JP2007106722A5

JP2007106722A5 - A method for producing a precursor of amino acid O- (2- [18F] fluoroethyl) -L-Tyrosine labeled with 18F.

Info

Publication number: JP2007106722A5
Application number: JP2005301071A
Authority: JP
Filing date: 2005-10-14
Publication date: 2008-10-02

Description

以下において本発明の実施例を説明する：
実施例：¹⁸Fの前駆体t-BOC-(O-tosyloxyethyl)-L-Tyr-Obzlを合成する方法。
１．Ethylene glycol-1,2-ditosylateの製造：
（１）toluenesulfonyl chloride (TsCl) １７ｇ (F.W.=190.65，0.089 mol)を採取して
、pyridine ２０ｍＬを入れた三角フラスコ（Ａ）中に加える。
（２）ethylene glycol １．１ｍＬ (F.W.=62.07，0.018 mol)を取って、pyridine ３０
ｍＬを入れた三角フラスコ（Ｂ）中に加える。
（３）ドライアイス-アセトン溶液の温度で（約−３０）、三角フラスコ（Ａ）の溶液
を（Ｂ）に加えて、直ちに三角フラスコを−１８に置き、２〜３日間反応させる。
（４）反応完了後、氷水と砕氷を入れた５００ｍＬのビーカーに、三角フラスコ（Ｂ）
の反応物を加えて攪拌すると白い固体が析出する。
（５）適量の1N HClを上記のビーカーに入れて、ＰＨ６〜７に調整する。
（６）濾過によって白い固体が得られた後、methylene chlorideとnormal hexaneの混合
溶液中で再結晶化させて精製すると収率８０％でethylene glycol-1,2-ditosylate ５．
３３ｇが得られた。

ethylene glycol-1,2-ditosylateの合成反応式。

２. t-BOC-(O-tosyloxyethyl)-L-Tyr-Obzlの製造：
t-BOC-L-Tyr-Obzlを原料として、t-BOC-(O-tosyloxyethyl)-L-Tyr-Obzlを合成する反応過
程は以下の化学式５の通りである：

t-BOC-L-Tyr-Obzlを原料としてt-BOC-(O-tosyloxyethyl)-L-Tyr-Obzlを合成する反応式。

(１) N-tert-butyloxycarbonyl- L-tyrosine benzylester (t-BOC-L-Tyr-OBzl) ４５０
ｍｇ ( F.W.=361, 1.24 mmol )を２０ｍｇの potassium carbonateと１．３８４ｇの et
hylene glycol-1,2- ditosylate (F.W.=370.35，3.73 mmol)を容量５０ｍＬの丸底フラ
スコに入れて、更に２５ｍＬの anhydrous acetonitrileを加えて９０で３．５時間程
度攪拌する。
（２）反応終了後、回転する蒸発器（Rota vapor）で溶剤を蒸発させていって、更にchlo
roformで抽出を行う (5ｍＬ× ３)。Chloroform抽出物を取り出して、負圧の下で溶剤を
除去する。
（３）最小量のmethylene chlorideで残留物を溶解して、シリカゲルコラムでクロマトグ
ラフィーを行う；移動相に関する初期条件は１００％のＣＨ₂Ｃｌ₂で、ethylene glycol-
1,2-ditosylateが流出した後、移動相をＣＨ₂Ｃｌ₂／CHCl₃＝１／１に変更すると粗精製
物が溶離され出したので、更に減圧して乾燥させて固体状の粗精製物が得られた。
（４）この粗精製物を最小量のＣＨ₂Ｃｌ₂：ＣＨＣｌ₃＝８／２の溶解溶剤でシリカゲル
コラムのクロマトグラフィーを行う。移動相に関する初期条件はＣＨ₂Ｃｌ₂／ＣＨＣｌ₃
＝８／２（０．１％ triethyl amine）を加えると油状の淡い黄色物質(３９８ｍｇ)とし
て純粋な
N-tert-butyloxycarbonyl-(O-tosyloxyethyl)-L-tyrosine benzylester (t-BOC-(O-tosy
loxyethyl)-L-Tyr-OBzl)が溶離され、２塩化メチルと自身のアルキル溶液の中で再結晶し
て精製すると融点が８５〜８６で、収率６０．１％の白色の固体が得られた。
（５）Nuclear Magnetic Resonance (NMR)：t-BOC-(O-tosyloxyethyl)-L-Tyr-OBzl 20 ｍ
ｇを採取し、０．６ｍＬ CDCl₃に溶解して¹H-NMR spectrum（化学式５）を測定する。¹H
NMR (CDCl₃) ・.80 (d, 2H, J=8.4 Hz, Haryl), 7.31 (m, 7H, Haryl), 6.89 (d, 2H, J
=8.4 Hz, Haryl), 6.62 (d, 2H, J=8.4 Hz, Haryl), 5.15 (d, 1H, 12.2 Hz, CH of benz
yl), 5.08 (d, 1H, 12.2 Hz, CH of benzyl), 4.92 (d, 1H, J=8.0Hz, NH), 4.54 (m, 1H
, CH), 4.33 (t, 2H, J=4.6 Hz, CH₂), 4.07 (t, 2H, J=4.6 Hz, CH₂), 2.99 (d, 2H, J=
5.8 Hz, CH₂ of Tyr), 2.43 (s, 3H, CH₃ of toluene), 1.39 (s, 9H, CH₃ of t-BOC)。
（６）元素分析：t-BOC-(O-tosyloxyethyl)-L-Tyr-Obzlの分子式は、C₃₀H₃₅NO₈Sで、元素
分析計算値はC, 63.27; H, 6.15; N, 2.46、実測値は：C, 63.34; H, 5.62; N, 2.33であ
った。

In the following, examples of the invention are described:
Example: A method for synthesizing the precursor of ¹⁸ F, t-BOC- (O-tosyloxyethyl) -L-Tyr-Obzl.
1. Production of Ethylene glycol-1,2-ditosylate:
(1) Toluenesulfonyl chloride (TsCl) 17 g (FW = 190.65, 0.089 mol) is collected and added to an Erlenmeyer flask (A) containing 20 mL of pyridine.
(2) Taking 1.1 mL of ethylene glycol (FW = 62.07, 0.018 mol), pyridine 30
Add into an Erlenmeyer flask (B) containing mL.
(3) At the temperature of the dry ice-acetone solution (about −30), add the Erlenmeyer flask (A) solution to (B), immediately place the Erlenmeyer flask at −18, and allow to react for 2-3 days.
(4) After completion of the reaction, place the Erlenmeyer flask (B) in a 500 mL beaker containing ice water and crushed ice.
A white solid precipitates when the reaction product is added and stirred.
(5) An appropriate amount of 1N HCl is put into the above beaker and adjusted to PH 6-7.
(6) After a white solid is obtained by filtration, it is purified by recrystallization in a mixed solution of methylene chloride and normal hexane to give ethylene glycol-1,2-ditosylate in a yield of 80%.
33 g was obtained.

Synthesis reaction formula of ethylene glycol-1,2-ditosylate.

2. Production of t-BOC- (O-tosyloxyethyl) -L-Tyr-Obzl:
The reaction process of synthesizing t-BOC- (O-tosyloxyethyl) -L-Tyr-Obzl using t-BOC-L-Tyr-Obzl as a raw material is shown in the following chemical formula 5 :

Reaction formula for synthesizing t-BOC- (O-tosyloxyethyl) -L-Tyr-Obzl from t-BOC-L-Tyr-Obzl.

(1) N-tert-butyloxycarbonyl- L-tyrosine benzylester (t-BOC-L-Tyr-OBzl) 450
mg (FW = 361, 1.24 mmol) with 20 mg potassium carbonate and 1.384 g et
Add hylene glycol-1,2-ditosylate (FW = 370.35, 3.73 mmol) into a 50 mL round bottom flask, add 25 mL anhydrous acetonitrile, and stir at 90 for about 3.5 hours.
(2) After completion of the reaction, the solvent is evaporated with a rotating evaporator (Rota vapor), and further chlo
Extract with roform (5 mL x 3). Remove the Chloroform extract and remove the solvent under negative pressure.
(3) Dissolve the residue with a minimum amount of methylene chloride and chromatograph on a silica gel column; the initial conditions for the mobile phase are 100% CH ₂ Cl ₂ and ethylene glycol-
After 1,2-ditosylate flowed out, when the mobile phase was changed to CH ₂ Cl ₂ / CHCl ₃ = 1/1, the crude product was eluted. was gotten.
(4) The crude product is chromatographed on a silica gel column with a minimum amount of CH ₂ Cl ₂ : CHCl ₃ = 8/2 dissolving solvent. The initial conditions for the mobile phase are CH ₂ Cl ₂ / CHCl ₃
= 8/2 (0.1% triethyl amine) was added and pure as an oily pale yellow substance (398 mg)
N-tert-butyloxycarbonyl- (O-tosyloxyethyl) -L-tyrosine benzylester (t-BOC- (O-tosy
loxyethyl) -L-Tyr-OBzl) is eluted and purified by recrystallization in methyl dichloride and its own alkyl solution to give a white solid with a melting point of 85-86 and a yield of 60.1%. It was.
(5) Nuclear Magnetic Resonance (NMR): t-BOC- (O-tosyloxyethyl) -L-Tyr-OBzl 20 m
g is collected, dissolved in 0.6 mL CDCl ₃ , and ¹ H-NMR spectrum ( chemical formula 5) is measured. ¹ H
NMR (CDCl ₃ ) ・ .80 (d, 2H, J = 8.4 Hz, Haryl), 7.31 (m, 7H, Haryl), 6.89 (d, 2H, J
= 8.4 Hz, Haryl), 6.62 (d, 2H, J = 8.4 Hz, Haryl), 5.15 (d, 1H, 12.2 Hz, CH of benz
yl), 5.08 (d, 1H, 12.2 Hz, CH of benzyl), 4.92 (d, 1H, J = 8.0Hz, NH), 4.54 (m, 1H
, CH), 4.33 (t, 2H, J = 4.6 Hz, CH ₂ ), 4.07 (t, 2H, J = 4.6 Hz, CH ₂ ), 2.99 (d, 2H, J =
5.8 Hz, CH ₂ of Tyr), 2.43 (s, 3H, CH ₃ of toluene), 1.39 (s, 9H, CH ₃ of t-BOC).
(6) Elemental analysis: The molecular formula of t-BOC- (O-tosyloxyethyl) -L-Tyr-Obzl is C ₃₀ H ₃₅ NO ₈ S, and the calculated elemental analysis is C, 63.27; H, 6.15; N, 2.46 The measured values were: C, 63.34; H, 5.62; N, 2.33.

Claims

Following Chemical labeled with ¹⁸ F represented by the formula amino acid ^{O- (2- [18 F] fluoroethyl} ) A method for manufacturing a precursor of -L-Tyrosine,

R1 is a protecting group for a carboxyl functional group and is an arylalkyl group;
R2 is a protecting group for the amino functional group and is a carboxyl group;
R3 is a leaving group, which is p-tosyloxy, methane sulfonyloxy group, trifluoromethanesulfonyloxy group or bromine group.

The following (1) production process of ethylene glycol-1,2-ditosylate, and (2) N-tert-butyloxycarbonyl- (O-tosyloxyethyl) -L-tyrosine benzylester (t-BOC- (O-tosyloxyethyl) -L- tyr-OBzl) amino acid labeled with ¹⁸ F, characterized in that it consists of the manufacturing process ^{O- (2- [18 F] fluoroethyl} ) method for producing -L-Tyrosine precursor.

(1) Production process of ethylene glycol-1,2-ditosylate
(i) Add toluenesulfonyl chloride (TsCl) to pyridine,
(ii) adding thylene glycol to pyridine,
(iii) Add the former to the latter in a dry ice-acetone bath (about −30 ° C.), keep the solution at −18 ° C. and let it react for 2-3 days,
(iv) After completion of the reaction, poured into ice water and stirred to precipitate a white solid,
(v) Add 1N HCl to adjust PH to 6-7,
(vi) The white solid is filtered, recrystallized in a mixed solution of methylene chloride and normal hexane and purified to obtain ethylene glycol-1,2-ditosylate.
The reaction formula is as follows.

(2) Production process of N-tert-butyloxycarbonyl- (O-tosyloxyethyl) -L-tyrosine benzylester (t-BOC- (O-tosyloxyethyl) -L-Tyr-OBzl)

(i) Add N-tert-butyloxycarbonyl- L-tyrosine benzylester (t-BOC-L-Tyr-OBzl) to the mixture of potassium carbonate and ethylene glycol-1,2-ditosylate, and then add anhydrous acetonitrile at 90 ° C. For about 3.5 hours.
(Ii) After the reaction, the solvent is evaporated from the solution of (1), and further extracted with chloroform and collected.
(Iii) Dissolve the solid residue with methylene chloride, purify by chromatography on a silica gel column,
The initial condition for the fluid phase is 100% CH ₂ Cl ₂ , and after unreacted ethylene glycol-1,2-ditosylate has flowed out, the fluid phase is changed to CH ₂ Cl ₂ / CHCl ₃ = 1/1 to roughen it. Separate the product.
(iv) The crude product is dried under reduced pressure to give a solid product.
(v) The crude product is redissolved with a minimum amount of CH ₂ Cl ₂ : CHCl ₃ = 8/2 and purified by chromatography on a silica gel column (with 0.1% triethyl amine added).
The initial conditions for the mobile phase are CH ₂ Cl ₂ / CHCl ₃ = 8/2 (with 0.1% triethyl amine added) and oily light yellow pure N-tert-butyloxycarbonyl- (O-tosyloxyethyl) -L-tyrosine benzylester (t-BOC- (O-tosyloxyethyl) -L-Tyr-OBzl) is isolated,
(vi) Recrystallize the product in methyl dichloride and alkyl solution to give a white solid.
The reaction formula is as follows.