JP2008520206A - Candidaantarcticaリパーゼを使用した光学分割による光学活性N−カルバメート保護化β−ラクタムを調製するためのプロセス - Google Patents
Candidaantarcticaリパーゼを使用した光学分割による光学活性N−カルバメート保護化β−ラクタムを調製するためのプロセス Download PDFInfo
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- JP2008520206A JP2008520206A JP2007541425A JP2007541425A JP2008520206A JP 2008520206 A JP2008520206 A JP 2008520206A JP 2007541425 A JP2007541425 A JP 2007541425A JP 2007541425 A JP2007541425 A JP 2007541425A JP 2008520206 A JP2008520206 A JP 2008520206A
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- Prior art keywords
- group
- lipase
- diyl
- lactam
- protected
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000003952 β-lactams Chemical class 0.000 title claims abstract description 39
- 102000004882 Lipase Human genes 0.000 title claims abstract description 29
- 108090001060 Lipase Proteins 0.000 title claims abstract description 29
- 239000004367 Lipase Substances 0.000 title claims abstract description 26
- 235000019421 lipase Nutrition 0.000 title claims abstract description 26
- 241001661345 Moesziomyces antarcticus Species 0.000 title claims abstract description 20
- 230000003287 optical effect Effects 0.000 title description 4
- 238000004519 manufacturing process Methods 0.000 title description 2
- 239000000203 mixture Substances 0.000 claims abstract description 25
- 125000006239 protecting group Chemical group 0.000 claims abstract description 15
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 12
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical group NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 230000003197 catalytic effect Effects 0.000 claims description 6
- 125000003367 polycyclic group Chemical group 0.000 claims description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 5
- 125000002950 monocyclic group Chemical group 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- QYCGBAJADAGLLK-UHFFFAOYSA-N 1-(cyclohepten-1-yl)cycloheptene Chemical group C1CCCCC=C1C1=CCCCCC1 QYCGBAJADAGLLK-UHFFFAOYSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 claims description 3
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- ARUKYTASOALXFG-UHFFFAOYSA-N cycloheptylcycloheptane Chemical group C1CCCCCC1C1CCCCCC1 ARUKYTASOALXFG-UHFFFAOYSA-N 0.000 claims description 3
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 239000011347 resin Substances 0.000 claims description 3
- 229920005989 resin Polymers 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000003125 aqueous solvent Substances 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 125000006736 (C6-C20) aryl group Chemical group 0.000 claims 1
- GNVMUORYQLCPJZ-UHFFFAOYSA-N carbamothioic s-acid Chemical group NC(S)=O GNVMUORYQLCPJZ-UHFFFAOYSA-N 0.000 claims 1
- 239000007795 chemical reaction product Substances 0.000 claims 1
- 229940125904 compound 1 Drugs 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- 125000000547 substituted alkyl group Chemical group 0.000 claims 1
- 108090000790 Enzymes Proteins 0.000 abstract description 22
- 102000004190 Enzymes Human genes 0.000 abstract description 22
- 238000006555 catalytic reaction Methods 0.000 abstract description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract description 3
- 238000006911 enzymatic reaction Methods 0.000 abstract description 2
- -1 β-lactam compounds Chemical class 0.000 description 88
- 239000000047 product Substances 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 16
- 238000002360 preparation method Methods 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 10
- 125000002947 alkylene group Chemical group 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 150000001721 carbon Chemical group 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 230000002255 enzymatic effect Effects 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- 125000001188 haloalkyl group Chemical group 0.000 description 6
- 150000003951 lactams Chemical group 0.000 description 6
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 description 5
- 150000001336 alkenes Chemical class 0.000 description 5
- 125000003342 alkenyl group Chemical group 0.000 description 5
- 150000001345 alkine derivatives Chemical class 0.000 description 5
- 125000000304 alkynyl group Chemical group 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- 230000000707 stereoselective effect Effects 0.000 description 5
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 5
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 5
- 125000005915 C6-C14 aryl group Chemical group 0.000 description 4
- 0 CC(C)(C)OC(N[C@@]([C@]1C=C[C@@]2C1)[C@]2C(N)=*)=O Chemical compound CC(C)(C)OC(N[C@@]([C@]1C=C[C@@]2C1)[C@]2C(N)=*)=O 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
- 230000002210 biocatalytic effect Effects 0.000 description 4
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012736 aqueous medium Substances 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 238000004296 chiral HPLC Methods 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthene Chemical compound C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- DHXVLRDECZGGEN-UHFFFAOYSA-N tert-butyl 4-oxo-1-azatricyclo[4.2.1.02,5]non-7-ene-3-carboxylate Chemical compound C1N2C3C(C(=O)OC(C)(C)C)C(=O)C3C1C=C2 DHXVLRDECZGGEN-UHFFFAOYSA-N 0.000 description 3
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- WHPFEQUEHBULBW-UHFFFAOYSA-N 2,4-dichloro-5-fluoropyrimidine Chemical group FC1=CN=C(Cl)N=C1Cl WHPFEQUEHBULBW-UHFFFAOYSA-N 0.000 description 2
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
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- UNSHMXUHOHBLIQ-UHFFFAOYSA-N 3-[4-chloro-3-(2-methylphenoxy)naphthalen-1-yl]-6-(trifluoromethyl)-1H-pyrimidine-2,4-dione Chemical compound ClC1=C(C=C(C2=CC=CC=C12)N1C(NC(=CC1=O)C(F)(F)F)=O)OC1=C(C=CC=C1)C UNSHMXUHOHBLIQ-UHFFFAOYSA-N 0.000 description 2
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- VIUBJDIKPUGNPQ-UHFFFAOYSA-N 5-fluoro-2-n-[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine Chemical compound C1CN(C)CCN1C(C(=C1)C)=CC=C1NC1=NC=C(F)C(N)=N1 VIUBJDIKPUGNPQ-UHFFFAOYSA-N 0.000 description 1
- 208000032170 Congenital Abnormalities Diseases 0.000 description 1
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Classifications
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- 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
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- 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
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- 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
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- 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
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- Chemical & Material Sciences (AREA)
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- 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)
Abstract
Description
本願は、米国特許法第119条第(e)項の下、2004年11月15日に出願された出願番号60/628,401に利益を主張し、これらの内容は本明細書中に参考として援用される。
本開示は、キラル合成に使用され得る、N−保護化β−ラクタムのラセミ混合物から立体特異的な生成物を生成するための方法と関連している。特に、この方法は立体異性的に純粋なβ−ラクタム化合物およびβ−アミノカルボン酸化合物を合成するために使用され得、それらは、幅広い種類の立体異性的に純粋な化合物を合成するための出発物質として使用され得る。
有機合成における酵素の使用は、広く普及してきている。自然が提供する道具を開発することにより、その酵素自身が持つキラル性のおかげで、キラル分子は選択的に分離もしくは分割され得、もしくは、キラリティを持たない分子内にキラリティが組み込まれ得る。酵素は明確な立体的制御を提供し、化学的変換を促進させるが、もしそうでなければ、通常の合成化学の使用ではその変換を行うことは難しい。さらに重要なこととして、一般的に酵素は、化学合成中ではしばしば妨げになり、さらなる工程を加える保護基の操作の必要性を除去する。このように、酵素は、活性薬剤、およびそれに導く有用な中間体を合成および/もしくは分割するために、商業的に使用される。
本開示は、キラル合成で使用され得る、N−保護化β−ラクタムのラセミ混合物から立体特異的な生成物を生成するための方法を提供する。この方法は立体異性的に純粋なβ−ラクタムおよびβ−アミノカルボン酸の誘導体を合成するために使用され得、それらは、幅広い種類の分子の特定のジアステレオマーを合成するための出発物質として使用され得る。例えば、立体異性的に純粋なβ−ラクタムは、ジアステレオマー的に純粋な抗増殖性(1R,2R,3S,4S)−N4−(3−アミノカルボニルビシクロ[2.2.1]ヘプト−5−エン−2−イル)−5−フルオロ−N2−[3−メチル−4−(4−メチルピペラジン−1−イル)フェニル]−2,4−ピリミジンジアミン、および多種の化合物を合成するための出発物質として使用され得、この多種の化合物は同時係属中の、2005年5月18日に出願された出願番号11/133,419、国際出願番号PCT/US05/17470、および本明細書と同時に出願された出願番号_____、発明の名称“Stereoisomerically Enriched 3−Aminocarbonyl Bicycloheptene Pyrimidinediamine Compounds and Their Uses”(代理人事件番号375462−039USで確認される)に記載されている。
(5.1 定義)
本明細書中で使用されている場合、以下に述べる用語は以下の意味をもつと意図される。
一つの局面では、Candida antarcticaからのリパーゼ酵素を使用する、β−ラクタムジアステレオマーおよび/またはβ−ラクタムエナンチオマーの混合物(例えば、(2−エキソ,3−エキソ)シスβ−ラクタムのラセミ混合物)を立体異性的に純粋な生成物へ分割するための方法が提供される。いくつかの実施形態において、その方法は、構造式1および2:
上記に述べたように、Candida antarcticaからのリパーゼは、構造式1のエナンチオマーをインタクトに残して、選択的に構造式2のエナンチオマーを加水分解する。それゆえに、この反応の生成物は、構造式1および構造式4に従う化合物の混合物であり:
本明細書中に記載される本発明は、以下の実施例の参照によりさらに定義され、これらの実施例は、本明細書中に記載される多種の化合物の調製、これらの生物学的活性のアッセイ方法、および、これらの使用方法を記載している。本発明の範囲から逸脱することなく、材料と方法との両方に対して、多くの修正が実施され得ることは当業者には明白である。
6.3.1 立体異性的に純粋なN−Boc−βラクタムの調製
Claims (13)
- 前記カルバメート保護基が式−C(O)OR1の保護基であり、R1が非置換または置換アルキル、非置換または置換(C6−C20)アリール、および置換または非置換(C7−C26)アリールアルキルから選択される請求項1に記載の方法。
- R1がt−ブチルおよびベンジルから選択される請求項2に記載の方法。
- Aがビシクロヘプテニル、ビシクロヘプチル、シクロヘプチル、シクロヘプテニル、シクロヘキシル、シクロヘキセニル、シクロペンチル、シクロペンテニル、シクロプロピルおよびシクロブチルから選択される請求項1に記載の方法。
- 前記リパーゼがタイプBリパーゼである請求項1に記載の方法。
- 前記リパーゼが樹脂に結合している請求項1に記載の方法。
- 触媒量の前記リパーゼが使用される請求項1に記載の方法。
- 約0〜80℃の範囲の温度で前記接触が行われる請求項1に記載の方法。
- 前記温度が約20〜60℃の範囲である請求項8に記載の方法。
- ジイソプロピルエーテル、テトラヒドロフラン、ブタノール、トルエン、ヘキサン、アセトニトリル、およびこれらの混合物から選択される溶媒内で前記接触が行われる請求項1に記載の方法。
- 前記溶媒が約0.1から1.0w%の範囲の含水量を有する請求項11に記載の方法。
- 化合物4から化合物1を単離する前記手段をさらに包含する請求項1に記載の方法。
- 水性溶媒および有機溶媒を使用した酸塩基抽出によって前記単離が行われる請求項12に記載の方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US62840104P | 2004-11-15 | 2004-11-15 | |
US60/628,401 | 2004-11-15 | ||
PCT/US2005/041276 WO2006055528A2 (en) | 2004-11-15 | 2005-11-15 | Process for the preparation of an optically acitive n-carbamate protected beta-lactam by optical resolution employing a candida antarctica lipase |
Publications (3)
Publication Number | Publication Date |
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JP2008520206A true JP2008520206A (ja) | 2008-06-19 |
JP2008520206A5 JP2008520206A5 (ja) | 2009-01-08 |
JP4738416B2 JP4738416B2 (ja) | 2011-08-03 |
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Application Number | Title | Priority Date | Filing Date |
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JP2007541425A Expired - Fee Related JP4738416B2 (ja) | 2004-11-15 | 2005-11-15 | Candidaantarcticaリパーゼを使用した光学分割による光学活性N−カルバメート保護化β−ラクタムを調製するためのプロセス |
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US (1) | US7459301B2 (ja) |
EP (1) | EP1812581B1 (ja) |
JP (1) | JP4738416B2 (ja) |
AT (1) | ATE421996T1 (ja) |
CA (1) | CA2580151C (ja) |
DE (1) | DE602005012597D1 (ja) |
DK (1) | DK1812581T3 (ja) |
ES (1) | ES2320364T3 (ja) |
PT (1) | PT1812581E (ja) |
WO (1) | WO2006055528A2 (ja) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1763514A2 (en) * | 2004-05-18 | 2007-03-21 | Rigel Pharmaceuticals, Inc. | Cycloalkyl substituted pyrimidinediamine compounds and their uses |
GB2420559B (en) * | 2004-11-15 | 2008-08-06 | Rigel Pharmaceuticals Inc | Stereoisomerically enriched 3-aminocarbonyl bicycloheptene pyrimidinediamine compounds and their uses |
EP1960372B1 (en) | 2005-12-15 | 2015-12-09 | Rigel Pharmaceuticals, Inc. | Kinase inhibitors and their uses |
HU227663B1 (en) * | 2007-07-09 | 2011-10-28 | Univ Szegedi | Resolution process |
KR101741168B1 (ko) | 2008-12-22 | 2017-05-29 | 밀레니엄 파머슈티컬스 인코퍼레이티드 | 오로라 키나아제 억제제 및 항cd 항체의 병용 |
EP2489663A1 (en) | 2011-02-16 | 2012-08-22 | Almirall, S.A. | Compounds as syk kinase inhibitors |
WO2015085289A1 (en) | 2013-12-06 | 2015-06-11 | Millennium Pharmaceuticals, Inc. | Combination of aurora kinase inhibitors and anti-cd30 antibodies |
US11874276B2 (en) | 2018-04-05 | 2024-01-16 | Dana-Farber Cancer Institute, Inc. | STING levels as a biomarker for cancer immunotherapy |
CN111194304B (zh) * | 2018-04-18 | 2022-09-27 | 宜昌东阳光长江药业股份有限公司 | 一种桥环化合物的制备方法 |
US20220305048A1 (en) | 2019-08-26 | 2022-09-29 | Dana-Farber Cancer Institute, Inc. | Use of heparin to promote type 1 interferon signaling |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002520027A (ja) * | 1998-07-09 | 2002-07-09 | ロンザ ア−ゲ− | (1r,4s)−2−アザビシクロ[2.2.1]ヘプタ−5−エン−3−オン誘導体の製造方法 |
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2005
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- 2005-11-15 DE DE602005012597T patent/DE602005012597D1/de active Active
- 2005-11-15 DK DK05826088T patent/DK1812581T3/da active
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- 2005-11-15 US US11/281,186 patent/US7459301B2/en active Active
- 2005-11-15 AT AT05826088T patent/ATE421996T1/de active
- 2005-11-15 JP JP2007541425A patent/JP4738416B2/ja not_active Expired - Fee Related
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JP2002520027A (ja) * | 1998-07-09 | 2002-07-09 | ロンザ ア−ゲ− | (1r,4s)−2−アザビシクロ[2.2.1]ヘプタ−5−エン−3−オン誘導体の製造方法 |
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Publication number | Publication date |
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EP1812581A2 (en) | 2007-08-01 |
JP4738416B2 (ja) | 2011-08-03 |
CA2580151A1 (en) | 2006-05-26 |
PT1812581E (pt) | 2009-04-22 |
ES2320364T3 (es) | 2009-05-21 |
DK1812581T3 (da) | 2009-05-11 |
EP1812581B1 (en) | 2009-01-28 |
WO2006055528A2 (en) | 2006-05-26 |
US7459301B2 (en) | 2008-12-02 |
DE602005012597D1 (de) | 2009-03-19 |
WO2006055528A3 (en) | 2006-08-31 |
US20060166308A1 (en) | 2006-07-27 |
ATE421996T1 (de) | 2009-02-15 |
CA2580151C (en) | 2014-02-04 |
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