.1-1.0% is advantageous.
• the catalytic amount of water can usually be achieved by using fresh commercially available anhydrous solvents without further distillation, as these solvents typically are not 100% water free.
• anhydrous solvents typically are not 100% water free.
• stereoisomerically pure ⁇ -lactam 1 and N-protected ⁇ -amino carboxylic acid 4 are both useful as starting materials to synthesize specific diastereomers of a wide variety of molecules.
• stereoisomerically pure ⁇ -lactam 1 can be used as a starting material to synthesize diastereomerically pure antiproliferative (IR, 2R, 3S, 4S)-N4-(3- aminocarbonylbicyclo [2.2.1] hept-5 -en-2-yl)-5 -fluoro-N2- [3 -methyl-4-(4- methylpiperazin-l-yl)phenyl]-2,4-pyrimidinediamine.
• N-Boc carboxylic acid (remains in organic phase) (remains in aqueous solution)
• Procedure A round bottom equipped with a rubber septum and a magnetic stilling bar was charged with a mixture of enantiomerically pure N-Boc-lactam 16a and N-Boc carboxylic acid 26b (4.0 g) under a positive pressure of nitrogen. To this were added ethyl acetate (50 mL) followed by 25% aqueous ammonium hydroxide (50 mL) and stirred at room temperature for 3 hours. The reaction progress was monitored by TLC.
• the resulting TFA salt 30a was treated with 2,4-dichloro-5-fluoropyrimidine 34 (1.58 g, 9.51 mmol) in MeOHrH 2 O (20:10 mL) in the presence OfNaHCO 3 (1.33 g, 15.84 mmol) at room temperature for 48 hours.
• the reaction mixture was diluted with H 2 O (25 mL), saturated with NaCl and extracted with EtOAc (3 x 50 mL).

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Zoology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• Wood Science & Technology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Genetics & Genomics (AREA)
• General Chemical & Material Sciences (AREA)
• Biotechnology (AREA)
• Microbiology (AREA)
• Health & Medical Sciences (AREA)
• Biochemistry (AREA)
• Bioinformatics & Cheminformatics (AREA)
• General Engineering & Computer Science (AREA)
• General Health & Medical Sciences (AREA)
• Analytical Chemistry (AREA)
• Preparation Of Compounds By Using Micro-Organisms (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Priority Applications (5)

Applications Claiming Priority (2)

Publications (2)

Family

ID=36190809

Family Applications (1)

Country Status (10)

Cited By (8)

Families Citing this family (3)

Family Cites Families (1)

• 2005
  • 2005-11-15 EP EP05826088A patent/EP1812581B1/en not_active Expired - Lifetime
  • 2005-11-15 PT PT05826088T patent/PT1812581E/pt unknown
  • 2005-11-15 CA CA2580151A patent/CA2580151C/en not_active Expired - Fee Related
  • 2005-11-15 AT AT05826088T patent/ATE421996T1/de active
  • 2005-11-15 ES ES05826088T patent/ES2320364T3/es not_active Expired - Lifetime
  • 2005-11-15 WO PCT/US2005/041276 patent/WO2006055528A2/en not_active Ceased
  • 2005-11-15 JP JP2007541425A patent/JP4738416B2/ja not_active Expired - Fee Related
  • 2005-11-15 DK DK05826088T patent/DK1812581T3/da active
  • 2005-11-15 US US11/281,186 patent/US7459301B2/en active Active
  • 2005-11-15 DE DE602005012597T patent/DE602005012597D1/de not_active Expired - Lifetime

Also Published As

Similar Documents

Legal Events