JP6145538B2 - 触媒を用いたシクロヘキサン−1,2−ジカルボン酸ジメチルの生物学的分割による(3aS,7aR)−ヘキサヒドロイソベンゾフラン−1(3H)−オンの製造方法 - Google Patents
触媒を用いたシクロヘキサン−1,2−ジカルボン酸ジメチルの生物学的分割による(3aS,7aR)−ヘキサヒドロイソベンゾフラン−1(3H)−オンの製造方法 Download PDFInfo
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- JP6145538B2 JP6145538B2 JP2016109985A JP2016109985A JP6145538B2 JP 6145538 B2 JP6145538 B2 JP 6145538B2 JP 2016109985 A JP2016109985 A JP 2016109985A JP 2016109985 A JP2016109985 A JP 2016109985A JP 6145538 B2 JP6145538 B2 JP 6145538B2
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- methoxycarbonyl
- dicarboxylate
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- hexahydroisobenzofuran
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- 238000000034 method Methods 0.000 title claims description 28
- 238000004519 manufacturing process Methods 0.000 title claims description 15
- WLYUMBPDHPMKHM-RNFRBKRXSA-N (3as,7ar)-3a,4,5,6,7,7a-hexahydro-3h-2-benzofuran-1-one Chemical compound C1CCC[C@H]2C(=O)OC[C@H]21 WLYUMBPDHPMKHM-RNFRBKRXSA-N 0.000 title claims description 12
- BEEPXSBZGLKIOT-UHFFFAOYSA-N 1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one Chemical compound C1=CC(F)=CC=C1N1C2(CCNCC2)C(=O)NC1 BEEPXSBZGLKIOT-UHFFFAOYSA-N 0.000 title description 10
- 239000003054 catalyst Substances 0.000 title description 3
- 102000004190 Enzymes Human genes 0.000 claims description 38
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- 125000003275 alpha amino acid group Chemical group 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 5
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- QSAWQNUELGIYBC-UHFFFAOYSA-L cyclohexane-1,2-dicarboxylate Chemical compound [O-]C(=O)C1CCCCC1C([O-])=O QSAWQNUELGIYBC-UHFFFAOYSA-L 0.000 claims 2
- YZQPVYAXNFBLAG-UHFFFAOYSA-N 1-methoxycarbonylcyclohexane-1-carboxylic acid Chemical compound COC(=O)C1(C(O)=O)CCCCC1 YZQPVYAXNFBLAG-UHFFFAOYSA-N 0.000 claims 1
- UXGVMFHEKMGWMA-UHFFFAOYSA-N 2-benzofuran Chemical compound C1=CC=CC2=COC=C21 UXGVMFHEKMGWMA-UHFFFAOYSA-N 0.000 claims 1
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- 108010093096 Immobilized Enzymes Proteins 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 150000002148 esters Chemical group 0.000 description 4
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- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 3
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
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- VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 description 2
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- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
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- NACWDKSYLMCVIK-DSMRVHDJSA-N (2S,3aR,7aS)-1-benzyl-2,3,3a,4,5,6,7,7a-octahydroindole-2-carboxylic acid hydrochloride Chemical compound Cl.N1([C@H]2CCCC[C@@H]2C[C@H]1C(=O)O)CC1=CC=CC=C1 NACWDKSYLMCVIK-DSMRVHDJSA-N 0.000 description 1
- PDELQDSYLBLPQO-JGVFFNPUSA-N (3as,7ar)-2,3,3a,4,5,6,7,7a-octahydro-1h-indole Chemical class C1CCC[C@H]2NCC[C@@H]21 PDELQDSYLBLPQO-JGVFFNPUSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- PODOUIALODEQFA-UHFFFAOYSA-N 3-methoxycarbonylcyclohexane-1-carboxylic acid Chemical compound COC(=O)C1CCCC(C(O)=O)C1 PODOUIALODEQFA-UHFFFAOYSA-N 0.000 description 1
- AMKGKYQBASDDJB-UHFFFAOYSA-N 9$l^{2}-borabicyclo[3.3.1]nonane Chemical compound C1CCC2CCCC1[B]2 AMKGKYQBASDDJB-UHFFFAOYSA-N 0.000 description 1
- FEJUGLKDZJDVFY-UHFFFAOYSA-N 9-borabicyclo[3.3.1]nonane Substances C1CCC2CCCC1B2 FEJUGLKDZJDVFY-UHFFFAOYSA-N 0.000 description 1
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- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- 101000898082 Homo sapiens Calbindin Proteins 0.000 description 1
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- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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Images
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
- C12P17/02—Oxygen as only ring hetero atoms
- C12P17/04—Oxygen as only ring hetero atoms containing a five-membered hetero ring, e.g. griseofulvin, vitamin C
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
-
- 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
- C12P7/00—Preparation of oxygen-containing organic compounds
- C12P7/40—Preparation of oxygen-containing organic compounds containing a carboxyl group including Peroxycarboxylic 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
- C12P7/00—Preparation of oxygen-containing organic compounds
- C12P7/62—Carboxylic acid esters
Description
特に断りのない限り、本願の化合物に関して以下の定義を用いる。特定の基に含まれる炭素原子の数は、通常、「Cx−Cy」(x及びyはそれぞれ下限及び上限)で表される。例えば、「C1−C6」で表される基は1〜6つの炭素原子を含む。本明細書中の定義においては、炭素数は主鎖部炭素及び枝部炭素をいうが、アルコキシ置換基などの置換基の炭素原子は含まない。
ジャケット付100mL容容器にシクロヘキサン−1,2−ジカルボン酸ジメチル((2)、4g、20mmol)と0.1Mリン酸カリウムバッファ(39mL、pH8)を入れた。その混合液を40℃で連続的に撹拌し、Novozym(登録商標)435(320mg)を添加した。40℃で43時間撹拌し続け、2M NaOH溶液を添加してpHを8に維持した。反応液のサンプルをGCで分析して出発物質が5%未満しか残っていないことを確認した。反応混合液を濾過して酵素を除去し、濾液をトルエン(20mL)で抽出して残った出発物質を除去した。2M HClを用いて水相のpHを3.5に再調整し、MTBE50mLで2回抽出した。抽出物を合わせて、硫酸マグネシウムで乾燥し、減圧濃縮して、3.2g(86%)の(1S,2R)−2−(メトキシカルボニル)シクロヘキサンカルボン酸(3)をee=98%の無色油状物として得た。分離した酵素は、次の基質/バッファバッチとともに再利用するために新品のバッファで洗浄する。
ジャケット付25mL容容器を0℃未満に冷却し、(1S,2R)−2−(メトキシカルボニル)シクロヘキサンカルボン酸((3)、880mg、4.72mmol)とトリエチルアミン(659μL、4.72mmol)をTHF(6.6mL)に溶解させた溶液を入れた。クロロギ酸エチル(512μL、4.72mmol)のTHF(1.2mL)溶液を数分かけてゆっくり添加し、得た混合液を30分間撹拌した。析出したトリエチルアミン塩酸塩を濾別し、水素化ホウ素ナトリウムを水(4.6mL)に懸濁した懸濁液に12℃で濾液を滴下した。滴下終了後、反応混合液をさらに3.5時間20℃で撹拌した。その後、反応混合液を10℃未満に冷却し、2M HCl溶液でpH4まで酸性化し、ジクロロメタン15mLで2回抽出した。有機抽出物を合わせて、硫酸マグネシウムで乾燥し、溶媒を減圧留去して、無色油状物450mgを得た。この物質を短行程蒸留により精製して、無色油状物170mgをee=98%及び[α]D 20=−39.3°(c1、メタノール)で得た。
30℃に設定したジャケット付2L容容器にシクロヘキサン−1,2−ジカルボン酸ジメチル((2)、84.6g、0.42mol)と0.1Mリン酸カリウムバッファ(900mL、pH8)を入れた。その混合液を30℃で連続的に撹拌し、PLE(600mg、10200ユニット)を添加した。混合液を91時間撹拌し、5M NaOH溶液を添加してpHを8に維持した。混合液の一部をGCで分析して出発物質が5%未満しか残っていないことを確認した。その後、反応混合液をCelite(登録商標)ベッドを通して濾過し、濾液をMTBE(250mL)で抽出して残った出発物質を除去した。その後、濃HClで水相をpH4まで酸性化し、MTBE500mLで3回抽出した。抽出物を合わせて、硫酸マグネシウムで乾燥し、溶媒を減圧留去して、69.28g(収率88%)の(1R,2S)−2−(メトキシカルボニル)シクロヘキサンカルボン酸(4)をee=79%の無色油状物として得た。
Claims (8)
- 配列番号3に記載のアミノ酸配列を含む酵素の存在下でシクロヘキサン−1,2−ジカルボン酸ジメチルを加水分解することを含む、(3aS,7aR)−ヘキサヒドロイソベンゾフラン−1(3H)−オンの製造方法。
- 前記酵素は固定化された形態である、請求項1に記載の製造方法。
- 少なくとも95%eeの(3aS,7aR)−ヘキサヒドロイソベンゾフラン−1(3H)−オンを製造する、請求項1または2に記載の製造方法。
- 少なくとも98%eeの(3aS,7aR)−ヘキサヒドロイソベンゾフラン−1(3H)−オンを製造する、請求項1〜3のいずれか1項に記載の製造方法。
- 配列番号3に記載のアミノ酸配列を含む酵素の存在下でシクロヘキサン−1,2−ジカルボン酸ジメチルを加水分解することを含む、(1S,2R)−2−(メトキシカルボニル)シクロヘキサンカルボン酸の製造方法。
- 前記酵素は固定化された形態である、請求項5に記載の製造方法。
- 95%ee以上の(1S,2R)−2−(メトキシカルボニル)シクロヘキサンカルボン酸を製造する、請求項5または6に記載の製造方法。
- 98%ee以上の(1S,2R)−2−(メトキシカルボニル)シクロヘキサンカルボン酸を製造する、請求項5〜7のいずれか1項に記載の製造方法。
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