JP7431999B2 - フッ素含有キラルアミン系化合物の合成方法 - Google Patents
フッ素含有キラルアミン系化合物の合成方法 Download PDFInfo
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- JP7431999B2 JP7431999B2 JP2022551242A JP2022551242A JP7431999B2 JP 7431999 B2 JP7431999 B2 JP 7431999B2 JP 2022551242 A JP2022551242 A JP 2022551242A JP 2022551242 A JP2022551242 A JP 2022551242A JP 7431999 B2 JP7431999 B2 JP 7431999B2
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- fluorine
- transaminase
- compound
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- dihydroxyketal
- Prior art date
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- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 title claims description 69
- 229910052731 fluorine Inorganic materials 0.000 title claims description 69
- 239000011737 fluorine Substances 0.000 title claims description 69
- -1 amine compounds Chemical class 0.000 title claims description 33
- 238000000034 method Methods 0.000 title claims description 17
- 230000002194 synthesizing effect Effects 0.000 title claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 87
- 102000003929 Transaminases Human genes 0.000 claims description 86
- 108090000340 Transaminases Proteins 0.000 claims description 86
- 238000006243 chemical reaction Methods 0.000 claims description 58
- 150000001875 compounds Chemical class 0.000 claims description 42
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- ISYORFGKSZLPNW-UHFFFAOYSA-N propan-2-ylazanium;chloride Chemical group [Cl-].CC(C)[NH3+] ISYORFGKSZLPNW-UHFFFAOYSA-N 0.000 claims description 20
- 238000001308 synthesis method Methods 0.000 claims description 19
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- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical compound CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 description 33
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- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 101100449067 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) cbs-2 gene Proteins 0.000 description 1
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- 150000001412 amines Chemical class 0.000 description 1
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- WGQKYBSKWIADBV-UHFFFAOYSA-N aminomethyl benzene Natural products NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
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- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
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- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
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Description
上記式1に示す経路の基質には限界があり、三段階反応を経てからこそ目的生成物を得ることができ、収率がやや低い。反応経路は長く、反応には化学試薬を用いて廃ガス、廃液、廃棄物の発生量が多い。式2に示す経路のステップは、二段階反応であるが、反応は、高価な金属リガンド又は触媒の使用を必要とする場合があり、高毒性化合物を使用する可能性もある。同様に、反応には化学試薬を用いて廃ガス、廃液、廃棄物の発生量が大きい。
ここで、Rは、アルキル基、シクロアルキル基、アリール基、ヘテロ原子含有アルキル基、ヘテロ原子含有シクロアルキル基、ヘテロ原子含有アリール基、アミド系化合物残基又はエーテル系化合物残基から選択され、R1とR2は、同一又は異なるH原子又はハロゲン原子であり、
より好ましくは、フッ素含有ジヒドロキシケタール系化合物は、構造式IIで表される構造を有する:
MQKQRTCSQWRELDAAHHLHPFTDTASLNQAGARVMTRGEGVYLWDCEGNKIIDGMAGLWCVNVGYGRKDFAEAARRQMEELPFYNTFYKTTHPAVVELSSLLAEVTPAGFDRVFYTNSGSESVDTMIRMVRRYWDVQGKPEKKTLIGRWWGYHGSTIGGASLGGFKYMHEQGDLPIPGMAHIEQPWWYKHGKDMTPDEFGVVAARWLEEKILEIGADKVAAFVGEPIQGAGGVIVPPATYWPEIERICRKYDVLLVADEVICGFGRTGEWFGHQHFGFQPDLFTAAKGLSSGYLPIGAVFVGKRVAEGLIAGGDFNHGFTYSGHPVCAAVAHANVAALRDEGIVQRVKDDIGPYMQKRWRETFSRFEHVDDVRGVGMLLAFTLVKNKAKRELFPDFGEIGTLCRDIFFRNNLIMDSCGDHIVCAPPLVMTRAEVDEMLAVAERCLEEFEQTLKARGLA(配列番号1)
MQKQRTCSQWRELDAAHHLHPFTDTASLNQAGARVMTRGEGVYLWDCEGNKIIDGMAGLWCVNVGYGRKDFAEAARRQMEELPFYNTFYKTTHPAVVELSSLLAEVTPAGFDRVFYTNSGSESVDTMIRMVRRYWDVQGKPEKKTLIGRWWGYHGSTIGGASLGGFKYMHEQGDLPIPGMAHIEQPWWYKHGKDMTPDEFGVVAARWLEEKILEIGADKVAAFVGEPIQGAGGVIVPPATYWPEIERICRKYDVLLVADEVICGFGRTGEWFGHQHFGFQPDLFTAAKGLSSGYLPIGAVFVGKRVAEGLIAGGDFNHGFTYSGHPVCAAVAHANVAALRDEGIVQRVKDDIGPYMQKRWRETFSRFEHVDDVRGVGMLLAFTLVKNKAKRELFPDFGEIGTLCRDIFFRNNLIMDSCGDHIVAAPPLVMTRAEVDEMLAVAERCLEEFEQTLKARGLA(配列番号2)
MQKQRTCSQWRELDAAHHLHPFTDTASLNQAGARVMTRGEGVYLWDCEGNKIIDGMAGLWCVNVGYGRKDFAEAARRQMEELPFYNTFYKTTHPAVVELSSLLAEVTPAGFDRVFYTNSGSESVDTMIRMVRRYWDVQGKPEKKTLIGRWWGYHGSTIGGASLGGFKYMHEQGDLPIPGMAHIEQPWWYKHGKDMTPDEFGVVAARWLEEKILEIGADKVAAFVGEPIQGAGGVIVPPATYWPEIERICRKYDVLLVADEVICGFGRTGEWFGHQHFGFQPDLFTAAKGLSSGYLPIGAVFVGKRVAEGLIAGGDFNHGFTYSGHPVCAAVAHANVAALRDEGIVQRVKDDIGPYMQKRWRETFSRFEHVDDVRGVGMLLAFTLVKNKAKRELFPDFGEIGTLCRDIFQRNNLIMDSCGDHIVSAPPLVMTRAEVDEMLAVAERCLEEFEQTLKARGLA(配列番号3)
MQKQRTCSQWRELDAAHHLHPFTDTASLNQAGARVMTRGEGVYLWDCEGNKIIDGMAGLWCVNVGYGRKDFAEAARRQMEELPFYNTFYKTTHPAVVELSSLLAEVTPAGFDRVFYTNSGSESVDTMIRMVRRYWDVQGKPEKKTLIGRWWGYHGSTIGGASLGGFKYMHEQGDLPIPGMAHIEQPWWYKHGKDMTPDEFGVVAARWLEEKILEIGADKVAAFVGEPIQGAGGVIVPPATYWPEIERICRKYDVLLVADEVICGFGRTGEWFGHQHFGFQPDLFTAAKGLSSGYLPIGAVFVGKRVAEGLIAGGDFNHGFTYSGHPVCAAVAHANVAALRDEGIVQRVKDDIGPYMQKRWRETFSRFEHVDDVRGVGMLLAFTLVKNKAKRELFPDFGEIGTLCRDIFHRNNLIMDSCGDHIVSAPPLVMTRAEVDEMLAVAERCLEEFEQTLKARGLA(配列番号4)
前記のように、本出願の上記トランスアミナーゼは、フッ素含有ジヒドロキシケタール系化合物に対して基質特異性を有し、このような基質のフッ素含有キラルアミン系化合物への変換を効果的に触媒することができ、かつ、該トランスアミナーゼは、複数種のフッ素含有ジヒドロキシケタール系化合物に対して触媒活性を有し、反応選択性と活性はいずれも高い。該生物酵素触媒合成方法は、経路が短く、製品収率が高いだけでなく、生産コストを大幅に低下させ、有機溶剤と廃水、排気、固体廃棄物の生成を減少させる。
ここで、Rは、アルキル基、シクロアルキル基、アリール基、ヘテロ原子含有アルキル基、ヘテロ原子含有シクロアルキル基、ヘテロ原子含有アリール基、アミド系化合物残基又はエーテル系化合物残基から選択され、R1とR2は、同一又は異なるH原子又はハロゲン原子である。
(実施例1)
室温で250mLの四つ口フラスコに50mLの100mmol/Lリン酸塩緩衝液(5vol)、32mLの5mol/Lイソプロピルアミン塩酸塩溶液(3.2vol、3eq)を添加し、pH=7.5~8.0に調整する。さらに0.1gのピリドキサールリン酸(1wt%)、10gの
(実施例2)
室温で250mLの四つ口フラスコに50mLの100mmol/Lリン酸塩緩衝液(5vol)、25mLの5mol/Lイソプロピルアミン塩酸塩溶液(2.5vol、3eq)を添加し、pH=8.0~8.5に調整する。さらに0.1gのピリドキサールリン酸(1wt%)、10gの
(実施例3)
室温で250mLの四つ口フラスコに50mLの100mmol/Lリン酸塩緩衝液(5vol)、31mLの5mol/Lイソプロピルアミン塩酸塩溶液(3.1vol、3eq)を添加し、pH=7.0~7.5に調整する。さらに0.1gのピリドキサールリン酸(1wt%)、10gの
(実施例4)
室温で250mLの四つ口フラスコに50mLの100mmol/Lリン酸塩緩衝液(5vol)、24mLの5mol/Lイソプロピルアミン塩酸塩溶液(2.4vol、3eq)を添加し、pH=8.5~9.0に調整する。さらに0.1gのピリドキサールリン酸(1wt%)、10gの
(実施例5)
室温で250mLの四つ口フラスコに50mLの100mmol/Lリン酸塩緩衝液(5vol)、20mLの5mol/Lイソプロピルアミン塩酸塩溶液(2vol、3eq)を添加し、pH=7.5~8.0に調整する。さらに0.1gのピリドキサールリン酸(1wt%)、10gの
(実施例6)
室温で250mLの四つ口フラスコに50mLの100mmol/Lリン酸塩緩衝液(5vol)、23mLの5mol/Lイソプロピルアミン塩酸塩溶液(2.3vol、3eq)を添加し、pH=7.0~7.5に調整する。さらに0.1gのピリドキサールリン酸(1wt%)、10gの
(実施例7)
室温で500mLの四つ口フラスコに200mLの100mmol/Lリン酸塩緩衝液(10vol)、60mLの5mol/Lイソプロピルアミン塩酸塩溶液(3vol、3eq)を添加し、pH=7.5~8.0に調整する。さらに0.2gのピリドキサールリン酸(1wt%)、20gの
(実施例8)
室温で250mLの四つ口フラスコに80mLの100mmol/Lリン酸塩緩衝液(8vol)、23mLの5mol/Lイソプロピルアミン塩酸塩溶液(2.3vol、3eq)を添加し、pH=7.0~7.5に調整する。さらに0.1gのピリドキサールリン酸(1wt%)、10gの
(実施例9)
室温で250mLの四つ口フラスコに50mLの100mmol/Lリン酸塩緩衝液(10vol)、16mLの5mol/Lイソプロピルアミン塩酸塩溶液(3.2vol、3eq)を添加し、pH=7.5~8.0に調整する。さらに0.05gのピリドキサールリン酸(1wt%)、5gの
(実施例10)
室温で250mLの四つ口フラスコに50mLの100mmol/Lリン酸塩緩衝液(10vol)、18mLの5mol/Lイソプロピルアミン塩酸塩溶液(3.6vol、3eq)を添加し、pH=7.5~8.0に調整する。さらに0.05gのピリドキサールリン酸(1wt%)、5gの
(実施例11)
室温で250mLの四つ口フラスコに50mLの100mmol/Lリン酸塩緩衝液(10vol)、14mLの5mol/Lイソプロピルアミン塩酸塩溶液(2.8vol、3eq)を添加し、pH=7.5~8.0に調整する。さらに0.05gのピリドキサールリン酸(1wt%)、5gの
(実施例12)
室温で250mLの四つ口フラスコに60mLの100mmol/Lリン酸塩緩衝液(12vol)、13mLの5mol/Lイソプロピルアミン塩酸塩溶液(2.6vol、3eq)を添加し、pH=7.5~8.0に調整する。さらに0.05gのピリドキサールリン酸(1wt%)、5gの
(実施例13)
実施例1を例として、反応する酵素量を最適化する具体的操作は以下のとおりである:室温で10mLバイアル瓶に1mLの100mmol/Lリン酸塩緩衝液(5vol)、0.64mlの5mol/Lイソプロピルアミン塩酸塩溶液(3.2vol、3eq)を添加し、pH=7.5~8.0に調整する。さらに0.002gのピリドキサールリン酸(1wt%)、0.2gの
(実施例14)
実施例1を例として、基質濃度を最適化する具体的操作は以下のとおりである:室温で10~50mLのバイアル瓶(反応体積に応じて適切な振盪瓶を選択する。)にそれぞれ0.3mL、0.38mL、0.50mL、0.62mL、0.78mL、0.96mL、1.16mL、1.46ml、1.82ml、2.28ml、2.96ml、3.96ml、5.56ml、8.96mlの100mmol/Lリン酸塩緩衝液(それぞれ1.5vol、1.9vol、2.5vol、3.1vol、3.9vol、4.8vol、5.8vol、7.3vol、9.1vol、11.4vol、14.8vol、19.8vol、27.8vol、44.8volである。)、0.64mlの5mol/Lのイソプロピルアミン塩酸塩溶液(3.2vol,3eq)を添加し、pH=7.5~8.0に調整する。さらに0.002gのピリドキサールリン酸(1wt%)、0.2gの
(実施例15)
実施例1を例として、アミノドナーに対する最適化の具体的操作は以下のとおりである:室温で10~50mLバイアル瓶(反応体積に応じて適当な振盪瓶を選択する。)にlmlの100mmol/Lリン酸塩緩衝液(5vol)を添加し、それぞれ3eqのアミノドナーのシステム(アミノドナーは、それぞれイソプロピルアミン、イソプロピルアミン塩酸塩、アラニン、アニリン、n-ブチルアミン)を使用し、PH=7.5~8.0に調整する。さらに0.002gのピリドキサールリン酸(1wt%)、0.2gの
(実施例16)
実施例1の基質を例として、Mycobacterium goodii(GenBank:AKS36000.1)に由来するトランスアミナーゼ番号TA1、Fonsecaea pedrosoi CBS 271.37(NCBI Reference Sequence:XP_013286281.1)に由来するトランスアミナーゼ番号TA2、Klebsiella pneumoniae subsp. pneumoniae Ecl8(GenBank:CCN29541.1)に由来するトランスアミナーゼ番号TA3、Chromobacterium violaceum DSM30191(CVTA)(NCBI Reference Sequence:WP_011135573.1)に由来するトランスアミナーゼ番号TA4、Paracoccus denitrificans(NCBI Reference Sequence:WP_011746975.1)に由来するトランスアミナーゼ番号TA5、Penicillium brasilianum(GenBank:CEJ55334.1)に由来するトランスアミナーゼ番号TA6、Enterobacter sp.TL3(NCBI Reference Sequence:WP_014885677.1)に由来するトランスアミナーゼ番号TA7、Aspergillus terreus NIH2624(NCBI Reference Sequence:XP_001209325.1)に由来するトランスアミナーゼ番号TA8、Exophiala spinifera(NCBI Reference Sequence:XP_016233821.1)に由来するトランスアミナーゼ番号TA9、Deinococcus geothermalis(strain DSM 11300)(NCBI Reference Sequence:WP_011530545.1)に由来するトランスアミナーゼ番号TA10、Geomyces destructans 20631-21(GdTA)in E.coli(GenBank:ELR05573.1)に由来するトランスアミナーゼ番号TA 11、Pseudomonas putida KT2440(NCBI Reference Sequence:WP_010954554.1)に由来するトランスアミナーゼ番号TA12、Lysinibacillus sphaericus(NCBI Reference Sequence:WP_024363741.1)に由来するトランスアミナーゼ番号TA13、Bacillus megaterium DSM 319(NCBI Reference Sequence:WP_013082219.1)に由来するトランスアミナーゼ番号TA14、Trichoderma harzianum(GenBank:KKP07030.1)に由来するトランスアミナーゼ番号TA15、Aspergillus fumigatus R-ATAs(AspFum)(NCBI Reference Sequence:XP_748821.1)に由来するトランスアミナーゼ番号TA16、Geobacillus thermodenitrificans subsp. thermodenitrificans DSM 465(NCBI Reference Sequence:WP_008879436.1)に由来するトランスアミナーゼ番号TA17、Cladophialophora bantiana CBS 173.52(NCBI Reference Sequence:XP_016617948.1)に由来するトランスアミナーゼ番号TA18、Bacillus megaterium(NCBI Reference Sequence:WP_016763026.1)に由来するトランスアミナーゼ番号TA19、Burkholderia thailandensis MSMB121(BtS-TA)(GenBank:AGK49399.1)に由来するトランスアミナーゼ番号TA20、Klebsiella pneumoniae subsp. pneumoniae MGH 78578(NCBI Reference Sequence: WP_002920226.1)に由来するトランスアミナーゼ番号TA21、Geobacillus toebii(NCBI Reference Sequence:WP_062753894.1)に由来するトランスアミナーゼ番号TA22、Talaromyces cellulolyticus(GenBank:GAM37533.1)に由来するトランスアミナーゼ番号TA23、Chromobacterium violaceum DSM30191(CVTA)(NCBI Reference Sequence:WP_011135573.1)に由来するトランスアミナーゼで進化して得られた突然変異体TA4-V1(対応配列配列番号1)、TA4-V2(対応配列配列番号2)、TA4-V3(対応配列配列番号3)、TA4-V4(対応配列配列番号4)に対して、10mgレベルのスクリーニング反応を実行し、操作は以下のとおりである:
100mmol/Lのリン酸塩緩衝液、5mol/Lイソプロピルアミン塩酸塩溶液を体積比5:2になるように50ml溶液を配合し、さらに0.005gのピリドキサールリン酸を加え、撹拌して均一に混合する。上記の溶液0.3mlを取って、それぞれ96ウェルプレートに追加し、10mg
Claims (13)
- リン酸緩衝液と前記アミノドナーを混合し、第1混合液を得て、
前記第1混合液に前記フッ素含有ジヒドロキシケタール系化合物を添加し、第2混合液を得ることと、
前記第2混合液に前記トランスアミナーゼを添加して、反応混合液を得ることと、
前記反応混合液から前記フッ素含有キラルアミン系化合物を分離して得ることとを含む、請求項1に記載の合成方法。 - 前記第1混合液に前記フッ素含有ジヒドロキシケタール系化合物を添加する前に、前記合成方法は、前記第1混合液のpH値を7.0~9.0に調整することをさらに含む、請求項2に記載の合成方法。
- 前記第2混合液に前記トランスアミナーゼを添加し、かつ前記トランスアミナーゼを添加した前記第2混合液のpHを7.0~9.0に調整して、前記反応混合液を得ることをさらに含む、請求項3に記載の合成方法。
- 前記反応混合液から前記フッ素含有キラルアミン系化合物を分離して得ることは、
前記反応混合液の酸性度を調整して前記トランスアミナーゼを変性させることと、
変性後の前記トランスアミナーゼを濾過除去して濾液を得ることと、
前記濾液を抽出して、前記フッ素含有キラルアミン系化合物を得ることとを含む、請求項2に記載の合成方法。 - 前記反応混合液のpH値を1~2に調整する、請求項5に記載の合成方法。
- ジクロロメタンを用いて前記濾過を行う、請求項5に記載の合成方法。
- ジクロロメタンを用いて前記抽出を行う、請求項5に記載の合成方法。
- 前記抽出は2~5回であり、前記抽出の後に、抽出した有機相を乾燥するステップをさらに含む、請求項5に記載の合成方法。
- 毎回の抽出で得られた有機相を合わせて抽出物を得て、
前記抽出物を乾燥して、乾燥した有機相生成物を得て、
前記乾燥した有機相生成物を、温度<35℃、圧力≦-0.06Mpaの条件で留分なしまでに濃縮して、前記フッ素含有キラルアミン系化合物を得る、請求項5に記載の合成方法。 - 前記トランスアミナーゼと前記フッ素含有ジヒドロキシケタール系化合物の質量比は0.4:1~1.0:1である、請求項1~10のいずれか一項に記載の合成方法。
- 前記フッ素含有ジヒドロキシケタール系化合物の濃度は60g/L~100g/Lである、請求項1~10のいずれか一項に記載の合成方法。
- 前記アミノドナーは、イソプロピルアミン、イソプロピルアミンの塩酸塩、アラニン、アニリン又はn-ブチルアミンから選択される、請求項1~10のいずれか一項に記載の合成方法。
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US11952575B2 (en) * | 2017-11-15 | 2024-04-09 | Asymchem Life Science (Tianjin) Co., Ltd | Transaminase mutant and use thereof |
CN108384767B (zh) * | 2018-02-05 | 2020-08-14 | 凯莱英生命科学技术(天津)有限公司 | 转氨酶突变体及其应用 |
ES2931540T3 (es) * | 2018-02-05 | 2022-12-30 | Asymchem Life Science Tianjin Co Ltd | Mutante de transaminasa y aplicación del mismo |
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