JP4781597B2 - N-acetylglucosaminyl tyrosine derivative - Google Patents
N-acetylglucosaminyl tyrosine derivative Download PDFInfo
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- JP4781597B2 JP4781597B2 JP2002069679A JP2002069679A JP4781597B2 JP 4781597 B2 JP4781597 B2 JP 4781597B2 JP 2002069679 A JP2002069679 A JP 2002069679A JP 2002069679 A JP2002069679 A JP 2002069679A JP 4781597 B2 JP4781597 B2 JP 4781597B2
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- tyrosine
- acetylglucosaminyl
- tyrosine derivative
- protecting group
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- 0 *CC(C(C(*)C1*#C)O)OC1Oc1ccc(CC(*)*#C)cc1 Chemical compound *CC(C(C(*)C1*#C)O)OC1Oc1ccc(CC(*)*#C)cc1 0.000 description 1
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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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Description
【0001】
【発明の属する技術分野】
本発明は糖アミノ酸に関する。具体的にはN−アセチルグルコサミンがチロシンの側鎖水酸基にα−O−グリコシド結合したN−アセチルグルコサミニルチロシン誘導体に関する。糖ペプチドは医薬品や試薬などとして注目されている。糖ペプチドの合成には、原料となる糖アミノ酸が必要であり、今日では一般的な糖アミノ酸の合成技術が確立されてきている。
【0002】
【従来の技術】
医薬品や試薬などとして注目されている糖ペプチドの原料となる糖アミノ酸は、目的とする医薬品等により、特定の糖アミノ酸が必要である。その中で、重要な糖ペプチドの原料となる糖アミノ酸の一つ、即ちN−アセチルグルコサミンがチロシンの側鎖水酸基にα−O−グリコシド結合したN−アセチルグルコサミニルチロシン誘導体が多くの産業界から求められている。
【0003】
しかしながら、N−アセチルグルコサミンを糖供与体として用いるグリコシル化反応においてはβ−グリコシドの生成が優先されるためα−グリコシド結合を形成させるのは非常に困難である。そのため、N−アセチルグルコサミンがチロシンの側鎖水酸基にα−O−グリコシド結合したN−アセチルグルコサミニルチロシン誘導体は、今なお製造例がなく、産業界の要求に応じ得ていないのである。
【0004】
【発明が解決しようとする課題】
本発明の課題は、糖ペプチドの合成原料となるN−アセチルグルコサミンがチロシンの側鎖水酸基にα−O−グリコシド結合したN−アセチルグルコサミニルチロシン誘導体を提供することである。
【0005】
【課題を解決するための手段】
本発明者らはグリコシル化反応の例を参考に鋭意検討し、本発明に到達した。すなわち、本発明は、一般式[I]
【化2】
(式中Xはアミノ基の保護基またはHを表す。Yはカルボキシル基の保護基またはHを表す。R1、R2、R3は水酸基の保護基または単糖または糖鎖、またはHを表す。)で表されるN−アセチルグルコサミニルチロシン誘導体である。
【0006】
すなわち、種々検討の結果、1位がアセチルで保護されたN−アセチルグルコサミンアセテート誘導体と、チロシン誘導体との反応により、N−アセチルグルコサミニルチロシン誘導体を製造することに成功したのである。反応を行うにあたっては、特開平11−116587に記載された、1位がアセチル基で保護された糖誘導体を活性化剤の存在下、三フッ化ホウ素エーテル錯体共存下で糖受容体と反応させる方法を参考にした。しかし、この特許には本発明の特徴となる反応基質の濃度についての記載がない。発明者は、反応の基質濃度を従来の濃度より高濃度で行うことにより、高収率で目的物が得られることを見出した。本発明のN−アセチルグルコサミニルチロシンは、N−アセチルグルコサミンの還元末端がチロシンの側鎖水酸基にα−O−グリコシド結合したことを特徴とするN−アセチルグルコサミニルチロシンである。本発明により、本発明のN−アセチルグルコサミニルチロシンを、これを求めていた医薬等の産業界に供することが可能となった。
【0007】
【発明の実施の形態】
以下、本発明を詳細に説明する。
一般式[I]において、アミノ基の保護基としては何ら制限はないが、好ましくはベンジルオキシカルボニル基、9−フルオレニルオキシカルボニル基、第3ブチルオキシカルボニル基である。
カルボキシル基の保護基も何ら制限はないが、例えばメチル基、ベンジル基、第3ブチル基、フェナシル基である。
R1、R2及びR3は、それぞれ独立して水酸基の保護基、単糖、糖鎖、またはHである。水酸基の保護基は何ら制限はないが、例えばベンジル基、アセチル基、ベンゾイル基等を挙げることができる。また単糖および糖鎖も何ら制限はない。ピラノースでもフラノースでも、これらに含まれる水酸機基が置換されていてもかまわない。例えば、グルコース、ガラクトース、マンノース、フコース、N−アセチルグルコサミン、N−アセチルガラクトサミン、リボース、ラクトース、マルトース等を挙げることができる。
【0008】
次に本発明化合物の製造法を詳細に説明する。
まず、原料となる糖供与体は1位がアセチルで保護されたN−アセチルグルコサミンアセテート誘導体である。またN−アセチルグルコサミンの1位以外の水酸基の保護基は周知の保護基を使用することができる。例えば、アセチル基やベンゾイル基等のアシル型保護基や、アリル基やベンジル基等のエーテル型保護基、イソプロピリデン基やベンジリデン基等のアセタール型保護基を挙げることができる。
【0009】
一方の原料となるチロシン誘導体としては周知の誘導体を使用できる。具体的には、αアミノ基の保護基として周知の保護基を使用できる。例えばベンジルオキシカルボニル基、9−フルオレニルオキシカルボニル基、第3ブチルオキシカルボニル基等を挙げることができる。
【0010】
また、カルボキシル基の保護基としては周知の保護基を使用できる。例えばメチルエステル、ベンジルエステル、第3ブチルエステル、フェナシルエステル等を挙げることができる。
【0011】
反応溶媒は、アルコールを除く周知の有機溶媒を使用することができる。例えばベンゼン、トルエン、クロロホルム、ジクロロメタン、ジクロロエタン、酢酸エチル、エーテル、テトラヒドロフラン、ジメチルホルムアミド、アセトニトリル等を挙げることができる。これらの内、原料の溶解性を考慮するとジクロロメタンが好ましい。
【0012】
反応温度には特に制限がない。通常−78℃から溶媒の沸点までで、好ましくは、0℃から室温の範囲である。
【0013】
活性化剤は周知のパーフルオロアルキルスルホン酸希土類塩を使用することができる。具体的にはトリフルオロメタンスルホン酸イッテリビウム(III)、トリフルオロメタンスルホン酸スカンジウム(III)、トリフルオロメタンスルホン酸イットリウム(III)、トリフルオロメタンスルホン酸ランタン(III)、等を挙げることができる。特に目的物のα−グリコシド選択性を考慮すると、トリフルオロメタンスルホン酸イッテリビウム(III)が好ましい。
【0014】
パーフルオロアルキルスルホン酸希土類塩の使用量についても特に制限はない。通常、糖受容体に対して5〜300モル%用いることができるが、好ましくは30〜150モル%で使用する。
【0015】
三フッ化ホウ素エーテル錯体の使用量についても特に制限はない。通常、糖受容体に対して0.5〜300モル%用いることができるが好ましくは1〜100モル%で使用する。
【0016】
反応濃度は、0.1モル/l〜1モル/lの範囲である。
【0017】
以下に実施例を挙げて本発明を更に具体的に説明するが、本発明はその要旨を超えない限り、以下の実施例に何等制限を受けるものではない。
【0018】
【実施例1】
アルゴン雰囲気下、トリフルオロメタンスルホン酸イッテリビウム(III)2.46g(3.96mmol)、2−アセトアミド−3,4,6−トリ−O−ベンジル−2−デオキシ−D−グルコピラノシル アセテート2.54g(4.76mmol)とベンジルオキシカルボニル(Z)−L−チロシン ベンジルエステル1.61g(3.96mmol)を20mlのジクロロメタンに溶解する。これに1.0M三フッ化ホウ素エーテル錯体のジクロロメタン溶液を0.12ml(0.12mmol)加え、19時間室温で撹拌した後に、5%炭酸水素ナトリウム水溶液20mlとジクロロメタンを100mlを加えて反応を停止する。反応混合物をジクロロメタンで抽出し、有機層を水、飽和の塩化ナトリウム水溶液で洗浄した後に、無水硫酸ナトリウムで乾燥する。無機塩を濾過した後に、有機溶媒を減圧下留去し、濃縮物をシリカゲルカラムクロマトグラフィー(展開溶媒:ジクロロメタン/酢酸エチル=19:1→4:1)で精製を行い、目的の、請求項2記載のN−アセチルグルコサミニルチロシン誘導体であるNα−ベンジルオキシカルボニル−O−(2−アセトアミド−3,4,6−トリ−O−ベンジル−2−デオキシ−α−D−グルコピラノシル)−L−チロシン ベンジルエステルが2.07g、収率60%で得られた。
1H NMR δ(CDCl3)=5.48(H−1)。
【0019】
【実施例2】
Nα−ベンジルオキシカルボニル−O−(2−アセトアミド−3,4,6−トリ−O−ベンジル−2−デオキシ−α−D−グルコピラノシル)−L−チロシンベンジルエステル 440mg(0.50mmol)をジクロロメタン(25ml)とエタノール(40ml)の混合溶媒に溶解させる。これに酢酸0.032ml(0.55mmol)とパラジウムカーボン450mgを加え、この反応混合物に18時間室温で水素ガスを通した。パラジウムカーボンをセライトにより濾過したのち、濾液を減圧下留去し、目的の、請求項3記載のO−(2−アセトアミド−2−デオキシ−α−D−グルコピラノシル)−L−チロシンが191mg(0.50mmol)と、定量的に得られた。Rf値(ジクロロメタン:メタノール:水=5:5:1)=0.21。
【0020】
【実施例3】
O−(2−アセトアミド−2−デオキシ−α−D−グルコピラノシル)−L−チロシン191mg(0.50mmol)を水10mlに溶解させる。これに炭酸水素ナトリウム168mg(2.0mmol)、1,4−ジオキサン10ml、N−(9−フルオレニルメチルオキシカルボニルオキシ)スクシンイミド(Fmoc−OSu)283mg(0.75mmol)を加え、4時間室温で反応させる。反応溶液をエーテルで洗浄し、得られた水層にクエン酸を加えて酸性にした。ダイヤイオンHP−20樹脂を充填したカラムに水層を展開させ固相抽出を行った。樹脂を水で洗浄した後、メタノールで溶出させ目的とする、請求項4記載のNα−(9−フルオレニルメチルオキシカルボニル)−O−(2−アセトアミド−2−デオキシ−α−D−グルコピラノシル)−L−チロシンが274mg(0.45 mmol)、収率90%で得られた。
1H NMR δ(D2O)=4.79(H−1)。
【0021】
【発明の効果】
本発明化合物であるN−アセチルグルコサミニルチロシン誘導体は糖ペプチドの合成原料として、その商業的、工業的価値は大である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to sugar amino acids. Specifically, the present invention relates to an N-acetylglucosaminyl tyrosine derivative in which N-acetylglucosamine is α-O-glycosidically bonded to a side chain hydroxyl group of tyrosine. Glycopeptides are attracting attention as pharmaceuticals and reagents. In order to synthesize a glycopeptide, a sugar amino acid as a raw material is required, and a general sugar amino acid synthesis technique has been established today.
[0002]
[Prior art]
A sugar amino acid used as a raw material of a glycopeptide that is attracting attention as a pharmaceutical or a reagent requires a specific sugar amino acid depending on the intended pharmaceutical or the like. Among them, one of the sugar amino acids used as an important glycopeptide raw material, that is, N-acetylglucosaminyl tyrosine derivatives in which N-acetylglucosamine is α-O-glycosidically bonded to the side chain hydroxyl group of tyrosine is used in many industries. It is demanded from.
[0003]
However, in the glycosylation reaction using N-acetylglucosamine as a sugar donor, it is very difficult to form an α-glycoside bond because the production of β-glycoside is prioritized. Therefore, an N-acetylglucosaminyl tyrosine derivative in which N-acetylglucosamine is α-O-glycoside-bonded to the side chain hydroxyl group of tyrosine has not yet been produced and has not been able to meet the demands of the industry.
[0004]
[Problems to be solved by the invention]
An object of the present invention is to provide an N-acetylglucosaminyl tyrosine derivative in which N-acetylglucosamine, which is a raw material for synthesizing a glycopeptide, is α-O-glycoside bonded to a side chain hydroxyl group of tyrosine.
[0005]
[Means for Solving the Problems]
The present inventors diligently studied with reference to examples of glycosylation reactions, and reached the present invention. That is, the present invention relates to the general formula [I]
[Chemical 2]
(Wherein X represents an amino-protecting group or H. Y represents a carboxyl-protecting group or H. R 1 , R 2 and R 3 represent a hydroxyl-protecting group, a monosaccharide or a sugar chain, or H. N-acetylglucosaminyl tyrosine derivative represented by:
[0006]
That is, as a result of various studies, the inventors succeeded in producing an N-acetylglucosaminyl tyrosine derivative by reacting an N-acetylglucosamine acetate derivative protected at the 1-position with acetyl and a tyrosine derivative. In carrying out the reaction, a sugar derivative protected at the 1-position with an acetyl group described in JP-A-11-116587 is reacted with a sugar acceptor in the presence of a boron trifluoride ether complex in the presence of an activator. Referenced the method. However, this patent does not describe the concentration of the reaction substrate that characterizes the present invention. The inventor has found that the target product can be obtained in a high yield by carrying out the substrate concentration of the reaction at a higher concentration than the conventional concentration. The N-acetylglucosaminyl tyrosine of the present invention is N-acetylglucosaminyl tyrosine characterized in that the reducing end of N-acetylglucosamine is α-O-glycoside bonded to the side chain hydroxyl group of tyrosine. According to the present invention, the N-acetylglucosaminyltyrosine of the present invention can be provided to the industry such as pharmaceuticals that have been seeking this.
[0007]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described in detail.
In the general formula [I], the amino-protecting group is not limited, but is preferably a benzyloxycarbonyl group, a 9-fluorenyloxycarbonyl group, or a tertiary butyloxycarbonyl group.
The protecting group for the carboxyl group is not limited, but is, for example, a methyl group, a benzyl group, a tertiary butyl group, or a phenacyl group.
R 1 , R 2 and R 3 are each independently a hydroxyl protecting group, a monosaccharide, a sugar chain, or H. The protecting group for the hydroxyl group is not limited at all, and examples thereof include a benzyl group, an acetyl group, and a benzoyl group. There are no restrictions on monosaccharides and sugar chains. In both pyranose and furanose, the hydroxyl group contained in these may be substituted. Examples thereof include glucose, galactose, mannose, fucose, N-acetylglucosamine, N-acetylgalactosamine, ribose, lactose, maltose and the like.
[0008]
Next, the production method of the compound of the present invention will be described in detail.
First, a sugar donor as a raw material is an N-acetylglucosamine acetate derivative protected at the 1-position with acetyl. Moreover, a well-known protecting group can be used for the protecting groups of hydroxyl groups other than 1-position of N-acetylglucosamine. For example, an acyl type protective group such as an acetyl group or a benzoyl group, an ether type protective group such as an allyl group or a benzyl group, and an acetal type protective group such as an isopropylidene group or a benzylidene group can be used.
[0009]
A well-known derivative can be used as the tyrosine derivative as one raw material. Specifically, a known protecting group can be used as the protecting group for the α-amino group. For example, a benzyloxycarbonyl group, a 9-fluorenyloxycarbonyl group, a tertiary butyloxycarbonyl group, and the like can be given.
[0010]
Moreover, a well-known protecting group can be used as a protecting group of a carboxyl group. For example, methyl ester, benzyl ester, tertiary butyl ester, phenacyl ester and the like can be mentioned.
[0011]
As the reaction solvent, a well-known organic solvent excluding alcohol can be used. Examples thereof include benzene, toluene, chloroform, dichloromethane, dichloroethane, ethyl acetate, ether, tetrahydrofuran, dimethylformamide, acetonitrile and the like. Of these, dichloromethane is preferred in consideration of the solubility of the raw materials.
[0012]
There is no particular limitation on the reaction temperature. Usually, from -78 ° C to the boiling point of the solvent, preferably in the range of 0 ° C to room temperature.
[0013]
As the activator, a well-known perfluoroalkylsulfonic acid rare earth salt can be used. Specific examples include ytterbium (III) trifluoromethanesulfonate, scandium (III) trifluoromethanesulfonate, yttrium (III) trifluoromethanesulfonate, and lanthanum (III) trifluoromethanesulfonate. Considering the α-glycoside selectivity of the target product, ytterbium (III) trifluoromethanesulfonate is preferred.
[0014]
There is no particular limitation on the amount of the perfluoroalkylsulfonic acid rare earth salt used. Usually, it can be used in an amount of 5 to 300 mol%, preferably 30 to 150 mol%, based on the sugar receptor.
[0015]
There is no restriction | limiting in particular also about the usage-amount of a boron trifluoride ether complex. Usually, it can be used in an amount of 0.5 to 300 mol%, preferably 1 to 100 mol%, based on the sugar receptor.
[0016]
The reaction concentration is in the range of 0.1 mol / L~1 mol / l.
[0017]
EXAMPLES The present invention will be described more specifically with reference to the following examples. However, the present invention is not limited to the following examples unless it exceeds the gist.
[0018]
[Example 1]
Under argon atmosphere, 2.46 g (3.96 mmol) of ytterbium trifluoromethanesulfonate (III), 2.54 g of 2-acetamido-3,4,6-tri-O-benzyl-2-deoxy-D-glucopyranosyl acetate (4 .76 mmol) and 1.61 g (3.96 mmol) of benzyloxycarbonyl (Z) -L-tyrosine benzyl ester are dissolved in 20 ml of dichloromethane. To this was added 0.12 ml (0.12 mmol) of a 1.0 M boron trifluoride ether complex in dichloromethane, and the mixture was stirred for 19 hours at room temperature. Then, 20 ml of 5% aqueous sodium hydrogen carbonate solution and 100 ml of dichloromethane were added to stop the reaction. To do. The reaction mixture is extracted with dichloromethane, and the organic layer is washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. After filtering the inorganic salt, the organic solvent is distilled off under reduced pressure, and the concentrate is purified by silica gel column chromatography (developing solvent: dichloromethane / ethyl acetate = 19: 1 → 4: 1). N α -benzyloxycarbonyl-O- (2-acetamido-3,4,6-tri-O-benzyl-2-deoxy-α-D-glucopyranosyl)-which is the N-acetylglucosaminyl tyrosine derivative according to 2. 2.07 g of L-tyrosine benzyl ester was obtained with a yield of 60%.
1 H NMR δ (CDCl 3 ) = 5.48 (H−1).
[0019]
[Example 2]
N α -benzyloxycarbonyl-O- (2-acetamido-3,4,6-tri-O-benzyl-2-deoxy-α-D-glucopyranosyl) -L-tyrosine benzyl ester 440 mg (0.50 mmol) was dissolved in dichloromethane. (25 ml) and ethanol (40 ml) in a mixed solvent. To this, 0.032 ml (0.55 mmol) of acetic acid and 450 mg of palladium carbon were added, and hydrogen gas was passed through the reaction mixture for 18 hours at room temperature. After filtering the palladium carbon with celite, the filtrate was distilled off under reduced pressure, and the desired O- (2-acetamido-2-deoxy-α-D-glucopyranosyl) -L-tyrosine according to claim 3 was 191 mg (0 .50 mmol), which was obtained quantitatively. Rf value (dichloromethane: methanol: water = 5: 5: 1) = 0.21.
[0020]
[Example 3]
191 mg (0.50 mmol) of O- (2-acetamido-2-deoxy-α-D-glucopyranosyl) -L-tyrosine is dissolved in 10 ml of water. To this was added 168 mg (2.0 mmol) of sodium hydrogen carbonate, 10 ml of 1,4-dioxane, and 283 mg (0.75 mmol) of N- (9-fluorenylmethyloxycarbonyloxy) succinimide (Fmoc-OSu), and the mixture was added for 4 hours at room temperature. React with. The reaction solution was washed with ether, and citric acid was added to the resulting aqueous layer to make it acidic. A water layer was developed on a column packed with Diaion HP-20 resin to perform solid phase extraction. After the resin was washed with water, and an object is eluted with methanol, N of claim 4 wherein alpha - (9-fluorenyl methyloxy carbonyl) -O- (2-acetamido-2-deoxy-.alpha.-D- 274 mg (0.45 mmol) of glucopyranosyl) -L-tyrosine was obtained with a yield of 90%.
1 H NMR δ (D 2 O) = 4.79 (H-1).
[0021]
【The invention's effect】
The N-acetylglucosaminyl tyrosine derivative, which is a compound of the present invention, has great commercial and industrial value as a raw material for the synthesis of glycopeptides.
Claims (4)
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JP2002069679A JP4781597B2 (en) | 2002-03-14 | 2002-03-14 | N-acetylglucosaminyl tyrosine derivative |
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JP2003267988A JP2003267988A (en) | 2003-09-25 |
JP4781597B2 true JP4781597B2 (en) | 2011-09-28 |
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2002
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