JP4190879B2 - A novel intermediate for the production of theanine - Google Patents
A novel intermediate for the production of theanine Download PDFInfo
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- JP4190879B2 JP4190879B2 JP2002376770A JP2002376770A JP4190879B2 JP 4190879 B2 JP4190879 B2 JP 4190879B2 JP 2002376770 A JP2002376770 A JP 2002376770A JP 2002376770 A JP2002376770 A JP 2002376770A JP 4190879 B2 JP4190879 B2 JP 4190879B2
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- formula
- theanine
- glutamic acid
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Description
【0001】
【発明の属する技術分野】
本発明は、テアニンの有用な中間体となる新規な2−ニトロフェニルスルフェニル(以下、NPSという)−グルタミン酸−γ−エチルアミド及びその製造方法と、効率的なテアニンの製造方法に関する。
【0002】
【従来の技術】
グルタミン酸−γ−エチルアミド、すなわちテアニンは、緑茶の旨味成分としてよく知られている。そのほかにも、リラクゼーション効果、抗ストレス作用、カフェイン興奮抑制作用、制癌剤増強作用等のさまざまな生理作用のあることが解明されてきたことから、食品業界、医薬業界などでその需要はますます高くなっている。しかし、茶葉中には0.5〜2.0重量%しかこの成分が含まれておらず、抽出法では昨今の需要をカバーすることは難しい。そのため、大量合成が可能な化学的合成が必要とされている。
【0003】
これまでに開示されている化学的合成法としては、例えば、テアニンの合成出発原料として、L−ピロリドンカルボン酸の金属塩(特許文献1参照)、グルタミン酸−γ−ベンジルエステル(特許文献2参照)、ベンジルオキシカルボニル−L−ピロリドンカルボン酸(特許文献3参照)、ターシャリーブチルオキシカルボニル−L−グルタミン酸(特許文献4参照)、ベンジルオキシカルボニル−L−グルタミン酸の酸無水物(特許文献5参照)をそれぞれ重要な出発原料とし、エチルアミンを反応させた後N保護基を脱離させてテアニンを得る方法がある。
【0004】
【特許文献1】
特公昭37−11661号公報
【特許文献2】
特許第2947492号公報
【特許文献3】
特開平11−116542号公報
【特許文献4】
特開2000−26383号公報
【特許文献5】
特開2001−278848号公報
【0005】
【発明が解決しようとする課題】
しかしながら、従来の製法の多くは反応条件が過酷であるか、工程数が多く煩雑で、しかも収率が低い。
【0006】
例えば、特許文献1では、無水の100%エチルアミンを使用し、加圧、加熱条件下で行うため危険性を伴う。特許文献2、特許文献4では、酸性条件下で保護基の脱保護を行うため、得られたテアニンをイオン交換などの精製工程を必要とし煩雑である。また、特許文献3、特許文献5では、引火性の高い、水素を使用して脱保護を行うため、危険性を伴う。
【0007】
そこで本発明は、上記問題点を解決すべく、より有用な中間体を発明し、さらに現行法より少ない工程で安全に高純度のテアニンの製造方法を提供せんとするものである。
【0008】
【課題を解決するための手段】
本発明者らは、上記目的を達成するため、アミノ酸が塩を作らない条件下で脱保護を行うことのできる、有用な中間体を発明した。即ち、本発明(1)は、式1:
【化5】
(式中、Etはエチル基を表す)で示される化合物(2−ニトロフェニルスルフェニル−グルタミン酸−γ−エチルアミド)である。
【0009】
また、本発明者らは、上記の有用な中間体の製造方法を発明した。即ち、本発明(2)は、前記発明(1)中の式1で示される化合物(2−ニトロフェニルスルフェニル−グルタミン酸−γ−エチルアミド)の製造方法であって、式2:
【化6】
(式中、Rは、炭素数が1〜5の直鎖もしくは分岐したアルキル基またはベンジル基を表す)で示される化合物のα−アミノ基を2−ニトロフェニルスルフェニル基で保護し、式3:
【化7】
(式中、Rは前記と同義である)で示される化合物とした後、エチルアミンを反応させる工程を含む製造方法である。ここで、Rの例として、メチル、エチル、n−プロピル、i−プロピル、n−ブチル、t−ブチル、ベンジル基を挙げることができ、メチル、エチルが好適である。
【0010】
更に、本発明者らは、上記の有用な中間体を利用しての、新規なテアニンの製造方法を発明した。即ち、本発明(3)は、式4:
【化8】
(式中、Etはエチル基を表す)で示されるテアニンの製造方法において、前記発明(1)中の式1で示される化合物(2−ニトロフェニルスルフェニル−グルタミン酸−γ−エチルアミド)をチオアミド類で脱保護を行う工程を含むことを特徴とする方法である。この方法によれば、安全に高純度のテアニンを製造することが可能となる。
【0011】
【発明の実施の形態】
まず、式1で示されるNPS−グルタミン酸−γ−エチルアミドの製造方法について説明する。原料である式2の化合物を、メタノール、エタノール、塩化メチレン、テトラヒドロフラン、酢酸エチルなどの一般的な各種有機溶媒中にて、1.0〜2.0倍当量の2−ニトロフェニルスルフェニルクロライドと、塩基としてトリエチルアミン、トリブチルアミン、もしくはピリジン等を作用させることにより、式3で示される、アミノ基の保護されたNPS−グルタミン酸−γ−メチルエステルを得ることができる。更に、式3で示される化合物に、エチルアミンを反応させることにより、新規なテアニンの有用な中間体としての、式1で示されるNPS−グルタミン酸−γ−エチルアミドが得られる。この際、エチルアミンは、100%無水エチルアミンであってもよいが、常温で気体である為、取り扱いにくい。本発明においては、100%無水エチルアミンでなくとも、例えば、30〜70%のエチルアミンの水溶液でも可能であり、そして反応効率からは、70%程度のエチルアミン水溶液が好適である。
【0012】
次に、式1で示されるNPS−グルタミン酸−γ−エチルアミドを用いての、テアニンの製造方法について説明する。NPS−グルタミン酸−γ−エチルアミドに対して、1.0〜2.0倍当量のチオアミドを作用させることにより、速やかに反応し、テアニンが得られる。NPS基は、塩酸、硫酸、酢酸などの酸を用いても容易に脱保護することができるが、その後イオン交換など煩雑な精製工程が必要となり、収率低下の原因となる。チオアミド類は、特に限定されず、例えば、チオアセトアミド、チオベンズアミド、チオ尿素、2−メルカプト−5−メチル−1,3,5−チアジアゾールなどが挙げられる。また、溶媒としては、水や、酢酸エチル、テトラヒドロフラン、ジオキサン、メタノール、エタノールなどの一般的な有機溶媒を用いることができる。テアニンは水によく溶け、有機溶媒にはほとんど不溶であることを利用し、脱保護後は固相、有機相、水相のいずれかの2相系で分離容易なものを適宜選択することができる。
【0013】
反応終了後は、濃縮、ろ過、乾燥を行えば高純度のテアニンを得ることができる。以下に本発明の実施例を示して、さらに具体的に説明する。
【0014】
【実施例】
グルタミン酸−γ−メチルエステル16.1g(0.1mol)をメタノール84mlに溶かし、トリエチルアミン25.3g(0.25mol)と2−ニトロフェニルスルフェニルクロライド22.8g(0.12mol)を加え、3時間反応させた。反応終了後、減圧下にてメタノールを濃縮し、酢酸エチルで抽出することにより、NPS−グルタミン酸−γ−メチルエステル27.8g(89%)を得た。
【0015】
次に、得られたNPS−グルタミン酸−γ−メチルエステル27.8g(0.09mol)に70%−エチルアミン水溶液58g(0.9mol)を加え、15時間反応させた。その後、過剰のエチルアミンを減圧下にて留去し、黄色結晶を得た。これを酢酸エチルで再結晶化し、テアニンの有用な中間体であるNPS−グルタミン酸−γ−エチルアミド27.9g(95%)を得た。物理的特性は以下の通りである:
【0016】
1H−NMR(400MHz,CDCl3)δ 8.28(1H,d,J=8.29Hz)、8.02(1H,d,J=8.29Hz)、7.67(1H,dd,J=8.42,8.29Hz)、7.28(1H,dd,J=8.42,8.29Hz)、3.71(3H,s)、3.66(1H,m)、2.60(2H,m)、2.23(2H,m)
【0017】
更に、NSP−グルタミン酸−γ−エチルアミド13.9g(0.04mol)をメタノール112mlに溶かし、チオアセトアミド3.5g(0.05mol)を加え、30分間反応させた。その後、水50mlを加え、不溶物を濾過し、濾液を減圧下にて留去すると、白色結晶が析出した。これを70〜80℃にて加熱し、熱水に溶かし、99%エタノールを滴下し、析出する白色結晶を濾取した。これを乾燥することにより、テアニン5.4g(77%)を得た。得られたテアニンのNMR及び旋光度は以下の通りである:
【0018】
1H−NMR(400MHz,D2O)δ 3.65(1H,t,J=6.1Hz)、3.09(2H,q,J=7.3Hz)、2.29(2H,ddd,J=7.7,7.3,6.1Hz)、2.03(2H,dd,J=7.7,7.3Hz)、1.11(3H,t,J=7.3Hz)、旋光度 [α]D 20+8.0°(H2O)
【0019】
上記NMR及び旋光度の結果から得られたL−テアニンは、高純度であることがわかった。
【0020】
【発明の効果】
以上説明したように、従来の方法によれば、イオン交換法による精製工程の手間およびそれに伴う収率の低下があり、効率の良い方法とはいえなかった。だが、本発明の方法によれば、新規なテアニンの有用な中間体であるNPS−グルタミン酸−γ−エチルアミドを利用して、穏やかな反応条件下で安全に高収率、高純度でテアニンを製造することができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a novel 2-nitrophenylsulfenyl (hereinafter referred to as NPS) -glutamic acid-γ-ethylamide, which is a useful intermediate of theanine, a method for producing the same, and an efficient method for producing theanine.
[0002]
[Prior art]
Glutamic acid-γ-ethylamide, that is, theanine, is well known as an umami component of green tea. In addition, it has been elucidated that there are various physiological effects such as relaxation effect, anti-stress action, caffeine excitation suppression action, anticancer drug enhancement action, etc., so the demand in food industry, pharmaceutical industry etc. is higher It has become. However, only 0.5 to 2.0% by weight of this component is contained in tea leaves, and it is difficult to cover the current demand by the extraction method. Therefore, there is a need for chemical synthesis capable of mass synthesis.
[0003]
As chemical synthesis methods disclosed so far, for example, as a starting material for theanine synthesis, a metal salt of L-pyrrolidonecarboxylic acid (see Patent Document 1), glutamic acid-γ-benzyl ester (see Patent Document 2) , Benzyloxycarbonyl-L-pyrrolidonecarboxylic acid (see Patent Document 3), tertiary butyloxycarbonyl-L-glutamic acid (see Patent Document 4), acid anhydride of benzyloxycarbonyl-L-glutamic acid (see Patent Document 5) Is an important starting material, and after reacting with ethylamine, the N protecting group is eliminated to obtain theanine.
[0004]
[Patent Document 1]
Japanese Patent Publication No.37-11661 [Patent Document 2]
Japanese Patent No. 2947492 [Patent Document 3]
JP-A-11-116542 [Patent Document 4]
JP 2000-26383 A [Patent Document 5]
JP-A-2001-278848 [0005]
[Problems to be solved by the invention]
However, many of the conventional production methods have severe reaction conditions, a large number of steps, are complicated, and the yield is low.
[0006]
For example, in Patent Document 1, there is a danger because anhydrous 100% ethylamine is used under pressure and heating conditions. In Patent Document 2 and Patent Document 4, since the protecting group is deprotected under acidic conditions, the obtained theanine requires a purification step such as ion exchange, which is complicated. Moreover, in patent document 3 and patent document 5, since deprotection is performed using hydrogen having high flammability, there is a risk.
[0007]
Therefore, the present invention is to invent a more useful intermediate in order to solve the above problems, and to provide a method for producing high-purity theanine safely and with fewer steps than the current method.
[0008]
[Means for Solving the Problems]
In order to achieve the above object, the present inventors have invented a useful intermediate that can be deprotected under conditions in which an amino acid does not form a salt. That is, the present invention (1) is represented by the formula 1:
[Chemical formula 5]
(Wherein Et represents an ethyl group) (2-nitrophenylsulfenyl-glutamic acid-γ-ethylamide).
[0009]
In addition, the present inventors have invented a method for producing the above-mentioned useful intermediate. That is, the present invention (2) is a process for producing a compound represented by the formula 1 in the above invention (1) (2-nitrophenylsulfenyl-glutamic acid-γ-ethylamide),
[Chemical 6]
(Wherein R represents a linear or branched alkyl group having 1 to 5 carbon atoms or a benzyl group) and the α-amino group of the compound represented by formula 3 is protected with a 2-nitrophenylsulfenyl group; :
[Chemical 7]
(In the formula, R is as defined above), followed by reacting with ethylamine. Here, examples of R include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl and benzyl groups, and methyl and ethyl are preferred.
[0010]
Furthermore, the present inventors have invented a novel method for producing theanine using the above useful intermediate. That is, the present invention (3) has the formula 4:
[Chemical 8]
In the method for producing theanine represented by the formula (Et represents an ethyl group), the compound represented by formula 1 in the invention (1) (2-nitrophenylsulfenyl-glutamic acid-γ-ethylamide) is converted to a thioamide. The method includes a step of performing deprotection in step (b). According to this method, it is possible to produce highly pure theanine safely.
[0011]
DETAILED DESCRIPTION OF THE INVENTION
First, a method for producing NPS-glutamic acid-γ-ethylamide represented by Formula 1 will be described. The compound of formula 2 as a raw material is mixed with 1.0 to 2.0 times equivalent of 2-nitrophenylsulfenyl chloride in various general organic solvents such as methanol, ethanol, methylene chloride, tetrahydrofuran and ethyl acetate. By reacting triethylamine, tributylamine, pyridine or the like as a base, an amino group-protected NPS-glutamic acid-γ-methyl ester represented by formula 3 can be obtained. Further, by reacting the compound represented by Formula 3 with ethylamine, NPS-glutamic acid-γ-ethylamide represented by Formula 1 is obtained as a useful intermediate of the novel theanine. At this time, the ethylamine may be 100% anhydrous ethylamine, but is difficult to handle because it is a gas at room temperature. In the present invention, even if it is not 100% anhydrous ethylamine, for example, an aqueous solution of 30 to 70% ethylamine is also possible. From the viewpoint of reaction efficiency, an aqueous solution of about 70% ethylamine is preferred.
[0012]
Next, a method for producing theanine using NPS-glutamic acid-γ-ethylamide represented by Formula 1 will be described. By reacting 1.0 to 2.0 times equivalent of thioamide to NPS-glutamic acid-γ-ethylamide, it reacts quickly and theanine is obtained. The NPS group can be easily deprotected using an acid such as hydrochloric acid, sulfuric acid, and acetic acid. However, a complicated purification step such as ion exchange is required thereafter, which causes a decrease in yield. The thioamides are not particularly limited, and examples thereof include thioacetamide, thiobenzamide, thiourea, 2-mercapto-5-methyl-1,3,5-thiadiazole and the like. Moreover, as a solvent, common organic solvents, such as water and ethyl acetate, tetrahydrofuran, dioxane, methanol, ethanol, can be used. Utilizing the fact that theanine is well soluble in water and almost insoluble in organic solvents, after deprotection, it is possible to select a solid phase, an organic phase, or an aqueous phase that can be easily separated. it can.
[0013]
After completion of the reaction, highly purified theanine can be obtained by concentration, filtration and drying. Hereinafter, the present invention will be described more specifically with reference to examples.
[0014]
【Example】
Glutamic acid-γ-methyl ester (16.1 g, 0.1 mol) was dissolved in methanol (84 ml), and triethylamine (25.3 g, 0.25 mol) and 2-nitrophenylsulfenyl chloride (22.8 g, 0.12 mol) were added for 3 hours. Reacted. After completion of the reaction, methanol was concentrated under reduced pressure and extracted with ethyl acetate to obtain 27.8 g (89%) of NPS-glutamic acid-γ-methyl ester.
[0015]
Next, 58 g (0.9 mol) of 70% -ethylamine aqueous solution was added to 27.8 g (0.09 mol) of the obtained NPS-glutamic acid-γ-methyl ester and allowed to react for 15 hours. Thereafter, excess ethylamine was distilled off under reduced pressure to obtain yellow crystals. This was recrystallized with ethyl acetate to obtain 27.9 g (95%) of NPS-glutamic acid-γ-ethylamide which is a useful intermediate of theanine. The physical properties are as follows:
[0016]
1 H-NMR (400 MHz, CDCl 3 ) δ 8.28 (1H, d, J = 8.29 Hz), 8.02 (1H, d, J = 8.29 Hz), 7.67 (1H, dd, J = 8.42, 8.29 Hz), 7.28 (1H, dd, J = 8.42, 8.29 Hz), 3.71 (3H, s), 3.66 (1H, m), 2.60. (2H, m), 2.23 (2H, m)
[0017]
Further, 13.9 g (0.04 mol) of NSP-glutamic acid-γ-ethylamide was dissolved in 112 ml of methanol, and 3.5 g (0.05 mol) of thioacetamide was added and reacted for 30 minutes. Thereafter, 50 ml of water was added, insoluble matters were filtered, and the filtrate was distilled off under reduced pressure to precipitate white crystals. This was heated at 70 to 80 ° C., dissolved in hot water, 99% ethanol was added dropwise, and the precipitated white crystals were collected by filtration. This was dried to obtain 5.4 g (77%) of theanine. The NMR and optical rotation of the theanine obtained are as follows:
[0018]
1 H-NMR (400 MHz, D 2 O) δ 3.65 (1H, t, J = 6.1 Hz), 3.09 (2H, q, J = 7.3 Hz), 2.29 (2H, ddd, J = 7.7, 7.3, 6.1 Hz), 2.03 (2H, dd, J = 7.7, 7.3 Hz), 1.11 (3H, t, J = 7.3 Hz), optical rotation Degree [α] D 20 + 8.0 ° (H 2 O)
[0019]
L-theanine obtained from the NMR and optical rotation results was found to be highly pure.
[0020]
【The invention's effect】
As described above, according to the conventional method, there is a trouble in the purification process by the ion exchange method and a yield reduction accompanying it, and it cannot be said that it is an efficient method. However, according to the method of the present invention, theanine can be produced safely in high yield and high purity under mild reaction conditions using NPS-glutamic acid-γ-ethylamide, which is a useful intermediate of novel theanine. can do.
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JP4585266B2 (en) * | 2004-10-07 | 2010-11-24 | ホーユー株式会社 | Hair cosmetic composition |
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JP4585265B2 (en) * | 2004-10-07 | 2010-11-24 | ホーユー株式会社 | Hair cosmetic composition |
JP4634168B2 (en) | 2005-02-04 | 2011-02-16 | 純正化学株式会社 | Theanine production method |
KR100734069B1 (en) | 2005-05-19 | 2007-06-29 | 주식회사 카이로켐 | Process for the preparation of N5-ethylglutamine |
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