JP2008214345A - 光学活性化合物の製造方法 - Google Patents
光学活性化合物の製造方法 Download PDFInfo
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- JP2008214345A JP2008214345A JP2008028655A JP2008028655A JP2008214345A JP 2008214345 A JP2008214345 A JP 2008214345A JP 2008028655 A JP2008028655 A JP 2008028655A JP 2008028655 A JP2008028655 A JP 2008028655A JP 2008214345 A JP2008214345 A JP 2008214345A
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- Prior art keywords
- optically active
- acid
- reaction
- active compound
- ion
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- 238000000034 method Methods 0.000 claims abstract description 47
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- RSTKLPZEZYGQPY-UHFFFAOYSA-N 3-(indol-3-yl)pyruvic acid Chemical compound C1=CC=C2C(CC(=O)C(=O)O)=CNC2=C1 RSTKLPZEZYGQPY-UHFFFAOYSA-N 0.000 claims abstract description 25
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- 150000001370 alpha-amino acid derivatives Chemical class 0.000 claims abstract description 19
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- RMLYXMMBIZLGAQ-HZMBPMFUSA-N (2s,4s)-4-amino-2-hydroxy-2-(1h-indol-3-ylmethyl)pentanedioic acid Chemical compound C1=CC=C2C(C[C@](O)(C[C@H](N)C(O)=O)C(O)=O)=CNC2=C1 RMLYXMMBIZLGAQ-HZMBPMFUSA-N 0.000 claims description 24
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- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 4
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—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
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—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
- C07D209/20—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 substituted additionally by nitrogen atoms, e.g. tryptophane
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- Chemical & Material Sciences (AREA)
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Abstract
【解決手段】ピルビン酸とインドール−3−ピルビン酸との交差アルドール反応をする際に、2級アミン含有光学活性α−アミノ酸と金属イオンを共存させる。
【選択図】なし
Description
(1)オーガニック レターズ(Organic Letters)2000年2巻19号2967〜2970頁記載の方法。[非特許文献1]
(2)米国特許第5994559号記載の方法。[特許文献1]
(3)シンセティック コミュニケーション(Synthetic Communication)1994年24巻22号3197〜3211頁記載の方法。[非特許文献2]
(4)シンセティック コミュニケーション(Synthetic Communication)1993年23巻18号2511〜2526頁記載の方法。[非特許文献3]
(5)テトラヘドロン レターズ(Tetrahedron Letters)2001年42巻39号6793〜6796頁記載の方法。[非特許文献4]
(6)特開2002−060382号公報記載の方法。[特許文献2]
(7)特開2004−331650号公報記載の方法。[特許文献3]
(8)WO2004/067494記載の手法。[特許文献4]
(9)WO2003/059865記載の方法。[特許文献5]
(1)オーガニック アンド バイオモレキュラーケミストリー(Organic&Biomolecular Chemistry)2004年2巻1077〜1085頁記載の手法。[非特許文献5]
(2)ケミカル コミュニケーションズ(Chemical Communications)2000年2211〜2212頁記載の手法。[非特許文献6]
(3)オーガニック レターズ(Organic Letters)2005年7巻21号4657〜4660頁記載の手法。[非特許文献7]
〔1〕下記式(1)で表されるピルビン酸と下記式(2)で表されるインドール−3−ピルビン酸とを、2級アミン含有光学活性α−アミノ酸、および金属イオンの共存下にて反応させる工程を含有することを特徴とする、下記一般式(3)で表される光学活性化合物(塩の形態も含む)の製造方法。
・バチルス スフェリカス Bacillus sphaericus ATCC10208
・バチルス プルビファシエンス Bacillus pulvifaciens AJ1327
・パエニバチルス ラバエ サブスピシーズ プルビファシエンス Paenibacillus larvae subsp. pulvifaciens ATCC 13537
・バチルス マセランス Bacillus macerans AJ1617
・パエニバチルス マセランス Paenibacillus macerans ATCC 8244
・バチルス レンタス Bacillus lentus AJ12699
・バチルス レンタス Bacillus lentus ATCC 10840
上記培地成分として用いる具体的物質として、例えば、炭素源としては、利用する微生物が利用可能であれば制限は無く、例えばグルコース、シュークロース、フルクトース、グリセロール、酢酸等、又はこれらの混合物を使用することができる。窒素源としては、硫酸アンモニウム、塩化アンモニウム、尿素、酵母エキス、肉エキス、コーンスティープリカー、カゼイン加水分解物等、或いはこれらの混合物を使用することができる。具体的な培地組成として、例えばフマル酸 0.5g/dl、酵母エキス 1g/dl、ペプトン 1g/dl、硫安 0.3g/dl、K2HPO4 0.3g/dl、KH2PO4 0.1g/dl、FeSO4・7H2O 1mg/dl、及びMnSO4・4H2O 1mg/dl(pH7.0)を含む培地等が挙げられる。
1)4−ヒドロキシ−4−(3−インドリルメチル)−2−ケトグルタル酸を含むアルドール反応液に過剰量(インドール−3−ピルビン酸仕込みモル数の約4倍モル)のヒドキシアミンを加え、溶液のpH値が7.0〜10.0になるように2規定水酸化ナトリウム水溶液または1規定塩酸を加えて調節した。
2)室温にて終夜撹拌することで4−ヒドロキシ−4−(3−インドリルメチル)−2−ヒドロキシイミノグルタル酸に変換した。
3)得られた反応液の一部をメスフラスコに計り取り、4−ヒドロキシ−4−(3−インドリルメチル)−2−ヒドロキシイミノグルタル酸の濃度が100〜150ppmになるように反応液を純水で希釈し、分析用サンプルを調製した。
4)上記3)の分析用サンプルを下記高速液体クロマトグラフィー条件にかけ、4−ヒドロキシ−4−(3−インドリルメチル)−2−ヒドロキシイミノグルタル酸の標品溶液との面積百分率比較により生成量を計算し、使用したインドール−3−ピルビン酸に対する収率(%)を算出した。
カラム;CAPCELL PAK C18(MGII)5μm 4.6mm×250mm
カラム温度;25℃
検出波長;210nm
流速;1.0ml/min
移動液組成;
A液 KH2PO4(20mM)+K2HPO4(20mM)水溶液/アセトニトリル
=100/5
B液 KH2PO4(20mM)+K2HPO4(20mM)水溶液/アセトニトリル
=1/1
サンプル注入量;10μL
保持時間;11分(4−ヒドロキシ−4−(3−インドリルメチル)−2−ヒドロキシイミノグルタル酸)
5)上記3)の分析用サンプルを、下記の高速液体クロマトグラフィー条件にかけ、4−ヒドロキシ−4−(3−インドリルメチル)−2−ヒドロキシイミノグルタル酸の4位鏡像体に由来するピーク積分値を基に、下記手法により4位鏡像体選択性および4位鏡像体過剰率(%ee)を下式により求めた。
(符号+の場合は%ee4Sとし、符合−の場合は%ee4Rとする)
カラム;SUMICHIRAL OA7100 4.6mmx250mm
カラム温度;10℃
検出波長;210nm
流速;0.5ml/min
移動液組成;
A液 KH2PO4(20mM)+K2HPO4(20mM)水溶液/アセトニトリル
=100/5
B液 KH2PO4(20mM)+K2HPO4(20mM)水溶液/アセトニトリル
=1/1
注入量;10μL
保持時間;4R体 19分、4S体 21分
酢酸亜鉛0.36g(2.0ミリモル)とトランス−L−ヒドロキシプロリン1.07g(8.2ミリモル)を水25ミリリットルに溶解し、2規定水酸化ナトリウム水溶液を加えてpHを8.3に調節することで、トランス−L−ヒドロキシプロリン/亜鉛(II)錯体水溶液を調製した。
調製例1と同様にして、表1に示す金属塩と各種光学活性2級アミン含有アミノ酸を用いて、錯体水溶液を調製した。結果を表1に示した。
アルゴン気流下にて、インドール−3−ピルビン酸0.21gを水5.0mlにけん濁した後に、2規定水酸化ナトリウム水溶液を加えて溶解し、溶液のpHを12に調節した。続いて、1規定塩酸を加えて水溶液のpHを7〜10に調製した後に、ピルビン酸ナトリウム(0.34g)および、調製例1の溶液1.0mlを加えた。ここで再度溶液のpHをpHメーターを用いて確認し、必要に応じて2規定水酸化ナトリウム水溶液または1規定塩酸を加え、所定のpHに調整した。室温にて5時間撹拌した後に、反応液中の4−ヒドロキシ−4−(3−インドリルメチル)−2−ヒドロキシイミノグルタル酸の収率及び鏡像体過剰率を決定した。
実施例1と同様にして、表2に示す反応pH、錯体溶液、反応時間により、得られた反応液中の4−ヒドロキシ−4−(3−インドリルメチル)−2−ヒドロキシイミノグルタル酸の収率及び鏡像体過剰率を決定した。結果を表2に示した。
溶媒として水の代わりにメタノール5mlを使用する以外は、〔実施例2〕と同様に実験を行った。反応液を分析したところ、4−ヒドロキシ−4−(3−インドリルメチル)−2−ヒドロキシイミノグルタル酸は19%(鏡像体過剰率19%:選択性4−R体)であった。これにより溶媒としては、メタノールよりも水の方が収率および鏡像率過剰率のいずれも良好であることが分かった(実施例2、13)。
アルゴン気流下にて、インドール−3−ピルビン酸1.00gを水15.0mlにけん濁した後に、モルホリンを1.72ml(インドール−3−ピルビン酸に対し4倍モル)加えた。続いて、ピルビン酸1.03mlおよび、調製例1の溶液6.0mlを加えた。ここでの反応液pHは7.1であった。室温にて5時間撹拌した後に、反応液中の4−ヒドロキシ−4−(3−インドリルメチル)−2−ヒドロキシイミノグルタル酸の収率及び鏡像体過剰率を決定した。
実施例14と同様にして、表3に示す反応pH、塩基、錯体溶液、反応時間により、得られた反応液中の4−ヒドロキシ−4−(3−インドリルメチル)−2−ヒドロキシイミノグルタル酸の収率及び鏡像体過剰率を決定した。結果を表3に示した。
上記〔実施例2〕を24倍にスケールアップして、4−ヒドロキシ−4−(3−インドリルメチル)−2−ヒドロキシイミノグルタル酸を含有するアルドール反応液を調製した。得られたアルドール反応液に12規定塩酸を加えてpHを1.2に調節し、酢酸エチルで2回(100ミリリットルx2)抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥、硫酸マグネシウムを濾別後に、エバポレーターを用いて濃縮して残渣を得た。28%アンモニア水を20ミリリットル加えた後に、エタノール200ミリリットルを加え、5℃にて3日間保存した。析出した結晶を濾別後に減圧下で乾燥し、4−ヒドロキシ−4−(3−インドリルメチル)−2−ヒドロキシイミノグルタル酸ジアンモニウム塩を2.2グラム(純度88%、収率23%)。鏡像体選択性は44%eeであり、選択性は4R体であった。
1HNMR (DMSO-d6) d : 2.66 (s, 2H) , 2.89 (d, J= 14.4 Hz, 1H), 3.04 (d, J= 14.4 Hz, 1H) , 6.89‐6.94 (m, 1H), 6.97‐7.03 (m, 1H), 7.11 (d, J= 2.8Hz, 1H) , 7.27 (d, J= 7.8 Hz, 1H), 7.53 (d, J= 7.8Hz, 1H), 10.71(br s, 1H)。
(質量分析)
ESI-MS 計算値 C14H14N2O6 = 306.28, 分析値 305.17 (MH-)。
酢酸亜鉛0.36g(2.0ミリモル)とトランス−L−ヒドロキシプロリン1.07g(8.2ミリモル)を水20ミリリットルに溶解し、2規定水酸化ナトリウム水溶液を加えてpHを8.3に調節することで、トランス−L−ヒドロキシプロリン/亜鉛(II)錯体水溶液を調製した。
(1)BMDAT発現E.coliの調製
Bacillus macerans AJ1617株由来dat遺伝子(bmdat遺伝子)をpUC18のlacプロモーター下流に連結した発現プラスミドpUCBMDATは、 国際公開WO2004/053125パンフレット(国際公開日2003年12月9日)記載の方法に従って構築した。
S243N/A182S部位特異的変異(Site−Directed mutagenesis)による変異型BMDAT発現プラスミドを、前記(1)で得たプラスミドpUCBMDATから、 国際公開WO2004/053125号パンフレット記載の方法に従い、STRATAGENE社製QuikChange Site−Directed Mutagenesis Kitを使用して作製した。
S243N−S(配列番号3): gaaatcattg tgtcgtctgt aaattctgag gttacgccag
S243N−AS(配列番号4) ctggcgtaac ctcagaattt acagacgaca caatgatttc
A182S−S(配列番号5) gtgacagaat gctcttcatc taatgtttac ggaattaaag
A182S−AS(配列番号6) ctttaattcc gtaaacatta gatgaagagc attctgtcac
95℃ 30秒
55℃ 1分
68℃ 8分×18サイクル
Claims (8)
- 2級アミン含有光学活性α−アミノ酸が、ヒドロキシプロリン、およびプロリンから選ばれる1種または2種以上であることを特徴とする、請求項1記載の光学活性化合物(塩の形態も含む)の製造方法。
- 金属イオンが、マグネシウム(II)イオン、亜鉛(II)イオン、コバルト(II)乃至は(III)イオン、ニッケル(II)イオンから選ばれる1種または2種以上であることを特徴とする、請求項1記載の光学活性化合物(塩の形態も含む)の製造方法。
- 反応中、反応溶液のpHが7〜12であることを特徴とする、請求項1記載の光学活性化合物(塩の形態も含む)の製造方法。
- 請求項1〜6のいずれかに記載の光学活性化合物(塩の形態も含む)の製造方法を含有するモナティンまたはその塩の製造方法。
- 請求項1〜6のいずれかに記載の製造方法で得られた光学活性化合物に対して、更にトランスアミナーゼとアミノ供与体とを作用させる工程を含有することを特徴とする、モナティンまたはその塩の製造方法。
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- 2008-02-05 CN CN2008100084694A patent/CN101239941B/zh not_active Expired - Fee Related
- 2008-02-07 EP EP08250451A patent/EP1956003A3/en not_active Withdrawn
- 2008-02-08 US US12/028,360 patent/US7816541B2/en not_active Expired - Fee Related
- 2008-02-08 JP JP2008028655A patent/JP5303950B2/ja not_active Expired - Fee Related
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JP2006204285A (ja) * | 2004-06-07 | 2006-08-10 | Ajinomoto Co Inc | 新規アルドラーゼ並びに光学活性ihog及びモナティンの製造方法 |
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US7816541B2 (en) | 2010-10-19 |
EP1956003A2 (en) | 2008-08-13 |
CN101239941A (zh) | 2008-08-13 |
JP5303950B2 (ja) | 2013-10-02 |
EP1956003A3 (en) | 2010-11-24 |
US20080207920A1 (en) | 2008-08-28 |
CN101239941B (zh) | 2012-02-29 |
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